EP1077948A1 - Novel 1,2,5-trisubstituted 1,2-dihydro-indazol-3-ones with anti-asthmatic, anti-allergic, anti-inflammatory, immuno-modulating and neuro-protective effect, method for the production and use thereof as a medicament - Google Patents

Novel 1,2,5-trisubstituted 1,2-dihydro-indazol-3-ones with anti-asthmatic, anti-allergic, anti-inflammatory, immuno-modulating and neuro-protective effect, method for the production and use thereof as a medicament

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Publication number
EP1077948A1
EP1077948A1 EP99950343A EP99950343A EP1077948A1 EP 1077948 A1 EP1077948 A1 EP 1077948A1 EP 99950343 A EP99950343 A EP 99950343A EP 99950343 A EP99950343 A EP 99950343A EP 1077948 A1 EP1077948 A1 EP 1077948A1
Authority
EP
European Patent Office
Prior art keywords
dihydro
methoxy
indazol
alkyl
sulfonyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99950343A
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German (de)
French (fr)
Inventor
Rudolf Schindler
Norbert Höfgen
Hildegard Poppe
Kay Brune
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AWD Pharma GmbH and Co KG
Original Assignee
Arzneimittelwerk Dresden GmbH
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Publication of EP1077948A1 publication Critical patent/EP1077948A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention relates to the production and use of novel derivatives of indazol-3-one as medicaments with antiasthmatic, antiallergic, anti-inflammatory, immunomodulating and neuroprotective properties
  • Cyclosponn A (CsA) and FK 506 are immunosuppressive, fungal natural products that inhibit the Ca 2+ -dependent signaling pathway in some cell types. In T cells, both compounds inhibit the transcription of a number of genes CsA and FK506 both bind with high affinity soluble receptor proteins such as cyclophylin (Cyp) or FK-506 binding protein (FKBP) (G Fischer et al Nature 337 (1989), 476-478, MW Harding et al Nature 341 (1989), 755-760)
  • Cyp cyclophylin
  • FKBP FK-506 binding protein
  • the complex of CsA-Cyp or FK 506-FKBP binds calcmeurin (CN) and inhibits its phosphatase activity.
  • the cytosolic, phosphorylating component of the transcription factor NF-AT was recognized as the cellular target molecule of CN, so that in the absence of CN activity the active transcription complex on the IL -2 promoter cannot be switched on (MK Rosen, SL Schreiber, Angew Chem 104 (1992), 413-430, G Fischer Angew Chem 106 (1994), 1479-1501)
  • the allergic, asthmatic diseases are based on an inflammatory reaction that Controlled by T cells and their mediators. Corticosteroids are still the drug of choice in the treatment of many allergic diseases.
  • CsA and FK 506 have also proven to be a beneficial therapeutic agent in animal experiments and in clinical studies for bronchial asthma and underlying inflammation Despite the large number of approaches for the identification of new active immunophore inhibitors, no more effective structures than CsA, FK 506, rapamycin or derivatives of these natural products have been produced or isolated.
  • the high inhibitory potential of CsA FK 506 and rapamycin is, however, very significant due to the many Side effects, in particular the nephrotoxicity reduced (NH Sigal et al J Exp Med 173 (1991), 619-6128).
  • the background of this fact is the non-specificity of the interaction between immunophine ligands and the cell-specific binding proteins. This makes the known medical-therapeutic effect of these immunosuppressants considerable restricted Furthermore, the lack of selectivity of the compounds proves to be problematic, particularly in long-term therapy
  • PPIases peptidylproly somerases
  • Baiocchi et al [Synthesis 1978 (9) 633-648] provide an overview of the syntheses and properties of the 1,2-dihydro-3H-indazol-3-one
  • EP 0 199 543 contains 1, 6-d ⁇ subst ⁇ tu ⁇ erte 1 2-d ⁇ hydro- ⁇ ndazol-3-one and their use for pharmaceutical purposes
  • WO 94/24109 contains indazole derivatives which are suitable for the treatment of HIV infections
  • Ketami et al [J of Heterocycl Chem 7 (4) 807-813 (1970)] describes 1,5-di-substituted 1,2-dihydro-indazol-3-one
  • K v Auwers [Ber Dtsch Chem Ges 58 2081 -2088 (1925)] and K v Auwers et al [Justus Liebigs Ann Chem 451 281 -307 (1927)] describe the constitution of acyl-indazoles and their migration
  • the invention is based on the object of finding new compounds with rotamase-inhibiting properties and / or inhibiting pulmonary eosinophil infiltration and providing them by targeted synthesis.
  • a completely new class of substances that surprisingly specifically binds immunophiles is represented by the compounds of the formula I according to the invention.
  • This class of Compounds have a high affinity for immunophilins such as CypB Presentation of the invention
  • the new indazole derivatives are able to inhibit the action of the PPIase. Accordingly, these compounds are of great importance for the production of medicaments where the inhibition of the PPIase is useful.
  • diseases are, for example, penphere neuropathies, Neurodegeneration Stroke, Parkinson's and Alzheimer's Diseases, Traumatic Brain Diseases Multiple Sclerosis
  • the compounds according to the invention are able to inhibit the immigration of eosinophilic granulocytes into the tissue which is characteristic of the asthmatic late phase reaction
  • the invention relates to new 1 2 5-tr ⁇ subst ⁇ tu ⁇ erte 1, 2-D ⁇ hydro- ⁇ ndazol-3-one of the general formula I.
  • R 1 , R 2 and R 3 can be the same or different and have the following meaning:
  • Carbocycles with 5 ... 14 ring members especially phenyl, naphthyl, anthranyl, fluorenyl; or mono-, bi- or t ⁇ cyclic saturated or mono- or polyunsaturated heterocycles with 5-15 ring members and 1 ... 6 heteroatoms, which are preferably N. 0 and S, in particular thiophenyl, pyhdinyl, isoxazolyl, benzimidazolyl.
  • Heteroatoms which are preferably N. 0 and S, -F, -Cl, -Br, -I, -OH, -SH, -N0 2 , -NH 2 , -NHd 6 -alkyl -N (C. 6 -alkyl ) 2 -NHC 6 14 -aryl. -N (C 6 , 4 -aryl) 2 , -N (-C 6 alkyl) (C 6 ⁇ 4 aryl).
  • R 3 -Z can further be N0 2 .
  • the compounds according to the invention are new, but with the exception of compounds of the formula I.
  • the invention further relates to the physiologically acceptable salts of
  • the pharmacologically acceptable salts are obtained in the usual way by neutralizing the bases with inorganic or organic acids or by neutralizing the acids with inorganic or organic bases.
  • inorganic acids are hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid as organic acids, for example carbon or sulfo - or sulfonic acid such as acetic acid, tartaric acid, lactic acid, propionic acid, glycolic acid, malonic acid, maleic acid, fumaric acid, tannic acid, succinic acid, alginic acid, benzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, cinnamic acid, mandelic acid, salic acid, acetic acid, citric acid, citric acid , Isonicotinic acid, oxalic acid, amino acids methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1 2-disulf
  • inorganic bases which can be used are, for example, sodium hydroxide solution, potassium hydroxide solution, ammonia and organic bases, but preferably tertiary amines, such as T ⁇ methylamin, T ⁇ ethylamin, Py ⁇ din N N-Dimethylanihn, Chino n, Isoquinoline, ⁇ -Picohn, ß-Picolin ⁇ -Picohn, Quinaldin or Pynmidin in question.
  • physiologically acceptable salts of the compounds according to Formula I can be obtained by using derivatives, the tertiary amino Have groups, which are converted in a known manner with quaternizing agents into the corresponding quaternary ammonium salts.
  • quaternizing agents are alkyl halides such as methyl odide, ethyl bromide and n-propyl chloride, but also aryl alkyl halides such as benzyl chloride or 2-phenylethyl bromide
  • the invention further relates to compounds of the formula I which contain an asymmetric carbon atom, the D form, the L form and D, L mixtures and, in the case of a plurality of asymmetric carbon atoms, the diastereomeric forms.
  • Those compounds of the formula I which contain asymmetric carbon atoms and usually obtained as racemates, can be separated into the optically active isomers in a manner known per se, for example with an optically active acid.
  • an optically active starting substance from the outset, in which case a corresponding optically active or diastereomeric compound is used as the end product is obtained
  • the invention relates to the production and use of the compounds according to the invention or their physiologically acceptable salts as
  • diseases include, for example, pe ⁇ phere neuropathies, neurodegeneration, Parkinson's and Alzheimer's disease, traumatic brain diseases, multiple sclerosis, bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, eczema, allergic angstis, inflammation mediated by eosinophils, such as eosinophils, Eosinophilic pneumonia and PIE syndrome
  • eosinophils such as eosinophils, Eosinophilic pneumonia and PIE syndrome
  • eosinophils such as eosinophils, Eosinophilic pneumonia and PIE syndrome
  • eosinophils such as eosinophils, Eosinophilic pneumonia and PIE syndrome
  • eosinophils such as eosinophils, Eosinophilic pneumonia and PIE syndrome
  • rheumatoid arthritis rheumatoid s
  • an effective dose of the compounds according to the invention or their salts is used to prepare the medicaments
  • the dosage of the active ingredients can vary depending on the route of administration, age, weight of the active ingredients
  • the daily dose can be given as a single dose or divided into single doses
  • galenical preparation forms such as tablets, dragees, capsules, dispersible powders, granules, aqueous solutions, aqueous or non-aqueous suspensions, syrups, juices or drops are used
  • Solid pharmaceutical forms can contain inert ingredients and carriers, such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatin, guar gum, magnesium or aluminum stearate, methyl cellulose, talc, highly disperse silicic acids, sihkonol, high molecular fatty acids (such as stearic acid ), Gelatin agar-agar or vegetable or animal fats and oils, solid high-molecular polymers (such as polyethylene glycol), preparations suitable for oral application can, if desired, contain additional flavors and / or sweeteners
  • Liquid pharmaceutical forms can be sterilized and / or optionally contain auxiliaries such as preservatives, stabilizers, wetting agents, penetrants, emulsifiers, spreading agents, solubilizers, salts, sugar or sugar alcohols for regulating the osmotic pressure or for buffering and / or viscosity regulators
  • Such additives are, for example, tartrate and citrate buffers ethanol, complexing agents (such as ethylenediamine-tetraacetic acid and its non-toxic salts).
  • complexing agents such as ethylenediamine-tetraacetic acid and its non-toxic salts.
  • High-molecular-weight polymers such as, for example, liquid polyethylene oxide, microcrystalline celluloses are suitable for regulating the viscosity
  • Solid carriers are, for example, strong lactose mannitol, methyl cellulose, talcum highly disperse silica, high molecular weight fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate magnesium stearate, animal and vegetable fats such as polyethylene glycol
  • Ohge suspensions for parenteral or topical applications can vegetable synthetic or semi-synthetic oils such as liquid fatty acid esters with 8 to 22 carbon atoms in the fatty acid chains, for example palmitin, Laun ⁇ tridecyl, Margann stearin arachin Mynstin, Behen- Pentadecyl
  • Polyoxyethylene glycol oleate ethyl oleate wax-like fatty acid esters such as artificial duckling goose fat isopropyl coconut oil, olsaureol ethyl ester, oleic acid decyl ester, lactic acid ethyl ester, dibutyl phthalate, adipic acid diisopropyl ester, polyol fatty acid oleyl ester such as fatty alcohols, such as fatty alcohol ethers, such as fatty alcohol ethers, as well can vegetable oils such as castor oil, almond oil Olive oil, sesame oil, cotton seed oil, peanut oil or soybean oil are used
  • Suitable solvents, gelling agents and solubilizers are water or water-miscible solvents.
  • alcohols such as ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, propylene glycol, glycine, di- or tripropylene glycol, waxes, methyl cellosolve cellulose are suitable , Morphohne, Dioxane, Dimethylsulfoxid, Dimethylformamide Tetrahydrofuren, Cyclohexanon etc
  • Cellulose ethers which can dissolve or swell both in water and in organic solvents, such as, for example, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose or soluble starches, can be used as film formers
  • Ionic macromolecules in particular are used here, such as, for example, sodium carboxymethyl cellulose, polyacrylic acid, polymethacrylic acid and its salts, sodium amamylopectin semiglycolate, alginic acid or propylene glycol alginate as sodium salt, gum arabic, gum xanthane or gum guanine
  • Glycene, paraffin of different viscosities, tetrahanolamine collagen, allantoin, novantisol acid can also be used as additional shaping aids.
  • surfactants, emulsifiers or wetting agents may also be necessary for the formulation, for example Na-lauryl sulfate, fatty alcohol ether sulfates, di-Na-N-lauryl-ß -iminodipropionate, polyoxyethylene castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (e.g.
  • cetyl alcohol lecithin glycine monostearate, polyoxyethylene stearate, alkylphenol polyglycol ether, cetyltrimethylammonium phospholethanolamine or mono- / poly- / ethanol-mono-
  • Stabilizers such as Montmo ⁇ llonite or colloidal silica to stabilize emulsions or to prevent the breakdown of active substances such as antioxidants, such as tocopherols or butylated hydroxyanisole, or Preservatives, such as p-hydroxybenzoic acid esters, may also be necessary to prepare the desired formulations
  • the preparation, filling and sweating of the preparations takes place under the usual antimicrobial and aseptic conditions
  • the dosage of the pharmaceutical preparations depends on the age, condition and weight of the patient and on the form of administration. As a rule, the daily dose of active ingredient is between 0 001 -25 mg / kg body weight
  • the compounds of general formula I can be prepared by the following methods
  • the compounds were characterized by means of melting point, thin layer chromatography, elemental analysis, NMR spectroscopy, IR and UV ⁇ / IS spectroscopy and, if appropriate, mass spectrometry
  • the compounds of the general formula I are more polar than the compounds of the general formula V, so that the compounds of the general formula I are eluted under these chromatographic conditions according to the compounds of the general formula V. This cleaning operation is applicable to all examples 1 to 35.
  • Table 1 The compounds shown in Table 1 are prepared by an analogous procedure. Table 1:
  • R 1 CH 3 0
  • R 1 CH 3 0
  • the compounds of the formula I according to the invention are surprisingly distinguished by immunophiline binding and inhibit their peptidyl-prolyl-cis-trans-isomerase (PPIase) actinate.
  • PPIase peptidyl-prolyl-cis-trans-isomerase
  • the PPIase activity is checked according to a generally known enzyme test G Fischer, H Bang, C Mech, Biomed Biochim Acta 43 1 101 -111 1, G Fischer, H Bang, A Schellenberger, Biochim Biophys Acta 791 (1984), 87 -97, DH Rieh et al. J Med Chem 38: 4164-4170 (1995)
  • the compounds of general formula I according to the invention are praincubated together with 10 nmol Cyp B for 15 minutes at 4 ° C.
  • the enzyme reaction is started with the test peptide Suc-Ala-Ala-Pro-Phe-Nan after adding chymotrypsin and HEPES buffer the change in absorbance at 390 nm is monitored and evaluated The change in absorbance determined photometrically results from two partial reactions a) the rapid chymotryptic cleavage of the trans-peptide, b) the non-enzymatic cis-trans-isomerization, which is catalyzed by cyclophones, the inhibition of PPIase Activity of selected compounds of general formula I is shown in Table 4
  • OVA ovalbumin
  • the sensitization is carried out by two intrapentonal injections of a suspension of 20 ⁇ g OVA together With 20 mg aluminum hydroxide as an adjuvant in 0.5 ml of physiological saline solution per animal on two consecutive days 14 days after the second injection, the animals are pretreated with mepyramine maleate (10 mg / kg ip) to protect them from anaphylactic death for 30 minutes the animals are later exposed in a plastic box for 30 seconds to an OVA aerosol (0.5 mg / ml) that is generated by a nebulizer driven with compressed air (19.6 kPa) (allergen challenge).
  • Confronters are nebulized with physiological saline solution 24 Hours after the challenge, the animals are anesthetized with an overdose of ethyl urethane (1.5 g / kg body weight ip) and one bronchoalveolar lavage (BAL) with 2 x 5 ml of physiological saline solution.
  • BAL liquid is collected at 300 rpm for 10 min. and then the cell pellet is resuspended in 1 ml of physiological saline solution.
  • the eosinophils are analyzed using the Becton-Dickinson Test Kit (N 5877 ) stained for eosinophils and paid in a new building chamber. 2 control groups (nebulization with physiological saline solution and nebulization with OVA solution) are included in each test
  • test substances are intrapentoneally or orally as a suspension in 10% polyethylene glycol 300 and 0 5% 5-hydroxyethyl cellulose 2 hours before Allergen challenge applied
  • control groups are treated with the vehicle according to the application form of the test substance.
  • the number of animals per control and test group is 3-10. The results are shown in Table 5
  • the compounds according to the invention are therefore particularly suitable for the production of medicaments for the treatment of diseases which are associated with the suppression of immunological processes

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Abstract

The invention relates to novel 1,2,5-tri-substituted 1,2-dihydro-indazol-3-ones and to a method for the production and the pharmaceutical use thereof. The compounds have anti-asthmatic, anti-allergic and anti-inflammatory immuno-modulating and neuro-protective effects.

Description

Neue 1,2,5-trisubstituierte 1,2-Dihydro-indazol-3-one mit antiasthmatischer, antiallergischer, entzündungshemmender, immunmodulierender und neuroprotektiver Wirkung, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel. New 1,2,5-trisubstituted 1,2-dihydro-indazol-3-ones with antiasthmatic, antiallergic, anti-inflammatory, immunomodulating and neuroprotective effects, processes for their preparation and their use as medicines.
Technisches GebietTechnical field
Die Erfindung betrifft die Herstellung und Verwendung von neuartigen Derivaten des lndazol-3-ons als Arzneimittel mit antiasthmatischen, antiallergischen, entzündungshemmenden, immunmodulierenden und neuroprotektiven EigenschaftenThe invention relates to the production and use of novel derivatives of indazol-3-one as medicaments with antiasthmatic, antiallergic, anti-inflammatory, immunomodulating and neuroprotective properties
Stand der TechnikState of the art
Cyclosponn A (CsA) und FK 506 sind immunsuppressive, von Pilzen stammende Naturstoffe, die den Ca2+ -abhangigen Signalubertragungsweg in einigen Zelltypen inhibieren In T-Zellen hemmen beide Verbindungen die Transkription einer Reihe von Genen CsA und FK506 binden beide mit hoher Affinitat an lösliche Rezeptorproteine wie zum Beispiel Cyclophylin (Cyp) oder FK-506 bindendes Protein (FKBP) (G Fischer et al Nature 337 (1989), 476-478, M W Harding et al Nature 341 (1989), 755-760)Cyclosponn A (CsA) and FK 506 are immunosuppressive, fungal natural products that inhibit the Ca 2+ -dependent signaling pathway in some cell types. In T cells, both compounds inhibit the transcription of a number of genes CsA and FK506 both bind with high affinity soluble receptor proteins such as cyclophylin (Cyp) or FK-506 binding protein (FKBP) (G Fischer et al Nature 337 (1989), 476-478, MW Harding et al Nature 341 (1989), 755-760)
Der Komplex aus CsA-Cyp bzw FK 506-FKBP bindet Calcmeurin (CN) und inhibiert dessen Phosphataseaktivitat Als zellulares Zielmolekul von CN wurde die cytosolische, phosphorylierende Komponente des Transkriptionsfaktors NF-AT erkannt, so daß bei fehlender CN-Aktivitat der aktive Transkriptionskomplex am IL-2 Promoter nicht angeschaltet werden kann (M K Rosen, S L Schreiber, Angew Chem 104 (1992), 413-430, G Fischer Angew Chem 106 (1994), 1479-1501 ) Den allergischen, asthmatischen Erkrankungen hegt eine entzündliche Reaktion zugrunde, die von T-Zellen und ihren Mediatoren gesteuert wird Corticosteroide stellen immer noch das Mittel der Wahl in der Behandlung vieler allergischer Erkrankungen dar Auch CsA und FK 506 erwiesen sich sowohl im Tierexperiment als auch in klinischen Studien beim Asthma bronchiale und zugrunde liegenden Entzündungen als gunstiges Therapeutikum Trotz der Vielzahl von Ansätzen zur Identifikation neuer aktiver Immunophihn- Inhibitoren konnten bisher keine wirksameren Strukturen als CsA, FK 506, Rapamycin bzw Derivate von diesen Naturstoffen hergestellt bzw isoliert werden Das hohe inhibitorische Potential von CsA FK 506 und Rapamycin wird jedoch ganz erheblich durch die mannigfaltigen Nebenwirkungen, insbesondere der Nephrotoxizitat reduziert (N H Sigal et al J Exp Med 173 (1991 ), 619-6128) Hintergrund dieser Tatsache ist die Unspezifitat der Wechselwirkung zwischen Immunophihn-Liganden und den zellspezifischen Bindungsproteinen Dadurch ist die bekannte medizinisch-therapeutische Wirkung dieser Immunsuppressiva erheblich eingeschränkt Ferner erweist sich die fehlende Selektivität der Verbindungen gerade in der Langzeittherapie als problematischThe complex of CsA-Cyp or FK 506-FKBP binds calcmeurin (CN) and inhibits its phosphatase activity. The cytosolic, phosphorylating component of the transcription factor NF-AT was recognized as the cellular target molecule of CN, so that in the absence of CN activity the active transcription complex on the IL -2 promoter cannot be switched on (MK Rosen, SL Schreiber, Angew Chem 104 (1992), 413-430, G Fischer Angew Chem 106 (1994), 1479-1501) The allergic, asthmatic diseases are based on an inflammatory reaction that Controlled by T cells and their mediators. Corticosteroids are still the drug of choice in the treatment of many allergic diseases. CsA and FK 506 have also proven to be a beneficial therapeutic agent in animal experiments and in clinical studies for bronchial asthma and underlying inflammation Despite the large number of approaches for the identification of new active immunophore inhibitors, no more effective structures than CsA, FK 506, rapamycin or derivatives of these natural products have been produced or isolated. The high inhibitory potential of CsA FK 506 and rapamycin is, however, very significant due to the many Side effects, in particular the nephrotoxicity reduced (NH Sigal et al J Exp Med 173 (1991), 619-6128). The background of this fact is the non-specificity of the interaction between immunophine ligands and the cell-specific binding proteins. This makes the known medical-therapeutic effect of these immunosuppressants considerable restricted Furthermore, the lack of selectivity of the compounds proves to be problematic, particularly in long-term therapy
Substanzen, die die Aktivität von Peptidylproly somerasen (PPIasen) wie Cyp oder FKBP inhibieren besitzen neuroprotektive Eigenschaften, stimulieren das neuronale Wachstum und sind zur Behandlung von neurodegenerativen Krankheiten geeignet (WO 96/40140, US 5,696,135, WO 97/18828)Substances that inhibit the activity of peptidylproly somerases (PPIases) such as Cyp or FKBP have neuroprotective properties, stimulate neuronal growth and are suitable for the treatment of neurodegenerative diseases (WO 96/40140, US 5,696,135, WO 97/18828)
Bekannt sind substituierte Indazol-Deπvate die sich jedoch hinsichtlich der Substituenten X Y, Z, R1, R2 und R3 und ihrer pharmakodynamischen Wirkung von den beanspruchten Verbindungen unterscheidenSubstituted indazole derivatives are known which, however, differ from the claimed compounds in terms of the substituents XY, Z, R 1 , R 2 and R 3 and their pharmacodynamic action
Baiocchi et al [Synthesis 1978 (9) 633-648] geben einen Überblick zu Synthesen und Eigenschaften der 1 ,2-Dιhydro-3H-ιndazol-3-oneBaiocchi et al [Synthesis 1978 (9) 633-648] provide an overview of the syntheses and properties of the 1,2-dihydro-3H-indazol-3-one
Schindler et al [WO 97/34871] beschreiben 1 3,5-trιsubstιtuιerte Indazole mit antiasthmatischer, antiallergischer entzündungshemmender und immunmodulierender WirkungSchindler et al [WO 97/34871] describe 1 3,5-trisubstituted indazoles with antiasthmatic, antiallergic anti-inflammatory and immunomodulating effects
EP 0 199 543 beinhaltet 1 ,6-dιsubstιtuιerte 1 2-Dιhydro-ιndazol-3-one und deren Verwendung für pharmazeutische Zwecke WO 94/24109 beinhaltet Indazol-Deπvate welche zur Behandlung von HIV- Infektionen geeignet sindEP 0 199 543 contains 1, 6-dιsubstιtuιerte 1 2-dιhydro-ιndazol-3-one and their use for pharmaceutical purposes WO 94/24109 contains indazole derivatives which are suitable for the treatment of HIV infections
Ketami et al [J of Heterocycl Chem 7 (4) 807-813 (1970)] beschreibt 1 ,5-dιsubstιtuιerte 1 ,2-Dιhydro-ιndazol-3-oneKetami et al [J of Heterocycl Chem 7 (4) 807-813 (1970)] describes 1,5-di-substituted 1,2-dihydro-indazol-3-one
US 3,470,194 erwähnt die Bildung disubstituierter (1 ,2-Dιhydro-3-oxy-ιndazol-2-yl)- alkansauren bei Verwendung von polaren LosungsmittelnNo. 3,470,194 mentions the formation of disubstituted (1,2-dihydro-3-oxy-indazol-2-yl) alkanoic acids when using polar solvents
K v Auwers [Ber Dtsch Chem Ges 58 2081 -2088 (1925)] und K v Auwers et al [Justus Liebigs Ann Chem 451 281 -307 (1927)] beschreiben die Konstitution von Acyl-indazolen und deren WanderungK v Auwers [Ber Dtsch Chem Ges 58 2081 -2088 (1925)] and K v Auwers et al [Justus Liebigs Ann Chem 451 281 -307 (1927)] describe the constitution of acyl-indazoles and their migration
Zoni et al [II Farmaco Ed Sei 23 (5) 490-501 (1968)] und Zoni et al [Boll Chim Farm 107, 598-605 (1968)] beschreiben die Alkylierung von 1 -substituierten 1 H-lndazol-3-olenZoni et al [II Farmaco Ed Sei 23 (5) 490-501 (1968)] and Zoni et al [Boll Chim Farm 107, 598-605 (1968)] describe the alkylation of 1-substituted 1 H-indazole-3- oil
Evans et al [Tetrahedron 21 , 3351 -3361 (1965)] beschreiben die Synthese von 1 ,3-substιtuιerten Acyl- und Tosyl-indazolenEvans et al [Tetrahedron 21, 3351 -3361 (1965)] describe the synthesis of 1,3-substituted acyl and tosyl indazoles
Tse et al [Arch Pharm 329 (1 ) 35-40 (1996)] berichten über antientzundhche Eigenschaften von N-substituierten IndazolenTse et al [Arch Pharm 329 (1) 35-40 (1996)] report anti-inflammatory properties of N-substituted indazoles
Anderson et al [J Chem Soc C 3313-3314 ( 1971 )] beschreiben 1 ,3-substιtuιerte Tosyl-indazoleAnderson et al [J Chem Soc C 3313-3314 (1971)] describe 1,3-substituted tosyl indazoles
Palazzo et al [J Med Chem 9 38-41 (1966)] und Gyula et al [Acta pharm Hung 44, 49-57 (1974)] beschreiben die Synthese von 2-Dιmethylamιnoalkyl-1 -phenyl- ιndazol-3-onenPalazzo et al [J Med Chem 9 38-41 (1966)] and Gyula et al [Acta pharm Hung 44, 49-57 (1974)] describe the synthesis of 2-dimethylaminoalkyl-1-phenyl-indazol-3-ones
Klιcnar [Coll Czech Chem Comm 42 327-337 (1977)] beschreibt Acetyl-indazoleKlιcnar [Coll Czech Chem Comm 42 327-337 (1977)] describes acetyl-indazoles
Tsemg et al [J Org Chem 38 3498-3502 (1973)] beschreibt die Synthese von 1 ,2-dιsubstιtuιerten 1 2-Dιhydro-ιndazol-3-onen Aran et al [Heterocycles 45, 129-136 (1997)] beschreibt die selektive Synthese von 2-substιtuιerten lndazol-3-onen ohne N-1 SubstitutionTsemg et al [J Org Chem 38 3498-3502 (1973)] describes the synthesis of 1,2-di-substituted 1 2-dihydro-indazol-3-ones Aran et al [Heterocycles 45, 129-136 (1997)] describes 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] und Aran et al [J Chem Soc Perkin Trans I 1 1 19-1127 (1993)] beschreiben 1 ,2-substιtuιerte 5-nιtro-ιndazol-3-one und deren cytostatische AktivitätAran 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 1 1 19-1127 (1993)] describe 1, 2-substιtuιerte 5-nitro-indazol-3-one and its cytostatic activity
Bruneau et al [J Med Chem 34 1028-1036 (1991 )] beschreiben 1 - und 2-substιtuιerte lndazol-3-one als 5-LιpoxygenasehemmerBruneau et al [J Med Chem 34 1028-1036 (1991)] describe 1- and 2-substituted indazol-3-ones as 5-lipoxgenase inhibitors
Wyrick et al [J Med Chem 27 768-772 (1984)] beschreiben 1 2-dιsubstιtuιerte lndazol-3-one mit cholesteπnsenkender WirkungWyrick et al [J Med Chem 27 768-772 (1984)] describe 1 2-dιsubstιtuιerte indazol-3-one with cholesterol-lowering effect
Schmutz et al [Helv Chim Acta 47 1986-1996 (1964)] beschreiben die Alkyherung von IndazolonenSchmutz et al [Helv Chim Acta 47 1986-1996 (1964)] describe the alkylation of indazolones
Yamaguchi et al [Chem Pharm Bull 43 (2) 332-334 (1995)] beschreiben 2-substιtuιerte (1-Pyπdιn-3-yl)-ιndazol-3-one und deren antiasthmatische WirkungYamaguchi et al [Chem Pharm Bull 43 (2) 332-334 (1995)] describe 2-substituted (1-pyridn-3-yl) -ndazol-3-one and its anti-asthmatic effect
Zur Behandlung von asthmatischen Erkrankungen besteht aufgrund zahlreicher Nebenwirkungen der eingeführten Präparate mangelnder Heilerfolge und der bislang zu unspezifischen Therapie weiterhin ein großer Bedarf an Verbindungen mit einer hohen Effektivität und SicherheitFor the treatment of asthmatic diseases, there is still a great need for connections with a high effectiveness and safety due to numerous side effects of the introduced preparations with insufficient healing success and the previously unspecific therapy
Der Erfindung hegt die Aufgabe zugrunde neue Verbindungen mit Rotamase inhibierenden und/oder die pulmonale Eosinophilen-Infiltration hemmenden Eigenschaften zu finden und durch gezielte Synthese bereitzustellen Eine völlig neuartige Substanzklasse die Immunophihne überraschenderweise spezifisch bindet, wird durch die erfindungsgemaßen Verbindungen der Formel I dargestellt Diese Klasse von Verbindungen weist eine hohe Affinitat zu Immunophilinen wie CypB auf Darstellung der ErfindungThe invention is based on the object of finding new compounds with rotamase-inhibiting properties and / or inhibiting pulmonary eosinophil infiltration and providing them by targeted synthesis. A completely new class of substances that surprisingly specifically binds immunophiles is represented by the compounds of the formula I according to the invention. This class of Compounds have a high affinity for immunophilins such as CypB Presentation of the invention
Überraschenderweise wurde nun gefunden daß die neuen Indazol-Deπvate in der Lage sind, die Wirkung der PPIase zu inhibieren Demzufolge sind diese Verbindungen für die Herstellung von Arzneimitteln von großer Bedeutung, wo die Hemmung der PPIase von Nutzen ist Solche Krankheiten sind zum Beispiel penphere Neuropathien, Neurodegeneration Schlaganfall, Parkinson und Alzheimer Erkrankungen, traumatische Gehirnerkrankungen Multiple Sclerose Weiterhin wurde nachgewiesen daß die erfindungsgemaßen Verbindungen in der Lage sind, die für die asthmatische late phase Reaktion charakteristische Einwanderung von eosinophilen Granulozyten in das Gewebe zu inhibierenSurprisingly, it has now been found that the new indazole derivatives are able to inhibit the action of the PPIase. Accordingly, these compounds are of great importance for the production of medicaments where the inhibition of the PPIase is useful. Such diseases are, for example, penphere neuropathies, Neurodegeneration Stroke, Parkinson's and Alzheimer's Diseases, Traumatic Brain Diseases Multiple Sclerosis Furthermore, it has been demonstrated that the compounds according to the invention are able to inhibit the immigration of eosinophilic granulocytes into the tissue which is characteristic of the asthmatic late phase reaction
Die Erfindung betrifft neue 1 2 5-trιsubstιtuιerte 1 ,2-Dιhydro-ιndazol-3-one der allgemeinen Formel IThe invention relates to new 1 2 5-trιsubstιtuιerte 1, 2-Dιhydro-ιndazol-3-one of the general formula I.
Formel IFormula I.
worin X, Y, Z ,R , R und R folgende Bedeutung habenwherein X, Y, Z, R, R and R have the following meaning
X kann -S02-, -SO-, -(CH2)P- -(CH2)p-0- -(CH2)p-(C=0)-, -(CH2)p-(C=0)-NH- -(CH2)p-CHOH-, -CHOH-(CH2)p-, -(CH2)P-CH=CH-, -CH=CH-(CH2)P- mit p = 1 4 sein,X can -S0 2 -, -SO-, - (CH 2 ) P - - (CH 2 ) p -0- - (CH 2 ) p - (C = 0) -, - (CH 2 ) p - (C = 0) -NH- - (CH 2 ) p -CHOH-, -CHOH- (CH 2 ) p -, - (CH 2 ) P -CH = CH-, -CH = CH- (CH 2 ) P - with p = 1 4
Y kann -(C=0)-, -(C=0)-NH- -(C=0)-NH-(CH2)p-, -(C=0)-(CH2)p-, -(CH2)P-, -(CH2)p-0-, -(CH2)p-(C=0)- -(CH2)p-(C=0)-NH-, -(CH2)P-(C=0)-NH-(CH2)P- -(CH2)p-CHOH-, -CHOH-(CH?)p-, -(CH2)p-CH=CH-, -CH=CH-(CH2)P- mit p = 1 4 sein,Y can - (C = 0) -, - (C = 0) -NH- - (C = 0) -NH- (CH 2 ) p -, - (C = 0) - (CH 2 ) p -, - (CH 2 ) P -, - (CH 2 ) p -0-, - (CH 2 ) p - (C = 0) - - (CH 2 ) p - (C = 0) -NH-, - (CH 2 ) P - (C = 0) -NH- (CH 2 ) P - - (CH 2 ) p -CHOH-, -CHOH- (CH ? ) P -, - (CH 2 ) p -CH = CH-, - CH = CH- (CH 2 ) P - with p = 1 4,
Z kann -O-, -0-(CH2)p- mit p = 1 4 -NH- -NH-(C=0)-, -NH-(C=0)-NH- -NH-(C=0)-0-, -NH-CH -(C=0)- und -NH- C=0)-CH2- sein,Z can -O-, -0- (CH 2 ) p - with p = 1 4 -NH- -NH- (C = 0) -, -NH- (C = 0) -NH- -NH- (C = 0) -0-, -NH-CH - (C = 0) - and -NH- C = 0) -CH 2 -,
R1, R2 und R3 können gleich oder verschieden sein und folgende Bedeutung haben:R 1 , R 2 and R 3 can be the same or different and have the following meaning:
Mono-, bi- oder tπcyclische gesättigte oder ein- oder mehrfach ungesättigteMono-, bi- or tπcyclic saturated or mono- or polyunsaturated
Carbocyclen mit 5...14 Ringgliedern, insbesondere Phenyl, Naphthyl, Anthranyl, Fluorenyl; oder mono-, bi- oder tπcyclische gesättigte oder ein- oder mehrfach ungesättigte Heterocyclen mit 5-15 Ringgliedern und 1...6 Heteroatomen, die vorzugsweise N. 0 und S sind, insbesondereThiophenyl, Pyhdinyl, Isoxazolyl, Benzimidazolyl. Benz[1.3]dioxolyl, Pyrimidinyl, Chinolyl,Carbocycles with 5 ... 14 ring members, especially phenyl, naphthyl, anthranyl, fluorenyl; or mono-, bi- or tπcyclic saturated or mono- or polyunsaturated heterocycles with 5-15 ring members and 1 ... 6 heteroatoms, which are preferably N. 0 and S, in particular thiophenyl, pyhdinyl, isoxazolyl, benzimidazolyl. Benz [1.3] dioxolyl, pyrimidinyl, quinolyl,
Chinazolinyl, Morpholinyl. Pyrrolidmyl, Pyrrolyl, Phenyl[1 ,2,4]oxadiazolyl, Phenylthiazolyl,Quinazolinyl, morpholinyl. Pyrrolidmyl, pyrrolyl, phenyl [1, 2,4] oxadiazolyl, phenylthiazolyl,
wobei die Carbocyclen bzw die Heterocyclen einfach oder mehrfach substituiert sein können mitwhere the carbocycles or the heterocycles can be substituted one or more times with
-Cι 6- Alkyl, -O-C1 6 -Alkyl -0-C3 7 -Cycloalkyl, mono-, bi- oder tricyclische gesättigte oder ein- oder mehrfach ungesättigte Carbocyclen mit 3...14 Ringgliedern, mono-, bi- oder tricyclische gesättigte oder ein- oder mehrfach ungesättigte Heterocyclen mit 5 15 Ringgliedern und 1...6-Cι 6 - alkyl, -OC 1 6 alkyl -0-C 3 7 -cycloalkyl, mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3 ... 14 ring members, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5 15 ring members and 1 ... 6
Heteroatomen, die vorzugsweise N. 0 und S sind, -F, -Cl, -Br, -I, -OH, -SH, -N02, -NH2, -NHd 6 -Alkyl -N(C . 6 -Alkyl)2 -NHC6 14 -Aryl. -N(C6 ,4 -Aryl)2, -N(Cι. 6 -Alkyl) (C6 ι4 -Aryl). -NHCOd 6 -Alkyl, -NHCOC6 ι -Aryl, -CONHC1 6 -Alkyl, -CONHC6 14 -Aryl, -CONHSO2C1 β -Alkyl, -CONHS02C6 ι4 -Aryl, -CN. -(CO)Cι 6 -Alkyl, -(CS)d 6 -Alkyl, -COOH,Heteroatoms, which are preferably N. 0 and S, -F, -Cl, -Br, -I, -OH, -SH, -N0 2 , -NH 2 , -NHd 6 -alkyl -N (C. 6 -alkyl ) 2 -NHC 6 14 -aryl. -N (C 6 , 4 -aryl) 2 , -N (-C 6 alkyl) (C 6 ι 4 aryl). -NHCOd 6 alkyl, -NHCOC 6 ι aryl, -CONHC 1 6 alkyl, -CONHC 6 14 aryl, -CONHSO2C1 β alkyl, -CONHS0 2 C 6 ι 4 aryl, -CN. - (CO) -C 6 alkyl, - (CS) d 6 alkyl, -COOH,
-COOCi e- Alkyl, -0-C6 -Aryl, -0-(CO)d 6 -Alkyl, -0-(CO)C6.14 -Aryl, Benzyl, Benzyloxy, -S-d „ -Alkyl. -S-C6 π -Aryl, -CF3, -(CH2)p-COOH mit p = 1 bis 4, -(CH2)P- COOC, 6- Alkyl mit p = 1 bis 4, -S02-d 6 Alkyl, -S02-C6 14 Aryl,-COOCi e- alkyl, -0-C 6 -aryl, -0- (CO) d 6 -alkyl, -0- (CO) C 6 . 14- aryl, benzyl, benzyloxy, -Sd "alkyl. -SC 6 π -aryl, -CF 3 , - (CH 2 ) p -COOH with p = 1 to 4, - (CH 2 ) P - COOC, 6 - alkyl with p = 1 to 4, -S0 2 -d 6 alkyl, -S0 2 -C 6 14 aryl,
R1 kann weiter H sein (allerdings nicht, wenn X = CH2),R 1 can also be H (but not if X = CH 2 ),
R3-Z kann weiter N02 sein. Die erfindungsgemaßen Verbindungen sind neu, jedoch ausgenommen Verbindungen gemäß Formel IR 3 -Z can further be N0 2 . The compounds according to the invention are new, but with the exception of compounds of the formula I.
Wenn Z gleich -NH-(C=0)-, -NH-(C=0)-NH- -NH-(C=0)-0-, -NH-(C=0)-CH2- und gleichzeitig R1 = Phenyl einfach oder mehrfach substituiert ist mit -COOH, -COOd 6- Alkyl, -(CH2)p-COOH mit p = 1 bis 4 -(CH2)P- COOCi 6- Alkyl mit p = 1 4, -CONHd 6 -Alkyl, -CONHC6 ,4 -Aryl -CONHS02Cι 6 -Alkyl, -CONHS02C6 ι4 -Aryl, 1 H-Tetrazol-5-yl dann darf R2 nicht gleich Phenyl, einfach oder mehrfach substituiert mit CN Halogen C, 4 -Alkyl, Ci 4 -Alkyloxy, CF3 seinIf Z is -NH- (C = 0) -, -NH- (C = 0) -NH- -NH- (C = 0) -0-, -NH- (C = 0) -CH 2 - and simultaneously R 1 = phenyl is mono- or polysubstituted with -COOH, -COOd 6 - alkyl, - (CH 2 ) p -COOH with p = 1 to 4 - (CH 2 ) P - COOCi 6 - alkyl with p = 1 4, -CONHd 6 alkyl, -CONHC 6 , 4 aryl -CONHS0 2 Cι 6 alkyl, -CONHS0 2 C 6 ι 4 aryl, 1 H-tetrazol-5-yl then R 2 must not be phenyl, single or multiple substituted with CN halogen C, 4 -alkyl, Ci 4 -alkyloxy, CF 3
Wenn R3-Z = N02 dann dürfen R1-X und R2-Y nicht gleichzeitig folgende Bedeutung haben R1-X = Benzyl, 4-Methoxybenzyl R2-Y = Benzyl, 2-PιcolylIf R 3 -Z = N0 2 then R 1 -X and R 2 -Y must not have the following meaning simultaneously: R 1 -X = benzyl, 4-methoxybenzyl R 2 -Y = benzyl, 2-pιcolyl
Weiterhin betrifft die Erfindung die physiologisch vertraglichen Salze derThe invention further relates to the physiologically acceptable salts of
Verbindungen gemäß Formel ICompounds according to formula I.
Die pharmakologisch vertraglichen Salze werden in üblicher Weise durch Neutralisation der Basen mit anorganischen oder organischen Sauren bzw durch Neutralisation der Sauren mit anorganischen oder organischen Basen erhalten Als anorganische Sauren kommen zum Beispiel Salzsaure, Schwefelsaure, Phosphorsaure oder Bromwasserstoffsaure als organische Sauren zum Beispiel Carbon-, Sulfo- oder Sulfonsaure wie Essigsaure, Weinsaure, Milchsäure, Propionsaure, Glykolsaure, Malonsaure Maleinsäure, Fumarsaure Gerbsaure, Succinsaure, Alginsaure, Benzoesaure 2-Phenoxybenzoesaure, 2-Acetoxybenzosaure, Zimtsaure Mandelsaure, Zitronensaure, Apfelsaure, Salicylsaure, 3-Amιnosahcylsaure Ascorbinsaure, Embonsaure, Nicotinsaure, Isonicotinsaure, Oxalsäure, Aminosäuren Methansulfonsaure, Ethansulfonsaure, 2-Hydroxyethansulfonsaure, Ethan-1 2-dιsulfonsaure, Benzolsulfonsaure,The pharmacologically acceptable salts are obtained in the usual way by neutralizing the bases with inorganic or organic acids or by neutralizing the acids with inorganic or organic bases. Examples of inorganic acids are hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid as organic acids, for example carbon or sulfo - or sulfonic acid such as acetic acid, tartaric acid, lactic acid, propionic acid, glycolic acid, malonic acid, maleic acid, fumaric acid, tannic acid, succinic acid, alginic acid, benzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, cinnamic acid, mandelic acid, salic acid, acetic acid, citric acid, citric acid , Isonicotinic acid, oxalic acid, amino acids methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1 2-disulfonic acid, benzenesulfonic acid,
4-Methylbenzolsulfonsaure oder Naphthahn-2-sulfonsaure in Frage Als anorganische Basen kommen zum Beispiel Natronlauge, Kalilauge, Ammoniak sowie als organische Basen Amme bevorzugt jedoch tertiäre Amme, wie Tπmethylamin, Tπethylamin, Pyπdin N N-Dimethylanihn, Chino n, Isochinolin, α- Picohn, ß-Picolin γ-Picohn, Chinaldin oder Pynmidin in Frage Desweiteren können physiologisch vertragliche Salze der Verbindungen gemäß Formel I dadurch gewonnen werden daß Derivate, die tertiäre Amino-Gruppen besitzen, in an sich bekannter Weise mit Quaternierungsmitteln in die entsprechenden quatemaren Ammoniumsalze überfuhrt werden Als Quaternierungsmittel kommen beispielsweise Alkylhalogenide wie Methy odid, Ethylbromid und n-Propylchlond aber auch Arylalkylhalogenide wie Benzylchloπd oder 2-Phenylethylbromιd in Frage4-methylbenzenesulfonic acid or naphthahn-2-sulfonic acid in question. Examples of inorganic bases which can be used are, for example, sodium hydroxide solution, potassium hydroxide solution, ammonia and organic bases, but preferably tertiary amines, such as Tπmethylamin, Tπethylamin, Pyπdin N N-Dimethylanihn, Chino n, Isoquinoline, α-Picohn, ß-Picolin γ-Picohn, Quinaldin or Pynmidin in question. Furthermore, physiologically acceptable salts of the compounds according to Formula I can be obtained by using derivatives, the tertiary amino Have groups, which are converted in a known manner with quaternizing agents into the corresponding quaternary ammonium salts. Examples of quaternizing agents are alkyl halides such as methyl odide, ethyl bromide and n-propyl chloride, but also aryl alkyl halides such as benzyl chloride or 2-phenylethyl bromide
Weiterhin betrifft die Erfindung von Verbindungen der Formel I, die ein asymmetrisches Kohlenstoffatom enthalten die D-Form, die L-Form und D,L-Mιschungen sowie im Falle mehrerer asymmetrischer Kohlenstoffatome die diastereomeren Formen Diejenigen Verbindungen der Formel I, die asymmetrische Kohlenstoffatome enthalten und in der Regel als Razemate anfallen, können in an sich bekannter Weise beispielsweise mit einer optisch aktiven Saure in die optisch aktiven Isomeren getrennt werden Es ist aber auch möglich, von vornherein eine optisch aktive Ausgangssubstanz einzusetzen wobei dann als Endprodukt eine entsprechende optisch aktive beziehungsweise diastereomere Verbindung erhalten wirdThe invention further relates to compounds of the formula I which contain an asymmetric carbon atom, the D form, the L form and D, L mixtures and, in the case of a plurality of asymmetric carbon atoms, the diastereomeric forms. Those compounds of the formula I which contain asymmetric carbon atoms and usually obtained as racemates, can be separated into the optically active isomers in a manner known per se, for example with an optically active acid. However, it is also possible to use an optically active starting substance from the outset, in which case a corresponding optically active or diastereomeric compound is used as the end product is obtained
Gegenstand der Erfindung ist die Herstellung und Verwendung der erfindungsgemaßen Verbindungen bzw deren physiologisch vertraglichen Salze alsThe invention relates to the production and use of the compounds according to the invention or their physiologically acceptable salts as
1 Inhibitoren von Rotamasen zur Herstellung von Arzneimitteln zur Behandlung von Erkrankungen, die durch dieses Enzym vermittelt werden und/oder1 Rotamase inhibitors for the manufacture of medicaments for the treatment of diseases mediated by this enzyme and / or
2 Inhibitoren der Spatphasen-Eosinophihe zur Herstellung von Arzneimitteln zur Behandlung von durch diese Zellen vermittelten Erkrankungen2 late phase eosinophil inhibitors for the manufacture of medicaments for the treatment of diseases mediated by these cells
Zu diesen Erkrankungen gehören beispielsweise peπphere Neuropathien, Neurodegeneration, Schlaganfall Parkinson und Alzheimer Erkrankungen, traumatische Gehirnerkrankungen Multiple Sclerose, Asthma bronchiale, allergische Rhinitis, allergische Konjunktivitis atopische Dermatitis, Ekzeme, allergische Angntis, durch Eosinophile vermittelte Entzündungen wie eosinophile Fascntis, eosinophile Pneumonie und PIE-Syndrom Autoimmunerkrankungen wie rheumatoide Arthritis rheumatoide Spondy tis Lupus erythematosus, Psoπasis, Glomerulonephπtis und Uveitis Insu n-abhangiger Diabetes melhtus und Sepsis Die erfindungsgemaßen Verbindungen bzw deren physiologisch vertragliche Salze werden weiterhin zur Herstellung von Arzneimitteln zur Verhinderung von Abstoßungsreaktionen nach Transplantationen von Zellen, Geweben oder Organen verwendetThese diseases include, for example, peπphere neuropathies, neurodegeneration, Parkinson's and Alzheimer's disease, traumatic brain diseases, multiple sclerosis, bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, eczema, allergic angstis, inflammation mediated by eosinophils, such as eosinophils, Eosinophilic pneumonia and PIE syndrome Autoimmune diseases such as rheumatoid arthritis, rheumatoid spondy tis lupus erythematosus, Psoπasis, glomerulonephπtis and uveitis Insu n-dependent diabetes melhtus and sepsis The compounds according to the invention or their physiologically tolerated salts continue to be used for the prevention of transplants after the manufacture of transplants for the preparation of medicinal products Cells, tissues or organs used
Zur Herstellung der Arzneimittel wird neben den üblichen Hilfsmitteln, Trager- und Zusatzstoffen eine wirksame Dosis der erfindungsgemaßen Verbindungen oder deren Salze verwendetIn addition to the usual auxiliaries, carriers and additives, an effective dose of the compounds according to the invention or their salts is used to prepare the medicaments
Die Dosierung der Wirkstoffe kann je nach Verabfolgungsweg, Alter, Gewicht desThe dosage of the active ingredients can vary depending on the route of administration, age, weight of the
Patienten, Art und Schwere der zu behandelnden Erkrankungen und ähnlichenPatients, type and severity of the diseases to be treated and the like
Faktoren variieren Die tägliche Dosis kann als einmal zu verabreichende Einzeldosis oder unterteilt inFactors vary The daily dose can be given as a single dose or divided into single doses
2 oder mehrere Tagesdosen gegeben werden und betragt in der Regel2 or more daily doses are given and usually amount
0,001 -1000 mg0.001-1000 mg
Als Applikationsform kommen orale parenterale, intravenöse, transdermale, topische, inhalative und intranasale Zubereitungen in FrageOral parenteral, intravenous, transdermal, topical, inhalative and intranasal preparations can be used as the application form
Zur Anwendung kommen die üblichen galenischen Zubereitungsformen wie Tabletten, Dragees, Kapseln, dispergierbare Pulver, Granulate, wäßrige Losungen, wäßrige oder ohge Suspensionen Sirup, Safte oder TropfenThe usual galenical preparation forms such as tablets, dragees, capsules, dispersible powders, granules, aqueous solutions, aqueous or non-aqueous suspensions, syrups, juices or drops are used
Feste Arzneiformen können inerte Inhalts- und Tragerstoffe enthalten, wie z B Calciumcarbonat, Calciumphosphat Natriumphosphat, Lactose, Starke, Mannit, Alginate, Gelatine, Guar-gummi, Magnesium- oder Aluminiumstearat Methylcellulose, Talkum, hochdisperse Kieselsauren, Sihkonol, hohermolekulare Fettsauren (wie Stearinsaure), Gelatine Agar-Agar oder pflanzliche oder tierische Fette und Ole, feste hochmolekulare Polymere (wie Polyethylenglykol), für orale Applikation geeignete Zuberpitungen können gewunschtenfalls zusatzliche Geschmacks- und/oder Süßstoffe enthalten Flussige Arzneiformen können sterilisiert sein und/oder gegebenenfalls Hilfsstoffe wie Konservierungsmittel Stabilisatoren Netzmittel, Penetrationsmittel, Emulgatoren, Spreitmittel Losungsvermittler Salze Zucker oder Zuckeralkohole zur Regelung des osmotischen Drucks oder zur Pufferung und/oder Viskositatsreguiatoren enthaltenSolid pharmaceutical forms can contain inert ingredients and carriers, such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatin, guar gum, magnesium or aluminum stearate, methyl cellulose, talc, highly disperse silicic acids, sihkonol, high molecular fatty acids (such as stearic acid ), Gelatin agar-agar or vegetable or animal fats and oils, solid high-molecular polymers (such as polyethylene glycol), preparations suitable for oral application can, if desired, contain additional flavors and / or sweeteners Liquid pharmaceutical forms can be sterilized and / or optionally contain auxiliaries such as preservatives, stabilizers, wetting agents, penetrants, emulsifiers, spreading agents, solubilizers, salts, sugar or sugar alcohols for regulating the osmotic pressure or for buffering and / or viscosity regulators
Derartige Zusätze sind zum Beispiel Tartrat- und Citrat-Puffer Ethanol, Komplexbildner (wie Ethylendiamin-tetraessigsaure und deren nicht-toxische Salze) Zur Regelung der Viskosität kommen hochmolekulare Polymere in Frage wie beispielsweise flussiges Polyethylenoxid mikrokristalline CellulosenSuch additives are, for example, tartrate and citrate buffers ethanol, complexing agents (such as ethylenediamine-tetraacetic acid and its non-toxic salts). High-molecular-weight polymers such as, for example, liquid polyethylene oxide, microcrystalline celluloses are suitable for regulating the viscosity
Carboxymethylcellulosen, Polyvinylpyrro done Dextrane oder Gelatine Feste Tragerstoffe sind zum Beispiel Starke Lactose Mannit, Methylcellulose, Talkum hochdisperse Kieselsauren, hohermolekulare Fettsauren (wie Stearinsaure), Gelatine, Agar-Agar, Calciumphosphat Magnesiumstearat, tierische und pflanzliche Fette, feste hochmolekulare Polymere wie PolyethylenglykolCarboxymethyl celluloses, polyvinylpyrro done dextrans or gelatin Solid carriers are, for example, strong lactose mannitol, methyl cellulose, talcum highly disperse silica, high molecular weight fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate magnesium stearate, animal and vegetable fats such as polyethylene glycol
Ohge Suspensionen für parenterale oder topische Anwendungen können vegetabile synthetische oder semisynthetische Ole wie beispielsweise flussige Fettsaureester mit jeweils 8 bis 22 C-Atomen in den Fettsaureketten, zum Beispiel Palmitin- , Launπ- Tridecyl-, Margann- Stearin- Arachin- Mynstin-, Behen- Pentadecyl-Ohge suspensions for parenteral or topical applications can vegetable synthetic or semi-synthetic oils such as liquid fatty acid esters with 8 to 22 carbon atoms in the fatty acid chains, for example palmitin, Launπ tridecyl, Margann stearin arachin Mynstin, Behen- Pentadecyl
Linol-, Elaidin-, Brasidin-, Eruca- oder Olsaure die mit ein- bis dreiwertigen Alkoholen mit 1 bis 6 C-Atomen wie beispielsweise Methanol, Ethanol Propanol, Butanol, Pentanol oder deren Isomere Glycol oder Glycerol verestert sind sein Derartige Fettsaureester sind beispielsweise handelsübliche Miglyole, Isopropyimynstat, Isopropylpalmitat Isopropylstearat, PEG 6-Caprιnsaure, Capryl/Capπnsaureester von gesattigten FettalkoholenLinoleic, elaidic, brasidinic, erucic or oleic acid which are esterified with monohydric to trihydric alcohols having 1 to 6 carbon atoms such as, for example, methanol, ethanol, propanol, butanol, pentanol or their isomers, glycol or glycerol Commercial Miglyole, Isopropyimynstat, Isopropylpalmitat Isopropylstearat, PEG 6-Caprιnsaure, Capryl / Capπnsaureester of saturated fatty alcohols
Polyoxyethylenglyceroltπoleate Ethyloleat wachsartige Fettsaureester wie künstliches Entenburzeldrusenfett Kokosfettsaure-isopropylester, Olsaureoleylester, Olsauredecyiester, Milchsaureethylester, Dibutylphthalat, Adipinsaurediisopropylester, Polyol-Fettsaureester u a Ebenso geeignet sind Silikonole verschiedener Viskosität oder Fettalkohole wie Isotndexylalkohol, 2-Octyldodecanol, Cetylstearyl-Alkohol oder Oleylalkohol Fettsauren wie beispielsweise Olsaure Weiterhin können vegetabile Ole wie Rizinusöl, Mandelöl Olivenöl, Sesamol, Baumwollsaatol Erdnußöl oder Sojabohnenol Verwendung findenPolyoxyethylene glycol oleate ethyl oleate wax-like fatty acid esters such as artificial duckling goose fat isopropyl coconut oil, olsaureol ethyl ester, oleic acid decyl ester, lactic acid ethyl ester, dibutyl phthalate, adipic acid diisopropyl ester, polyol fatty acid oleyl ester such as fatty alcohols, such as fatty alcohol ethers, such as fatty alcohol ethers, as well can vegetable oils such as castor oil, almond oil Olive oil, sesame oil, cotton seed oil, peanut oil or soybean oil are used
Als Losungsmittel, Gelbildner und Losungsvermittler kommen in Frage Wasser oder mit Wasser mischbare Losungsmittel Geeignet sind zum Beispiel Alkohole wie beispielsweise Ethanol oder Isopropylalkohol Benzylalkohol, 2-Octyldodecanol, Polyethylenglykole, Phthalate Λdipate Propylenglykol, Glyceπn, Di- oder Tripropylenglykol, Wachse, Methylcellosolve Cellosolve, Ester, Morphohne, Dioxan, Dimethylsulfoxid, Dimethylformamid Tetrahydrofuren, Cyclohexanon etcSuitable solvents, gelling agents and solubilizers are water or water-miscible solvents. For example, alcohols such as ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, propylene glycol, glycine, di- or tripropylene glycol, waxes, methyl cellosolve cellulose are suitable , Morphohne, Dioxane, Dimethylsulfoxid, Dimethylformamide Tetrahydrofuren, Cyclohexanon etc
Als Filmbiidner können Celluloseether verwendet werden, die sich sowohl in Wasser als auch in organischen Losungsmitteln losen bzw anquellen können, wie beispielsweise Hydroxypropylmpthylcellulose Methylcellulose, Ethylcellulose oder lösliche StarkenCellulose ethers which can dissolve or swell both in water and in organic solvents, such as, for example, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose or soluble starches, can be used as film formers
Mischformen zwischen Gel- und Filmbildnem sind durchaus ebenfalls möglich Hier kommen vor allem ionische Makromoleküle zur Anwendung, wie z B Natπumcarboxymethylcellulose Polyacrylsaure Polymethacrylsaure und deren Salze, Natπumamylopektinsemiglykolat Alginsaure oder Propylenglykol-Alginat als Natriumsalz, Gummi arabicum Xanthan-Gummi Guar-Gummi oder CarrageenanMixed forms between gel and film formers are also quite possible. Ionic macromolecules in particular are used here, such as, for example, sodium carboxymethyl cellulose, polyacrylic acid, polymethacrylic acid and its salts, sodium amamylopectin semiglycolate, alginic acid or propylene glycol alginate as sodium salt, gum arabic, gum xanthane or gum guanine
Als weitere Formuherungshilfsmittel können eingesetzt werden Glycenn, Paraffin unterschiedlicher Viskosität, Tπethanolamin Collagen, Allantoin, Novantisolsaure Auch die Verwendung von Tensiden Emulgatoren oder Netzmitteln kann zur Formulierung notwendig sein wie z B von Na-Laurylsulfat, Fettalkoholethersulfaten, Di-Na-N-lauryl-ß-iminodipropionat, polyoxyethyhertes Rizinusöl oder Sorbitan-Monooleat Sorbitan-Monostearat Polysorbaten (z B Tween), Cetylalkohol, Lecithin Glyceπnmonostearat, Polyoxyethylenstearat, Alkylphenolpolyglykolether, Cetyltrimethylammoniumchloπd oder Mono- /Dialkylpolyglykolether-orthophosphorsaure-monoethanolaminsalzenGlycene, paraffin of different viscosities, tetrahanolamine collagen, allantoin, novantisol acid can also be used as additional shaping aids. The use of surfactants, emulsifiers or wetting agents may also be necessary for the formulation, for example Na-lauryl sulfate, fatty alcohol ether sulfates, di-Na-N-lauryl-ß -iminodipropionate, polyoxyethylene castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (e.g. Tween), cetyl alcohol, lecithin glycine monostearate, polyoxyethylene stearate, alkylphenol polyglycol ether, cetyltrimethylammonium phospholethanolamine or mono- / poly- / ethanol-mono-
Stabilisatoren wie Montmoπllonite oder kolloidale Kieselsauren zur Stabilisierung von Emulsionen oder zur Verhinderung des Abbaus der aktiven Substanzen wie Antioxidantien, beispielsweise Tocopherole oder Butylhydroxyanisol, oder Konservierungsmittel, wie p-Hydroxybenzoesaureester, können ebenfalls zur Zubereitung der gewünschten Formulierungen gegebenenfalls erforderlich seinStabilizers such as Montmoπllonite or colloidal silica to stabilize emulsions or to prevent the breakdown of active substances such as antioxidants, such as tocopherols or butylated hydroxyanisole, or Preservatives, such as p-hydroxybenzoic acid esters, may also be necessary to prepare the desired formulations
Die Hersteilung, Abfüllung und Verschheßung der Präparate erfolgt unter den üblichen antimikrobiellen und aseptischen BedingungenThe preparation, filling and sweating of the preparations takes place under the usual antimicrobial and aseptic conditions
Die Dosierung der pharmazeutischen Zubereitungen hangt vom Alter, Zustand und Gewicht des Patienten sowie von der Applikationsform ab In der Regel betragt die tägliche Wirkstoffdosis zwischen 0 001 -25 mg/kg KorpergewichtThe dosage of the pharmaceutical preparations depends on the age, condition and weight of the patient and on the form of administration. As a rule, the daily dose of active ingredient is between 0 001 -25 mg / kg body weight
HerstellungManufacturing
Entsprechend der vorliegenden Erfindung können die Verbindungen der allgemeinen Formel I nach folgenden Verfahren hergestellt werdenAccording to the present invention, the compounds of general formula I can be prepared by the following methods
Verfahren zur Herstellung der Verbindungen der allgemeinen Formel I, dadurch gekennzeichnet, daßProcess for the preparation of the compounds of general formula I, characterized in that
a) für X = -S02- , -SO- entsprechend Schema 1 verfahren wirda) procedure for X = -S0 2 -, -SO- according to Scheme 1
Sulfonsaure-1 H-ιndazol-3-ylester II werden in Gegenwart einer Base und gegebenenfalls in Gegenwart eines Verdünnungsmittels zu Verbindungen der allgemeinen Formel III umgesetzt wobei R' R3 X und Z die oben genannte Bedeutung besitzen Sulfonsaure-1 H-ιndazol-3-ylester II oder 1 -Sulfonyl-ιndazole III werden gegebenenfalls in Gegenwart einer Base insbesondere Natriumhydrid, und gegebenenfalls in Gegenwart eines Verdünnungsmittels, insbesondere Dimethylsulfoxid, mit Verbindungen der folgenden allgemeinen FormelnSulfonic acid 1 H-indazol-3-yl ester II are reacted in the presence of a base and optionally in the presence of a diluent to give compounds of the general formula III where R 'R 3 X and Z have the meaning given above sulfonic acid 1 H-indazole-3 -ylester II or 1 -sulfonyl-indazole III are optionally in the presence of a base, in particular sodium hydride, and optionally in the presence of a diluent, in particular dimethyl sulfoxide, with compounds of the following general formulas
wobei R1, R2, R3, X, Y und Z die oben genannte Bedeutung besitzen und Hai ein Halogenatom F, Cl, Br oder Jod bedeutet zu Verbindungen der allgemeinen Formel I umgesetzt, wobei R1 R7 R3 X Y und Z die oben genannte Bedeutung besitzenwhere R 1 , R 2 , R 3 , X, Y and Z have the meaning given above and Hai represents a halogen atom F, Cl, Br or iodine to compounds of the general Formula I implemented, wherein R 1 R 7 R 3 XY and Z have the meaning given above
Schema 1Scheme 1
Formel II Formel IIIFormula II Formula III
Formelformula
b) fur X = -(CH2)P-, -(CH2)p-0- -(CH2)p-(C=0)- -(CH2)p-(C=0)-NH-,b) for X = - (CH 2 ) P -, - (CH 2 ) p -0- - (CH 2 ) p - (C = 0) - - (CH 2 ) p - (C = 0) -NH- ,
-(CH2)p-CHOH-, -CH0H-(CH2)p- -(CH2)P-CH=CH-, -CH=CH-(CH2)P- mit p = 1 4 entsprechend Schema 2 verfahren wird- (CH 2 ) p -CHOH-, -CH0H- (CH 2 ) p - - (CH 2 ) P -CH = CH-, -CH = CH- (CH 2 ) P - with p = 1 4 according to Scheme 2 is proceeded
Verbindungen der allgemeinen Formel III werden gegebenenfalls in Gegenwart einer Base, insbesondere Pyridin oder Natriumhydrid und gegebenenfalls in Gegenwart eines Verdünnungsmittels, insbesondere Tetrahydrofuran oder Dimethylsulfoxid, mit Verbindungen der folgenden allgemeinen FormelnCompounds of the general formula III are optionally in the presence of a base, in particular pyridine or sodium hydride and, if appropriate, in the presence of a diluent, in particular tetrahydrofuran or dimethyl sulfoxide, with compounds of the following general formulas
wobei R1, R2, R3, X, Y und Z die oben genannte Bedeutung besitzen und Hai ein Halogenatom F Cl, Br oder Jod bedeutet zu Verbindungen der allgemeinen Formel I umgesetzt, wobei R1, R?. R3. X. Y und Z die oben genannte Bedeutung besitzen.where R 1 , R 2 , R 3 , X, Y and Z have the meaning given above and Hai is a halogen atom F Cl, Br or iodine to compounds of the general Formula I implemented, wherein R 1 , R ? , R 3 . X. Y and Z have the meaning given above.
Schema 2:Scheme 2:
Formel III FormelFormula III formula
wobei Formel IM auch als tautomere Fom Formel IV entsprechend Schema 3 vorliegen kann.where formula IM can also exist as a tautomeric formula IV according to scheme 3.
a 3:a 3:
Form ei III Form el lVForm ei III Form el IV
Die Verbindungen der allgemeinen Formel I sind neu.The compounds of general formula I are new.
AusführunqsbeispieleExecution examples
Von den erfindungsgemäßen Verbindungen werden folgende Vertreter beispielhaft genannt:The following representatives of the compounds according to the invention are mentioned as examples:
2-(2-Hydroxy-5-nitrobenzyl)-5-methoxy-1 -(4-methoxybenzolsulfonyl)-1 ,2-dihydro- indazol-3-on 2-(2-Hydroxy-5-nitrobenzyl)-5-methoxy-1 -(toluol-4-sulfonyl)-1 ,2-dihydro-indazol-3-on 2-(2-Hydroxy-5-nιtrobenzyl)-5-methoxy-1 -(4-tπfluormethoxy- benzolsulfonyl)-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-dihydro-indazol-3-one 2- (2-hydroxy-5-nitrobenzyl) -5-methoxy-1 - (4-tπfluoromethoxybenzenesulfonyl) -
1 ,2-dιhydro-ιndazol-3-on 2-(2-Hydroxy-5-nιtrobenzyl)-5-methoxy-1-(4-chlorbenzolsulfonyl)-1 ,2-dιhydro- ιndazol-3-on 1 -(4-Fluorbenzolsulfonyl)-2-(2-hydroxy-5-nιtrobenzyl)-5-methoxy-1 ,2-dιhydro- ιndazol-3-on N-(4-[2-(2-Hydroxy-5-nιtrobenzyl)-5-methoxy-3-oxo-2,3-dιhydro-ιndazol-1 -sulfonyl]- phenyl)-acetamιd1,2-dihydro-indazol-3-one 2- (2-hydroxy-5-nitrobenzyl) -5-methoxy-1- (4-chlorobenzenesulfonyl) -1, 2-dihydro-indazol-3-one 1 - (4th -Fluorobenzenesulfonyl) -2- (2-hydroxy-5-nitrobenzyl) -5-methoxy-1,2-dydehydro-indazol-3-one N- (4- [2- (2-hydroxy-5-nitrobenzyl) -5 -methoxy-3-oxo-2,3-dihydro-indazole-1-sulfonyl] - phenyl) -acetamide
2-(4-Fluorbenzyl)-5-methoxy-1 -(toluol-4-sulfonyl)-1 2-dιhydro-ιndazol-3-on 2-(4-Fluorbenzyl)-5-methoxy-1 -(4-chlorbenzolsulfonyl)-1 ,2-dιhydro-ιndazol-3-on 1 -(4-Fluorbenzolsulfonyl)-2-(4-fluorbenzyl)-5-methoxy-1 ,2-dιhydro- ιndazol-3- on2- (4-fluorobenzyl) -5-methoxy-1 - (toluene-4-sulfonyl) -1 2-dihydro-indazol-3-one 2- (4-fluorobenzyl) -5-methoxy-1 - (4-chlorobenzenesulfonyl ) -1, 2-dιhydro-ιndazol-3-one 1 - (4-fluorobenzenesulfonyl) -2- (4-fluorobenzyl) -5-methoxy-1, 2-dιhydro- ιndazol-3- one
2-(2-Fluorbenzyl)-5-methoxy-1 -(toluol-4-sulfonyl)-1 2-dιhydro-ιndazol-3-on 1 -(4-Fluorbenzolsulfonyl)-2-(2-fluorbenzyl)-5-methoxy-1 ,2-dιhydro- ιndazol-3- on2- (2-fluorobenzyl) -5-methoxy-1 - (toluene-4-sulfonyl) -1 2-dihydro-indazol-3-one 1 - (4-fluorobenzenesulfonyl) -2- (2-fluorobenzyl) -5- methoxy-1,2-dihydro-indazole-3-one
2-(3-Methoxybenzyl)-5-methoxy-1 -(toluol-4-sulfonyl)-1 2-dιhydro-ιndazol-3-on2- (3-methoxybenzyl) -5-methoxy-1 - (toluene-4-sulfonyl) -1 2-dihydro-indazol-3-one
2-(3-Trιfluormethylbenzyl)-5-methoxy-1 -(toluol-4-sulfonyl)-1 ,2-dιhydro-ιndazol-3-on2- (3-trifluoromethylbenzyl) -5-methoxy-1 - (toluene-4-sulfonyl) -1, 2-dιhydro-indazol-3-one
2-[2-(4-Chlorphenyl)thιazol-4-ylmethyl]-5-methoxy-1 -(toluol-4-sulfonyl)-1 ,2-dιhydro- ιndazol-3-on 5-Methoxy-2-(3-phenylallyl)-1 -(toluol-4-sulfonyl)-1 2-dιhydro-ιndazol-3-on2- [2- (4-chlorophenyl) thιazol-4-ylmethyl] -5-methoxy-1 - (toluene-4-sulfonyl) -1, 2-dιhydro-indazol-3-one 5-methoxy-2- (3rd -phenylallyl) -1 - (toluene-4-sulfonyl) -1 2-dιhydro-ιndazol-3-one
5-Methoxy-2-(3-oxo-3-phenylpropvl)-1 -(toluol-4-sulfonyl)-1 2-dιhydro-ιndazol-3-on5-methoxy-2- (3-oxo-3-phenylpropvl) -1 - (toluene-4-sulfonyl) -1 2-dihydro-indazol-3-one
2-[2-(2,6-Dιfluorphenoxy)ethyl]-5 methoxy-1 -(toluol-4-sulfonyl)-1 ,2-dιhydro-ιndazol-2- [2- (2,6-Difluorophenoxy) ethyl] -5 methoxy-1 - (toluene-4-sulfonyl) -1, 2-dιhydro-indazole-
3-on3-one
2-[2-(2-Brom-4,6-dιfluorphenoxy)ethyl]-5-methoxy-1 -(toluol-4-sulfonyl)-1 ,2-dιhydro- ιndazol-3-on2- [2- (2-bromo-4,6-difluorophenoxy) ethyl] -5-methoxy-1 - (toluene-4-sulfonyl) -1, 2-dihydro-indazol-3-one
2-[2-(2-Brom-4,6-dιfluorphenoxy)ethyl]-5-methoxy-1 -(4-methoxy-benzolsulfonyl)-1 ,2- dιhydro-ιndazol-3-on2- [2- (2-bromo-4,6-difluorophenoxy) ethyl] -5-methoxy-1 - (4-methoxy-benzenesulfonyl) -1, 2- dιhydro-indazol-3-one
N-(4-{2-[2-(2,4-Dιoxo-1 ,4-dιhydro-2H-chιnazolιn-3-yl)ethyl]-5-methoxy-3-oxo-2,3- dιhydro-ιndazol-1-sulfonyl}phenyl)-acetamιd 2-{3-[4-(3-Chlorphenyl)-pιperazιn-1 yl]propyl}-5-methoxy-1 -(toluol-4-sulfonyl)-1 ,2- dιhydro-ιndazol-3-onN- (4- {2- [2- (2,4-Dιoxo-1, 4-dιhydro-2H-chιnazolιn-3-yl) ethyl] -5-methoxy-3-oxo-2,3-dιhydro-ιndazole -1-sulfonyl} phenyl) -acetamιd 2- {3- [4- (3-chlorophenyl) -pιperazιn-1 yl] propyl} -5-methoxy-1 - (toluene-4-sulfonyl) -1, 2- dιhydro -ιndazol-3-one
1-(4-Chlorbenzolsulfonyl)-2-{3-[4-(3-chlorphenyl)-pιperazιn-1yl]propyl}-5-methoxy-1-1- (4-chlorobenzenesulfonyl) -2- {3- [4- (3-chlorophenyl) -pιperazιn-1yl] propyl} -5-methoxy-1-
(toluol-4-sulfonyl)-1 ,2-dιhydro-ιndazol-3-on N-Benzyl-2-[5-methoxy-3-oxo-1 -(toluol-4-sulfonyl)-1 3-dιhydro-ιndazol-2-yl]-acetamιd 2-[5-Methoxy-3-oxo-1 -(toluol-4-sulfonyl)-1 3-dιhydro-ιndazol-2-yl]-N-(4- methoxyphenyl)-acetamιd(toluene-4-sulfonyl) -1, 2-dιhydro-ιndazol-3-one N-Benzyl-2- [5-methoxy-3-oxo-1 - (toluene-4-sulfonyl) -1 3-dihydro-indazol-2-yl] -acetamid 2- [5-methoxy-3-oxo-1 - (toluene-4-sulfonyl) -1 3-dιhydro-ιndazol-2-yl] -N- (4-methoxyphenyl) -acetamid
2-(2,6-Dιchlorbenzoyl)-5-nιtro-1-(toluol-4-sulfonyl)-1 2-dιhydro-ιndazol-3-on 1 -(3,4-Dιchlorbenzyl)-2-(2-hydrovy-5-nιtrobenzyl)-5-methylthιo-1 ,2-dιhydro-ιndazol-2- (2,6-dichlorobenzoyl) -5-nitro-1- (toluene-4-sulfonyl) -1 2-dihydro-indazol-3-one 1 - (3,4-dichlorobenzyl) -2- (2-hydrovy -5-nιtrobenzyl) -5-methylthιo-1, 2-dιhydro-ιndazol-
3-on3-one
2-(2-Hydroxy-5-nιtrobenzyl)-5-methoxy-1 -(3-nιtrobenzyl)-1 ,2-dιhydro-ιndazol-3-on 5-Methoxy-1-(3-nιtrobenzyl)-3-oxo-1 3-dιhydro-ιndazol-2-carbonsaure-(2- fluorphenyl)-amιd 5-Methoxy-1 -(3-nιtrobenzyl)-3-oxo-1 3-dιhydro-ιndazol-2-carbonsaure-(2,6- dιchlorphenyl)-amιd 5-Methoxy-1-(3-nιtrobenzyl)-3-oxo-1 3-dιhydro-ιndazol-2-carbonsaure-(2-fluor-6- trιfluormethylphenyl)-amιd2- (2-Hydroxy-5-nitrobenzyl) -5-methoxy-1 - (3-nitrobenzyl) -1, 2-dihydro-indazol-3-one 5-methoxy-1- (3-nitrobenzyl) -3-oxo -1 3-dihydro-indazole-2-carboxylic acid (2-fluorophenyl) amide 5-methoxy-1 - (3-nitrobenzyl) -3-oxo-1 3-dihydro-indazole-2-carboxylic acid (2.6 - Dιchlorphenyl) -amιd 5-methoxy-1- (3-nιtrobenzyl) -3-oxo-1 3-dιhydro-ιndazol-2-carboxylic acid- (2-fluoro-6-trιfluormethylphenyl) -amιd
3-[2-(2-Fluorphenylcarbamoyl)-5 methoxy-3-oxo-2 3-dιhydro-ιndazol-1 -ylmethyl]- benzoesauremethylester3- [2- (2-fluorophenylcarbamoyl) -5 methoxy-3-oxo-2 3-dihydro-indazole-1-methyl] benzoic acid methyl ester
1 -(4-Fluorbenzyl)-5-methoxy-3-oxo-1 3-dιhydro-ιndazol-2-carbonsaure-(2,6- dιchlorphenyl)-amιd1 - (4-fluorobenzyl) -5-methoxy-3-oxo-1 3-dιhydro-indazole-2-carboxylic acid- (2,6-dιchlorophenyl) -amιd
1 -(4-Fluorbenzyl)-5-methoxy-3-oxo-1 3-dιhydro-ιndazol-2-carbonsaure-4- nitrobenzylester 1 -(2,6-Dιfluorbenzyl)-5-methoxy- 3 oxo-1 3-dιhydro-ιndazol-2-carbonsaure-(2,6- dιchlorphenyl)-amιd1 - (4-fluorobenzyl) -5-methoxy-3-oxo-1 3-dihydro-indazole-2-carboxylic acid 4-nitrobenzyl ester 1 - (2,6-difluorobenzyl) -5-methoxy-3 oxo-1 3- dιhydro-ιndazol-2-carboxylic acid- (2,6-dιchlorphenyl) -amιd
1-(2-Chlor-6-fluorbenzyl)-5-methoxy-3-oxo-1 3-dιhydro-ιndazol-2-carbonsaure-(2,6- dιchlorphenyl)-amιd1- (2-chloro-6-fluorobenzyl) -5-methoxy-3-oxo-1 3-dihydro-indazole-2-carboxylic acid- (2,6-dimochlorophenyl) amide
Die Charakterisierung der Verbindungen erfolgte mittels Schmelzpunkt, Dunnschicht-chromatographie, Elementaranalyse, NMR-Spektroskopie, IR-und UVΛ/IS-Spektroskopie und gegebenfalls mit MassenspektroskopieThe compounds were characterized by means of melting point, thin layer chromatography, elemental analysis, NMR spectroscopy, IR and UVΛ / IS spectroscopy and, if appropriate, mass spectrometry
Reinigung mit Sauienflussigkeitschromatographie Bei der Herstellung der Verbindungen Beispiel 1 bis 35 können als Nebenprodukte die 1- und 3-0- substituierten 1 H-lndazole gemäß der allgemeinen Formel V gebildet werden Purification with acid liquid chromatography In the preparation of the compounds of Examples 1 to 35, the 1- and 3--0-substituted 1 H-indazoles according to the general formula V can be formed as by-products
Formel VFormula V
Die Verbindungen der allgemeinen Formel I lassen sich gewöhnlich durch Umkπstallisation von den Verbindungen der allgemeinen Formel V trennen. Gelingt dies nicht, ist eine säulenchromatographische Trennung unter folgenden Bedingungen erforderlich: Stationare Phase Normalphasen-Kieselgel, z.B. Si 60 bis 100 A Partikelgröße 5 bis 100 μM Eluent Methylenchlorid / Ethylacetat = 95 / 5 oder Methylenchlorid / Methanol = 95 / 5The compounds of the general formula I can usually be separated from the compounds of the general formula V by re-installation. If this does not succeed, a column chromatography separation is necessary under the following conditions: stationary phase normal phase silica gel, e.g. Si 60 to 100 A particle size 5 to 100 μM eluent methylene chloride / ethyl acetate = 95/5 or methylene chloride / methanol = 95/5
Die Verbindungen der allgemeinen Formel I sind polarer als die Verbindungen der allgemeinen Formel V, so daß die Verbindungen der allgemeinen Formel I unter diesen chromatographischen Bedingungen nach den Verbindungen der allgemeinen Formel V eluiert werden. Diese Reinigungsoperation ist für alle Beispiele 1 bis 35 anwendbar. The compounds of the general formula I are more polar than the compounds of the general formula V, so that the compounds of the general formula I are eluted under these chromatographic conditions according to the compounds of the general formula V. This cleaning operation is applicable to all examples 1 to 35.
Beispiel 1example 1
2-(2-Hydroxy-5-nitrobenzyl)-5-methoxy-1 -(4-methoxybenzolsulfonyl)-1 ,2-dihydro- indazol-3-on2- (2-Hydroxy-5-nitrobenzyl) -5-methoxy-1 - (4-methoxybenzenesulfonyl) -1, 2-dihydro-indazol-3-one
5,01 g (15 mmol) 4-Methoxy-benzolsulfonsaure-5-methoxy-1 H-indazol-3-ylester werden in 70 ml DMSO gelöst und portionsweise mit 1 ,5 g (37,5 mmol) Natriumhydrid (60proz.) versetzt Nach 2 Stunden Rühren wird eine Lösung von 2,81 g (15 mmol) 2-Hydroxy-5-nιtrobenzylchlorιd in 25 ml DMSO zugetropft und 3 Stunden bei 90-100°C gerührt Nach dem Erkalten werden 400 ml Wasser zugegeben, 3 Stunden gerührt und dreimal mit 400 ml Ethylacetat extrahiert. Die vereinten organischen Phasen werden mit 100 ml Wasser gewaschen, über Natriumsulfat getrocknet, im Vakuum zur Trockne destilliert und der Rückstand aus Ethanol umkristallisiert. Ausbeute: 3,0 g (41 ,1 % der Theorie) F. 215-217 °C5.01 g (15 mmol) of 5-methoxy-1H-indazol-3-yl 4-methoxy-benzenesulfonate are dissolved in 70 ml of DMSO and added in portions with 1.5 g (37.5 mmol) of sodium hydride (60%). After 2 hours of stirring, a solution of 2.81 g (15 mmol) of 2-hydroxy-5-nitrobenzylchloride in 25 ml of DMSO is added dropwise and the mixture is stirred at 90-100 ° C. for 3 hours. After cooling, 400 ml of water are added for 3 hours stirred and extracted three times with 400 ml of ethyl acetate. The combined organic phases are washed with 100 ml of water, dried over sodium sulfate, distilled to dryness in vacuo and the residue is recrystallized from ethanol. Yield: 3.0 g (41.1% of theory) mp 215-217 ° C
13C-NMR (DMSO-d6 ; 300 MHz). = 46.0 CH2N 55,8 2 x CH30; 165,1 C=0. IR (KBr): v = 1669 cm"1 C=0. 13 C NMR (DMSO-d 6 ; 300 MHz). = 46.0 CH 2 N 55.8 2 x CH 3 0; 165.1 C = 0. IR (KBr): v = 1669 cm "1 C = 0.
Nach analoger Verfahrensweise werden die in Tabelle 1 dargestellten Verbindungen hergestellt. Tabelle 1:The compounds shown in Table 1 are prepared by an analogous procedure. Table 1:
Formel VIFormula VI
R )11 - = CH30R) 1 1 - = CH 3 0
Beispiel R2 R3 Ausbeute F. IR (KBr) >3C-NMRExample R 2 R 3 Yield F. IR (KBr)> 3 C-NMR
(% d.Th.) [°C] [cm 1] (DMSO) 0=0 N-CH2 (% of theory) [° C] [cm 1 ] (DMSO) 0 = 0 N-CH 2
4-Tolyl 1673 46,62 4-Tolyl 1673 46.62
4-Trifluor- 67 99-103 1694 46,81 methoxy- (EtOH) phenyl4-trifluoro-67 99-103 1694 46.81 methoxy- (EtOH) phenyl
4-Chlor- 66 212-216 1690 45,33 phenyl (MeCN) 4-chloro-66 212-216 1690 45.33 phenyl (MeCN)
NO,NO,
4-Fluor- 690 46,54 phenyl CHfX 55 210-212 1 (EtOH) HO4-fluoro-690 46.54 phenyl C Hf X 55 210-212 1 (EtOH) HO
4-Acetyl- 25 242-244 1672; 46,50 aminop enyl (EtOH) 1713 4-acetyl-25 242-244 1672; 46.50 aminop enyl (EtOH) 1713
4-Tolyl 179 1704 49,81 -Chlor- ^-{ → (EtOH) phenyl4-tolyl 179 1704 49.81 -Chlor- ^ - { → (EtOH) phenyl
1708 49,53 -Fluor- CH.- -F 28 167-169 (EtOH) phenyl1708 49.53 -Fluor- CH.- -F 28 167-169 (EtOH) phenyl
4-Tolyl 4-tolyl
1713 49,361713 49.36
4-Fluor- phenyl4-fluorophenyl
4-Tolyl 4-tolyl
O-CF,O-CF,
110 1704 49,86 4-Tolyl 18110 1704 49.86 4-tolyl 18
HΓÖ (EtOH) HΓ Ö (EtOH)
4-Tolyl4-tolyl
4-Tolyl4-tolyl
4-Tolyl4-tolyl
4-Tolyl4-tolyl
4-Tolyl4-tolyl
4-Methoxy- phenyl4-methoxyphenyl
4-Acetyl- aminophenyl 21 4-Tolyl4-acetylaminophenyl 21 4-tolyl
22 4-Chlor- phenyl22 4-chlorophenyl
23 4-Tolyl23 4-tolyl
24 4-Tolyl 24 4-tolyl
Beispiel 25Example 25
2-(2,6-Dιchlorbenzoyl)-5-nιtro-1 -(toluol-4-sulfonyl)-1 2-dιhydro-ιndazol-3-on2- (2,6-dichlorobenzoyl) -5-nitro-1 - (toluene-4-sulfonyl) -1 2-dihydro-indazol-3-one
5 g (0,015 Mol) Toluol-4-sulfonsaure-5 nitro 1 M ιndazol-3-ylester werden in 50 ml Pyridin gelost und mit 3,77 g (0 018 Mol) ? 6 Die hlorbenzoylchlond 30 Minuten bei 80°C gerührt Nach dem Erkalten wird in 1 50 ml Wasser eingerührt mit 100 ml 5 N HCI versetzt, abgesaugt und mit Wassei gewaschen Die Reinigung des Rohproduktes erfolgt mit praparnliver I IPI C unter Verwendung von Kieselgel Si 60 und dem Eluent Methylenchloπd/ Fthylarptat 99/1 Ausbeute 2,4 g (32 % der Theono i F 195-197°C (EtOAc) 13C-NMR (DMSO-d6 , 300 MHz) δ = 20,27 CH3 , 159,33 C=0, 162,87 C=0 IR (KBr) v = 1726 cm 1 C=05 g (0.015 mol) of toluene-4-sulfonic acid 5 nitro 1 M ιndazol-3-yl ester are dissolved in 50 ml of pyridine and 3.77 g (0 018 mol)? 6 The chlorobenzoyl chloride is stirred at 80 ° C. for 30 minutes. After cooling, 100 ml of 5N HCl are added to 1 50 ml of water, the mixture is filtered off with suction and washed with water. The crude product is purified using preparative I IPI C using silica gel Si 60 and the eluent methylene chloride / Fthylar p tat 99/1 yield 2.4 g (32% of Theono i F 195-197 ° C (EtOAc) 13 C-NMR (DMSO-d 6 , 300 MHz) δ = 20.27 CH 3 , 159.33 C = 0, 162.87 C = 0 IR (KBr) v = 1726 cm 1 C = 0
Beispiel 26Example 26
1 -(3,4-Dιchlorbenzyl)-2-(2-hydroxy-5-nιtrobenzyl)-5-methylthιo-1 ,2-dιhydro-ιndazol- 3-on Hydrat1 - (3,4-Dιchlorobenzyl) -2- (2-hydroxy-5-nitrobenzyl) -5-methylthio-1, 2-dιhydro-indazole-3-one hydrate
3,6 g (1 1 mmol) 1 -(3,4-Dιchlorbenzyl)-5-methylthιo-1 H-ιndazol-3-ol werden in 100 ml DMSO gelost und portionsweise mit 0,34 g (13,2 mmol) Natriumhydrid (95proz ) versetzt Nach 2 Stunden Ruhren wird eine Losung von 2, 1 g (1 1 mmol) 2-Hydroxy- 5-nιtrobenzylchlorιd in 20 ml DMSO zugetropft und 3 Stunden bei 60°C gerührt Nach dem Erkalten werden 200 ml Wasser zugetropft 4 Stunden gerührt und abgesaugt Der Niederschlag wird mit Methanol heiß ausgeruhrt und aus 2- Propanol umkristallisiert Ausbeute 1 ,0 g (18,5 % der Theorie) F 225 °C 13C-NMR (DMSO-d6 , 300 MHz) δ = 13 7 CH3S , 48 8 2 x CH2N , 160 6 C=0 IR (KBr) v = 1623 cm 1 C=0 3.6 g (1 1 mmol) of 1 - (3,4-dichlorobenzyl) -5-methylthio-1H-indazol-3-ol are dissolved in 100 ml of DMSO and in portions with 0.34 g (13.2 mmol) Sodium hydride (95 percent) added After 2 hours of stirring, a solution of 2.1 g (1 1 mmol) of 2-hydroxy-5-nitrobenzylchloride in 20 ml of DMSO is added dropwise and the mixture is stirred at 60 ° C. for 3 hours. After cooling, 200 ml of water are added dropwise Stirred and suction filtered for 4 hours. The precipitate is extracted with hot methanol and recrystallized from 2-propanol. Yield 1.0 g (18.5% of theory) F 225 ° C. 13 C-NMR (DMSO-d 6 , 300 MHz) δ = 13 7 CH 3 S, 48 8 2 x CH 2 N, 160 6 C = 0 IR (KBr) v = 1623 cm 1 C = 0
Nach analoger Verfahrensweise werden die in Tabelle 2 dargestellte Verbindung unter Verwendung von 5-Methoxy-1 -(3-nιtrobenzyl)-1 H-ιndazol-3-ol als Ausgangsstoff hergestellt Tabelle 2:According to an analogous procedure, the compound shown in Table 2 are prepared using 5-methoxy-1 - (3-nitrobenzyl) -1 H-indazol-3-ol as starting material Table 2:
Formel VIIFormula VII
R1 = CH30R 1 = CH 3 0
Beispiel R2 R3 Ausbeute F. IR (KBr) ,3C-NMRExample R 2 R 3 Yield F. IR (KBr) , 3 C-NMR
(% .Th.) [°C] [cm 1] (DMSO)(% .Th.) [° C] [cm 1 ] (DMSO)
0=0 N-CH,0 = 0 N-CH,
Beispiel 28Example 28
5-Methoxy-1 -(3-nιtrobenzyl)-3-oxo-1 ,3-dihydro-indazol-2-carbonsaure-(2- fluorphenyl)-amιd5-methoxy-1 - (3-nitrobenzyl) -3-oxo-1,3-dihydro-indazole-2-carboxylic acid- (2-fluorophenyl) amide
Zu einer Losung von 3,0 g (0,01 Mol) 5-Methoxy-1 -(3-nιtrobenzyl)-1 H-ιndazol-3-ol in 100 ml Tetrahydrofuran werden 1 ,8 g (0,013 Mol) 2-Fluorphenylιsocyanat zugegeben und 4 Stunden unter Ruckfluß erhitzt Anschließend wird auf 20 ml eingeengt, der ausgefallene Niederschlag abgesaugt und aus Ethylacetat umkristallisiert.1.8 g (0.013 mol) of 2-fluorophenyl isocyanate are added to a solution of 3.0 g (0.01 mol) of 5-methoxy-1 - (3-nitrobenzyl) -1 H-indazol-3-ol in 100 ml of tetrahydrofuran added and heated under reflux for 4 hours. Then it is made up to 20 ml concentrated, the precipitate is filtered off and recrystallized from ethyl acetate.
Ausbeute: 1 ,1 g (25 % der Theorie)Yield: 1.1 g (25% of theory)
F. 149-151 °CMp 149-151 ° C
13C-NMR (DMSO-d6 ; 300 MHz): δ = 157,22 C=0; 165, 15 C=0 13 C NMR (DMSO-d 6 ; 300 MHz): δ = 157.22 C = 0; 165, 15 C = 0
IR (KBr): v = 1682; 1727 cm"1 C=0IR (KBr): v = 1682; 1727 cm "1 C = 0
• Nach analoger Verfahrensweise werden die in Tabelle 3 dargestellten Verbindungen hergestellt • The connections shown in Table 3 are produced according to an analogous procedure
Tabelle 3Table 3
Formel VIIIFormula VIII
R1 = CH30R 1 = CH 3 0
Beispiel R2 R3 Ausbeute F. IR (KBr) ' C-NMRExample R 2 R 3 Yield F. IR (KBr) 'C NMR
(% d.Th.) [-C] [cm 1] (CDCI3)(% of theory) [-C] [cm 1 ] (CDCI 3 )
0=0 C=00 = 0 C = 0
29 31 170-172 1684. 156.77, (EtOAc) 1730 164,88 29 31 170-172 1684. 156.77, (EtOAc) 1730 164.88
3030
33 CH,33 CH,
34 C34 C
35 C35 C.
Zur Bestimmung der Wirkung der erfindungsgemaßen Verbindungen auf antiasthmatische, antiallergische entzündungshemmende und/oder immunmodulierende Eigenschaften wurden in vitro und in vivo Untersuchungen durchgeführtIn vitro and in vivo tests were carried out to determine the effect of the compounds according to the invention on antiasthmatic, antiallergic anti-inflammatory and / or immunomodulating properties
Die erfindungsgemaßen Verbindungen gemäß Formel I zeichnen sich überraschenderweise durch Immunophihn-Bindung aus und hemmen deren Peptidyl- Prolyl-cis-trans-lsomerase (PPIase)-Aktιvιtat Für das Eingangsscreening (10 μmol/l) wird die Inhibition des humanen Cyclophihn B im PPIase-Test bestimmt Assay zur Bestimmung der Peptidylprolyhsomerase (PPIase)-Aktιvιtat und HemmungThe compounds of the formula I according to the invention are surprisingly distinguished by immunophiline binding and inhibit their peptidyl-prolyl-cis-trans-isomerase (PPIase) actinate. For the input screening (10 μmol / l), the inhibition of human cyclophil B in PPIase is Test determined Assay for the determination of the peptidylprolyhsomerase (PPIase) actinate and inhibition
Methodemethod
Die PPIase-Aktivitat wird nach einem allgemein bekannten Enzym-Test geprüft G Fischer, H Bang, C Mech, Biomed Biochim Acta 43 1 101 -111 1 , G Fischer, H Bang, A Schellenberger, Biochim Biophys Acta 791 (1984), 87-97, D H Rieh et al . J Med Chem 38 (1995), 4164-4170The PPIase activity is checked according to a generally known enzyme test G Fischer, H Bang, C Mech, Biomed Biochim Acta 43 1 101 -111 1, G Fischer, H Bang, A Schellenberger, Biochim Biophys Acta 791 (1984), 87 -97, DH Rieh et al. J Med Chem 38: 4164-4170 (1995)
Die erfindungsgemaßen Verbindungen der allgemeinen Formel I werden zusammen mit 10 nmol Cyp B für 15 Minuten bei 4°C prainkubiert Die Enzymreaktion wird nach Zugabe von Chymotrypsin und HEPES-Puffer mit dem Testpeptid Suc-Ala-Ala-Pro- Phe-Nan gestartet Anschließend wird die Extinktionsanderung bei 390 nm verfolgt und ausgewertet Die photometrisch ermittelte Extinktionsanderung resultiert aus zwei Teilreaktionen a) die schnelle chymotryptische Spaltung des trans-Peptides, b) die nicht-enzymatische cis-trans-lsomeπsierung, die durch Cyclophihne katalysiert ist Die ermittelte Hemmung der PPIase-Aktivitat von ausgewählten Verbindungen der allgemeinen Formel I ist in Tabelle 4 dargestelltThe compounds of general formula I according to the invention are praincubated together with 10 nmol Cyp B for 15 minutes at 4 ° C. The enzyme reaction is started with the test peptide Suc-Ala-Ala-Pro-Phe-Nan after adding chymotrypsin and HEPES buffer the change in absorbance at 390 nm is monitored and evaluated The change in absorbance determined photometrically results from two partial reactions a) the rapid chymotryptic cleavage of the trans-peptide, b) the non-enzymatic cis-trans-isomerization, which is catalyzed by cyclophones, the inhibition of PPIase Activity of selected compounds of general formula I is shown in Table 4
Tabelle 4Table 4
Hemmung der Spatphasen-Eosinophihe 24 h nach inhalativer Ovalbuminchallenqe an aktiv sensibilisierten Meerschweinchen Inhibition of late-phase eosinophil 24 hours after inhaled ovalbumin challenge in actively sensitized guinea pigs
Methodemethod
Die Hemmung der pulmonalen Eosiπophilen-Infiltration durch die Substanzen wird in einem in vivo Test an aktiv gegen Ovalbumin (OVA) sensibilisierten mannlichen Dunkin-Hartley Meerschweinchen (200-250 g) geprüft Die Sensibilisierung erfolgt durch zwei intrapentoneale Injektionen einer Suspension von 20 μg OVA zusammen mit 20 mg Aluminiumhydroxid als Adjuvans in 0,5 ml physiologischer Kochsalzlosung pro Tier an zwei aufeinanderfolgenden Tagen 14 Tage nach der zweiten Injektion werden die Tiere mit Mepyramin maleat (10 mg/kg i p ) vorbehandeit, um sie vor dem anaphylaktischen Tod zu schützen 30 Minuten spater werden die Tiere in einer Plastikbox für 30 sec einem OVA-Aerosol ausgesetzt (0,5 mg/ml) das von einem mit Pressluft (19,6 kPa) getriebenen Vernebler erzeugt wird (Allergen-Challenge) Konfrontiere werden mit physiologischer Kochsalzlosung vernebelt 24 Stunden nach der Challenge werden die Tiere mit einer Uberdosis Ethylurethan (1 ,5 g/kg Korpergewicht i p ) narkotisiert und eine bronchoalveolare Lavage (BAL) mit 2 x 5 ml physiologischer Kochsalzlosung durchgeführt Die BAL-Flussigkeit wird gesammelt bei 300 rpm für 10 min zentnfugiert und anschließend das Zellpellet in 1 ml physiologischer Kochsalzlosung resuspendiert Die Eosinophilen werden unter Verwendung des Becton-Dickinson Test Kit (N 5877) für Eosinophile gefärbt und in einer Neubauerkammer gezahlt Bei jedem Test werden 2 Kontrollgruppen (Vernebelung mit physiologischer Kochsalzlosung und Vernebelung mit OVA- Losung) mitgefuhrtThe inhibition of pulmonary eosiophil infiltration by the substances is tested in an in vivo test on male Dunkin-Hartley guinea pigs (200-250 g) actively sensitized to ovalbumin (OVA). The sensitization is carried out by two intrapentonal injections of a suspension of 20 μg OVA together With 20 mg aluminum hydroxide as an adjuvant in 0.5 ml of physiological saline solution per animal on two consecutive days 14 days after the second injection, the animals are pretreated with mepyramine maleate (10 mg / kg ip) to protect them from anaphylactic death for 30 minutes the animals are later exposed in a plastic box for 30 seconds to an OVA aerosol (0.5 mg / ml) that is generated by a nebulizer driven with compressed air (19.6 kPa) (allergen challenge). Confronters are nebulized with physiological saline solution 24 Hours after the challenge, the animals are anesthetized with an overdose of ethyl urethane (1.5 g / kg body weight ip) and one bronchoalveolar lavage (BAL) with 2 x 5 ml of physiological saline solution. The BAL liquid is collected at 300 rpm for 10 min. and then the cell pellet is resuspended in 1 ml of physiological saline solution. The eosinophils are analyzed using the Becton-Dickinson Test Kit (N 5877 ) stained for eosinophils and paid in a new building chamber. 2 control groups (nebulization with physiological saline solution and nebulization with OVA solution) are included in each test
Die prozentuale Hemmung der Eosinophi e der mit Substanz behandelten Versuchsgruppe wird nach folgender Formel berechnetThe percentage inhibition of the eosinophi e of the test group treated with the substance is calculated using the following formula
(A - C) - (B - C)/ (A - C) x 100 = % Hemmung(A - C) - (B - C) / (A - C) x 100 =% inhibition
Die Testsubstanzen werden intrapentoneal oder oral als Suspension in 10 % Poiyethylenglycol 300 und 0 5 %ιger 5-Hydroxyethylcellulose 2 Stunden vor der Allergen-Challenge appliziert Die Kontrollgruppen werden entsprechend der Applikationsform der Testsubstanz mit dem Vehicel behandelt Die Anzahl der Tiere pro Kontroll- und Versuchsgruppe beträgt 3-10 Die Ergebnisse sind in Tabelle 5 aufgeführtThe test substances are intrapentoneally or orally as a suspension in 10% polyethylene glycol 300 and 0 5% 5-hydroxyethyl cellulose 2 hours before Allergen challenge applied The control groups are treated with the vehicle according to the application form of the test substance. The number of animals per control and test group is 3-10. The results are shown in Table 5
Tabelle 5Table 5
A = Eosinophile in der Kontrollgruppe mit OVA-Challenge und Vehicel B = Eosinophile in der mit Substanz behandelten Gruppe mit OVA-Challenge C = Eosinophile in der Kontrollgruppe mit 0,9 %ιger NaCI-Challenge und Vehicel \ = Mittelwert s = StandardabweichungA = eosinophils in the control group with OVA-Challenge and Vehicel B = eosinophils in the substance-treated group with OVA-Challenge C = eosinophils in the control group with 0.9% NaCI-Challenge and Vehicel \ = mean s = standard deviation
Die erfindungsgemaßen Verbindungen sind somit besonders geeignet für die Herstellung von Arzneimitteln zur Behandlung von Erkrankungen die mit der Unterdrückung immunologischer Vorgange verbunden sind The compounds according to the invention are therefore particularly suitable for the production of medicaments for the treatment of diseases which are associated with the suppression of immunological processes

Claims

Patentansprüche claims
1 Neue 1 ,2,5-trιsubstιtuιerte 1 2-Dιhydro-ιndazol-3-one der allgemeinen1 New 1, 2,5-trisubstituted 1 2-dihydro-indazol-3-one of the general
Formel IFormula I.
Formel IFormula I.
worin X, Y, Z ,R1, R2 und R3 folgende Bedeutung habenwherein X, Y, Z, R 1 , R 2 and R 3 have the following meaning
X kann -S02-, -SO-, -(CH2)P- -(CH2)p-0- -(CH2)p-(C=0)-, -(CH2)p-(C=0)-NH- -(CH2)p-CHOH-, -CHOH-(CH2)p- -(CH2)P-CH=CH-, -CH=CH-(CH2)P- mit p = 1 4 sein,X can -S0 2 -, -SO-, - (CH 2 ) P - - (CH 2 ) p -0- - (CH 2 ) p - (C = 0) -, - (CH 2 ) p - (C = 0) -NH- - (CH 2 ) p -CHOH-, -CHOH- (CH 2 ) p - - (CH 2 ) P -CH = CH-, -CH = CH- (CH 2 ) P - with p = 1 4
Y kann -(C=0)-, -(C=0)-NH- -(C=0)-NH-(CH2)p-, -(C=0)-(CH2)p-, -(CH2)P-, -(CH2)p-0-, -(CH2)p-(C=0)- -(CH2)p-(C=0)-NH-, -(CH2)p-(C=0)-NH-(CH2)p-, -(CH2)p-CHOH-, -CHOH-(CH2)p-, -(CH2)P-CH=CH-, -CH=CH-(CH2)P- mit p = 1 4 sein,Y can - (C = 0) -, - (C = 0) -NH- - (C = 0) -NH- (CH 2 ) p -, - (C = 0) - (CH 2 ) p -, - (CH 2 ) P -, - (CH 2 ) p -0-, - (CH 2 ) p - (C = 0) - - (CH 2 ) p - (C = 0) -NH-, - (CH 2 ) p - (C = 0) -NH- (CH 2 ) p -, - (CH 2 ) p -CHOH-, -CHOH- (CH 2 ) p -, - (CH 2 ) P -CH = CH-, -CH = CH- (CH 2 ) P - with p = 1 4
Z kann -O-, -0-(CH2)p- mit p = 1 4 -NH- -NH-(C=0)-, -NH-(C=0)-NH- -NH-(C=0)-0-, -NH-CH2-(C=0)- und -NH-(C=0)-CH2- sein,Z can be -O-, -0- (CH 2 ) p - with p = 1 4 -NH- -NH- (C = 0) -, -NH- (C = 0) -NH- -NH- (C = 0) -0-, -NH-CH 2 - (C = 0) - and -NH- (C = 0) -CH 2 -,
R1, R2 und R3 können gleich oder verschieden sein und folgende Bedeutung habenR 1 , R 2 and R 3 can be the same or different and have the following meaning
Mono-, bi- oder tricyclische gesattigte oder ein- oder mehrfach ungesättigte Carbocyclen mit 5 14 Ringgliedern insbesondere Phenyl, Naphthyl, Anthranyl, Fluorenyl, oder mono- bi- oder tricyclische gesattigte oder ein- oder mehrfach ungesättigte Heterocyclen mit 5-15 Ringghedern und 1 6 Heteroatomen, die vorzugsweise N 0 und S sind, insbesondereThiophenyl,Mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 5 14 ring members, in particular phenyl, naphthyl, anthranyl, fluorenyl, or mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5-15 ring gethers and 1 6 heteroatoms, which are preferably N 0 and S, in particular thiophenyl,
Pyridinyl, Isoxazolyl, Benzimidazolyl Benz[1 ,3]dιoxolyl, Pynmidinyl Chinolyl, Chinazolinyl, Morpholinyl Pyrrohdinyl, Pyrrolyl, Phenyl[1 ,2,4]oxadιazolyl, Phenylthiazolyl,Pyridinyl, isoxazolyl, benzimidazolyl benz [1, 3] dioxolyl, pynmidinyl quinolyl, Quinazolinyl, morpholinyl pyrrohdinyl, pyrrolyl, phenyl [1, 2,4] oxadιazolyl, phenylthiazolyl,
wobei die Carbocyclen bzw die Heterocyclen einfach oder mehrfach substituiert sein können mitwhere the carbocycles or the heterocycles can be substituted one or more times with
-d 6- Alkyl, -O-C1 6 -Alkyl -0-C3 7 -Cycloalkyl, mono-, bi- oder tricyclische gesättigte oder ein- oder mehrfach ungesättigte Carbocyclen mit 3...14 Ringghedern, mono-, bi- oder tricyclische gesättigte oder ein- oder mehrfach ungesättigte Heterocyclen mit 5 15 Ringgliedern und 1 . 6-d 6 - alkyl, -OC 1 6 -alkyl -0-C 3 7 -cycloalkyl, mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3 ... 14 ring gethers, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5 15 ring members and 1. 6
Heteroatomen, die vorzugsweise N 0 und S sind, -F, -Cl, -Br, -I, -OH, -SH, -N02, -NH2, -NHCi 6 -Alkyl -N(d 6 -Alkyl)2 -NHC6 14 -Aryl, -N(C6 14 -Aryl)2, -N(d 6 -Alkyl) (Cβ ι4 -Aryl). -NHCOd 6 -Alkyl, -NHCOC6 ι -Aryl, -CONHd 6 -Alkyl, -CONHC6 14 -Aryl, -CONHS02Cι 6 -Alkyl, -CONHS02C6 -Aryl, -CN. -(CO)C, 6 -Alkyl, -(CS)d 6 -Alkyl, -COOH,Heteroatoms, which are preferably N 0 and S, -F, -Cl, -Br, -I, -OH, -SH, -N0 2 , -NH 2 , -NHCi 6 -alkyl -N (d 6 -alkyl) 2 -NHC 6 14 -aryl, -N (C 6 14 -aryl) 2 , -N (d 6 -alkyl) (C β ι 4 -aryl). -NHCOd 6 -alkyl, -NHCOC 6 ι -aryl, -CONHd 6 -alkyl, -CONHC 6 14 -aryl, -CONHS0 2 Cι 6 -alkyl, -CONHS0 2 C 6 -aryl, -CN. - (CO) C, 6 -alkyl, - (CS) d 6 -alkyl, -COOH,
-COOd 6- Alkyl, -0-C6 14 -Aryl, -0-(CO)d 6 -Alkyl, -0-(CO)C6 -Aryl, Benzyl, Benzyloxy, -S-d 6 -Alkyl. -S-C6 π -Aryl, -CF3, -(CH2)p-COOH mit p = 1 bis 4, -(CH2)P- COOC, 6- Alkyl mit p = 1 bis 4, -S02-d β Alkyl, -S02-C6 14 Aryl,-COOd 6 - alkyl, -0-C 6 14 -aryl, -0- (CO) d 6 -alkyl, -0- (CO) C 6 -aryl, benzyl, benzyloxy, -Sd 6 -alkyl. -SC 6 π -aryl, -CF 3 , - (CH 2 ) p -COOH with p = 1 to 4, - (CH 2 ) P - COOC, 6 - alkyl with p = 1 to 4, -S0 2 -d β alkyl, -S0 2 -C 6 14 aryl,
R1 kann weiter H sein (allerdings nicht wenn X = CH2),R 1 can also be H (but not if X = CH 2 ),
R3-Z kann weiter N02 sein,R 3 -Z can further be N0 2 ,
jedoch ausgenommen Verbindungen gemäß Formel Ibut excluding compounds according to formula I.
wenn Z gleich -NH-(C=0)-, -NH-(C=0)-NH-, -NH-(C=0)-0-, -NH-(C=0)-CH2- und gleichzeitig R1 = Phenyl einfach oder mehrfach substituiert ist mit -COOH, -COOd e- Alkyl, -(CH2)p-COOH mit p = 1 bis 4, -(CH2)P- COOCi 6- Alkyl mit p = 1... 4, -CONHCi 6 -Alkyl, -CONHC6 14 -Aryl -CONHS02Cι 6 -Alkyl,if Z is -NH- (C = 0) -, -NH- (C = 0) -NH-, -NH- (C = 0) -0-, -NH- (C = 0) -CH 2 - and at the same time R 1 = phenyl is mono- or polysubstituted with -COOH, -COOd e- alkyl, - (CH 2 ) p -COOH with p = 1 to 4, - (CH 2 ) P - COOCi 6 - alkyl with p = 1 ... 4, -CONHCi 6 alkyl, -CONHC 6 14 aryl -CONHS0 2 Cι 6 alkyl,
-C0NHS02C6 14 -Aryl, 1 H-Tetrazol-5-yl. dann darf R2 nicht gleich Phenyl, einfach oder mehrfach substituiert mit CN. Halogen, d 4 -Alkyl, Ci 4 -Alkyloxy, CF3 sein, weiterhin wenn R3-Z = N02 ,dann dürfen R1-X und R2-Y nicht gleichzeitig folgende-C0NHS0 2 C 6 14 aryl, 1 H-tetrazol-5-yl. then R 2 must not be phenyl, mono- or polysubstituted with CN. Halogen, d 4 -alkyl, Ci 4 -alkyloxy, CF 3 , furthermore if R 3 -Z = N0 2 , then R 1 -X and R 2 -Y must not follow at the same time
Bedeutung haben:Have meaning:
R1-X = Benzyl, 4-MethoxybenzylR 1 -X = benzyl, 4-methoxybenzyl
R -Y = Benzyl, 2-Picolyl.R -Y = benzyl, 2-picolyl.
2. Verbindungen nach Anspruch 1.2. Compounds according to claim 1.
2-(2-Hydroxy-5-nitrobenzyl)-5-methoxy-1 -(4-methoxybenzolsulfonyl)-1 ,2-dihydro- indazol-3-on2- (2-Hydroxy-5-nitrobenzyl) -5-methoxy-1 - (4-methoxybenzenesulfonyl) -1, 2-dihydro-indazol-3-one
2-(2-Hydroxy-5-nitrobenzyl)-5-methoxy-1 -(toluol-4-sulfonyl)-1 ,2-dihydro-indazol-3-on2- (2-Hydroxy-5-nitrobenzyl) -5-methoxy-1 - (toluene-4-sulfonyl) -1, 2-dihydro-indazol-3-one
2-(2-Hydroxy-5-nitrobenzyl)-5-methoxy-1 -(4-trifluormethoxy- benzolsulfonyl)-2- (2-hydroxy-5-nitrobenzyl) -5-methoxy-1 - (4-trifluoromethoxybenzenesulfonyl) -
1 ,2-dihydro-indazol-3-on1, 2-dihydro-indazol-3-one
2-(2-Hydroxy-5-nitrobenzyl)-5-methoxy-1-(4-chlorbenzolsulfonyl)-1 ,2-dihydro- indazol-3-on2- (2-Hydroxy-5-nitrobenzyl) -5-methoxy-1- (4-chlorobenzenesulfonyl) -1, 2-dihydro-indazol-3-one
1 -(4-Fluorbenzolsulfonyl)-2-(2-hydroxy-5-nitrobenzyl)-5-methoxy-1 ,2-dihydro- indazol-3-on1 - (4-fluorobenzenesulfonyl) -2- (2-hydroxy-5-nitrobenzyl) -5-methoxy-1,2-dihydro-indazol-3-one
N-(4-[2-(2-Hydroxy-5-nitrobenzyl)-5-methoxy-3-oxo-2,3-dihydro-indazol-1-sulfonyl]- phenyl)-acetamid 2-(4-Fluorbenzyl)-5-methoxy-1 -(toluol-4-sulfonyl)-1 ,2-dihydro-indazol-3-onN- (4- [2- (2-Hydroxy-5-nitrobenzyl) -5-methoxy-3-oxo-2,3-dihydro-indazole-1-sulfonyl] phenyl) acetamide 2- (4-fluorobenzyl) -5-methoxy-1 - (toluene-4-sulfonyl) -1, 2-dihydro-indazol-3-one
2-(4-Fluorbenzyl)-5-methoxy-1-(4-chlorbenzolsulfonyl)-1 ,2-dihydro-indazol-3-on2- (4-fluorobenzyl) -5-methoxy-1- (4-chlorobenzenesulfonyl) -1, 2-dihydro-indazol-3-one
1-(4-Fluorbenzolsulfonyl)-2-(4-fluorbenzyl)-5-methoxy-1 ,2-dihydro-indazol-3-on1- (4-fluorobenzenesulfonyl) -2- (4-fluorobenzyl) -5-methoxy-1,2-dihydro-indazol-3-one
2-(2-Fluorbenzyl)-5-methoxy-1-(toluol-4-sulfonyl)-1 ,2-dihydro-indazol-3-on2- (2-fluorobenzyl) -5-methoxy-1- (toluene-4-sulfonyl) -1, 2-dihydro-indazol-3-one
1-(4-Fluorbenzolsulfonyl)-2-(2-fluorbenzyl)-5-methoxy-1 ,2-dihydro-indazol-3-on 2-(3-Methoxybenzyl)-5-methoxy-1 -(toluol-4-sulfonyl)-1 ,2-dihydro-indazol-3-on1- (4-fluorobenzenesulfonyl) -2- (2-fluorobenzyl) -5-methoxy-1,2-dihydro-indazol-3-one 2- (3-methoxybenzyl) -5-methoxy-1 - (toluene-4- sulfonyl) -1, 2-dihydro-indazol-3-one
2-(3-Trifluormethylbenzyl)-5-methoxy-1 -(toluol-4-sulfonyl)-1 ,2-dihydro-indazol-3-on2- (3-trifluoromethylbenzyl) -5-methoxy-1 - (toluene-4-sulfonyl) -1, 2-dihydro-indazol-3-one
2-[2-(4-Chlorphenyl)thiazol-4-ylmethyl]-5-methoxy-1 -(toluol-4-sulfonyl)-1 ,2-dihydro- indazol-3-on2- [2- (4-chlorophenyl) thiazol-4-ylmethyl] -5-methoxy-1 - (toluene-4-sulfonyl) -1, 2-dihydro-indazol-3-one
5-Methoxy-2-(3-phenylallyl)-1 -(toiuol-4-sulfonyl)-1 ,2-dihydro-indazol-3-on 5-Methoxy-2-(3-oxo-3-phenylpropyl)-1 -(toluol-4-sulfonyl)-1 ,2-dihydro-indazol-3-on5-methoxy-2- (3-phenylallyl) -1 - (toiuol-4-sulfonyl) -1, 2-dihydro-indazol-3-one 5-methoxy-2- (3-oxo-3-phenylpropyl) -1 - (toluene-4-sulfonyl) -1, 2-dihydro-indazol-3-one
2-[2-(2,6-Difluorphenoxy)ethyl]-5-methoxy-1-(toluol-4-sulfonyl)-1 ,2-dihydro-indazol-2- [2- (2,6-difluorophenoxy) ethyl] -5-methoxy-1- (toluene-4-sulfonyl) -1, 2-dihydro-indazole-
3-on 2-[2-(2-Brom-4,6-difluorphenoxy)ethyl]-5-methoxy-1 -(toluol-4-sulfonyl)-1 ,2-dihydro- indazol-3-on3-one 2- [2- (2-bromo-4,6-difluorophenoxy) ethyl] -5-methoxy-1 - (toluene-4-sulfonyl) -1, 2-dihydro-indazol-3-one
2-[2-(2-Brom-4,6-difluorphenoxy)ethyl]-5-methoxy-1 -(4-methoxy-benzolsulfonyl)-1 ,2- dihydro-indazol-3-on N-(4-{2-[2-(2,4-Dioxo-1 ,4-dihydro-2H-chinazolin-3-yl)ethyl]-5-methoxy-3-oxo-2,3- dihydro-indazol-1-sulfonyi}phenyl)-acetamid 2-{3-[4-(3-Chlorphenyl)-piperazin-1 yl]propyl}-5-methoxy-1 -(toluol-4-sulfonyl)-1 ,2- dihydro-indazol-3-on2- [2- (2-bromo-4,6-difluorophenoxy) ethyl] -5-methoxy-1 - (4-methoxy-benzenesulfonyl) -1, 2-dihydro-indazol-3-one N- (4- { 2- [2- (2,4-dioxo-1, 4-dihydro-2H-quinazolin-3-yl) ethyl] -5-methoxy-3-oxo-2,3-dihydro-indazole-1-sulfonyi} phenyl ) acetamide 2- {3- [4- (3-chlorophenyl) piperazin-1 yl] propyl} -5-methoxy-1 - (toluene-4-sulfonyl) -1, 2-dihydro-indazol-3-one
1-(4-Chlorbenzolsulfonyl)-2-{3-[4-(3-chlorphenyl)-piperazin-1 yl]propyl}-5-methoxy-1- (toluol-4-sulfonyl)-1 ,2-dihydro-indazol-3-on1- (4-chlorobenzenesulfonyl) -2- {3- [4- (3-chlorophenyl) piperazin-1 yl] propyl} -5-methoxy-1- (toluene-4-sulfonyl) -1, 2-dihydro- indazol-3-one
N-Benzyl-2-[5-methoxy-3-oxo-1-(toluol-4-sulfonyl)-1 ,3-dihydro-indazol-2-yl]-acetamidN-benzyl-2- [5-methoxy-3-oxo-1- (toluene-4-sulfonyl) -1, 3-dihydro-indazol-2-yl] acetamide
2-[5-Methoxy-3-oxo-1-(toluol-4-sulfonyl)-1.3-dihydro-indazol-2-yl]-N-(4- methoxyphenyl)-acetamid2- [5-methoxy-3-oxo-1- (toluene-4-sulfonyl) -1,3-dihydro-indazol-2-yl] -N- (4-methoxyphenyl) acetamide
2-(2,6-Dichlorbenzoyl)-5-nitro-1 -(toluol-4-sulfonyl)-1 ,2-dihydro-indazol-3-on 1 -(3,4-Dichlorbenzyl)-2-(2-hydroxy-5-nitrobenzyl)-5-methylthio-1 ,2-dihydro-indazol-2- (2,6-dichlorobenzoyl) -5-nitro-1 - (toluene-4-sulfonyl) -1, 2-dihydro-indazol-3-one 1 - (3,4-dichlorobenzyl) -2- (2- hydroxy-5-nitrobenzyl) -5-methylthio-1,2-dihydro-indazole
3-on3-one
2-(2-Hydroxy-5-nitrobenzyl)-5-methoxy-1-(3-nitrobenzyl)-1 ,2-dihydro-indazol-3-on2- (2-Hydroxy-5-nitrobenzyl) -5-methoxy-1- (3-nitrobenzyl) -1, 2-dihydro-indazol-3-one
5-Methoxy-1-(3-nitrobenzyl)-3-oxo-1.3-dihydro-indazol-2-carbonsäure-(2- fluorphenyl)-amid 5-Methoxy-1-(3-nitrobenzyl)-3-oxo-1.3-dihydro-indazol-2-carbonsäure-(2,6- dichlorphenyl)-amid5-methoxy-1- (3-nitrobenzyl) -3-oxo-1,3-dihydro-indazole-2-carboxylic acid (2-fluorophenyl) -amide 5-methoxy-1- (3-nitrobenzyl) -3-oxo-1.3 -dihydro-indazole-2-carboxylic acid- (2,6-dichlorophenyl) -amide
5-Methoxy-1-(3-nitrobenzyl)-3-oxo-1 ,3-dihydro-indazol-2-carbonsäure-(2-fluor-6- trifluormethylphenyl)-amid5-methoxy-1- (3-nitrobenzyl) -3-oxo-1,3-dihydro-indazole-2-carboxylic acid (2-fluoro-6-trifluoromethylphenyl) amide
3-[2-(2-Fluorphenylcarbamoyl)-5-methoxy-3-oxo-2.3-dihydro-indazol-1 -ylmethyl]- benzoesäuremethylesterMethyl 3- [2- (2-fluorophenylcarbamoyl) -5-methoxy-3-oxo-2,3-dihydro-indazole-1-methyl] benzoate
1-(4-Fluorbenzyl)-5-methoxy-3-oxo-1 ,3-dihydro-indazol-2-carbonsäure-(2,6- dichlorphenyi)-amid1- (4-fluorobenzyl) -5-methoxy-3-oxo-1,3-dihydro-indazole-2-carboxylic acid (2,6-dichlorophenyi) amide
1-(4-Fluorbenzyl)-5-methoxy-3-oxo-1 ,3-dihydro-indazol-2-carbonsäure-4- nitrobenzylester 1-(2,6-Difluorbenzyl)-5-methoxy-3-oxo-1 ,3-dihydro-indazol-2-carbonsäure-(2,6- dichlorphenyl)-amid1- (4-fluorobenzyl) -5-methoxy-3-oxo-1, 3-dihydro-indazole-2-carboxylic acid 4-nitrobenzyl ester 1- (2,6-difluorobenzyl) -5-methoxy-3-oxo-1 , 3-dihydro-indazole-2-carboxylic acid (2,6-dichlorophenyl) amide
1 -(2-Chlor-6-fluorbenzyl)-5-methoxy-3-oxo-1.3-dihydro-indazol-2-carbonsäure-(2,6- dichlorphenyl)-amid 1 - (2-Chloro-6-fluorobenzyl) -5-methoxy-3-oxo-1,3-dihydro-indazole-2-carboxylic acid (2,6-dichlorophenyl) amide
3. Physiologisch verträgliche Salze der neuen Verbindungen nach Formel I gemäß den Ansprüchen 1 und 2. gekennzeichnet durch Neutralisation der Basen mit anorganischen oder organischen Säuren bzw. durch Neutralisation der Säuren mit anorganischen oder organischen Basen bzw. durch Quaternierung tertiärer Amine zu quaternären Ammoniumsalzen.3. Physiologically acceptable salts of the new compounds of formula I according to claims 1 and 2. characterized by neutralization of the bases with inorganic or organic acids or by neutralization of the acids with inorganic or organic bases or by quaternization of tertiary amines to quaternary ammonium salts.
4. Verwendung der Verbindungen nach Formel I und deren Salze gemäß den Ansprüchen 1 bis 3 als therapeutische Wirkstoffe zur Herstellung von Arzneimitteln zur Behandlung von Erkrankungen, die durch die PPIase vermittelt werden.4. Use of the compounds of formula I and their salts according to claims 1 to 3 as therapeutic active substances for the manufacture of medicaments for the treatment of diseases which are mediated by the PPIase.
5. Besonders bevorzugte Verwendung der Verbindungen nach Formel I und deren Salze gemäß den Ansprüchen 1 bis 3 als therapeutische Wirkstoffe zur Herstellung von Arzneimitteln zur Behandlung von Erkrankungen, die mit der Unterdrückung immunologischer Vorgänge verbunden sind.5. Particularly preferred use of the compounds of formula I and their salts according to claims 1 to 3 as therapeutic agents for the manufacture of medicaments for the treatment of diseases which are associated with the suppression of immunological processes.
6. Verfahren zur Herstellung der Verbindungen der allgemeinen Formel I, gemäß den Ansprüchen 1 bis 3, dadurch gekennzeichnet, daß6. A process for the preparation of the compounds of general formula I, according to claims 1 to 3, characterized in that
a) für X = -S02- , -SO- entsprechend Schema 1 verfahren wird, indema) for X = -S0 2 -, -SO-, proceed according to scheme 1 by
Sulfonsäure-1 H-indazol-3-ylester IISulfonic acid 1 H-indazol-3-yl ester II
Formelformula
in Gegenwart einer Base und gegebenenfalls in Gegenwart eines Verdünnungsmittels zu Verbindungen der allgemeinen Formel IM Formel IIIin the presence of a base and optionally in the presence of a diluent to give compounds of the general formula III Formula III
umgesetzt werden, wobei R1, R3. X und Z die im Anspruch 1 bzw. oben genannte Bedeutung besitzen, und Sulfonsäure-1 H-indazol-3-ylester II oder 1-Sulfonyl- indazole IM gegebenenfalls in Gegenwart einer Base, insbesondere Natriumhydrid, und gegebenenfalls in Gegenwart eines Verdünnungsmittels, insbesondere Dimethylsulfoxid. mit Verbindungen der folgenden allgemeinen Formelnare implemented, wherein R 1 , R 3 . X and Z have the meaning given in claim 1 or above, and sulfonic acid 1 H-indazol-3-yl ester II or 1-sulfonyl indazole IM, 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 formulas
Hal-Y-R . 0=C=N-(CH2)p-R'. [R -(CH2)p-C=0]20 mit p = 0...5,Hal-YR. 0 = C = N- (CH 2 ) p -R '. [R - (CH 2 ) p -C = 0] 2 0 with p = 0 ... 5,
wobei R1, R2, R3, X, Y und Z die im Anspruch 1 bzw. oben genannte Bedeutung besitzen und Hai ein Halogenatom F, Cl, Br oder Jod bedeutet, zu Verbindungen der allgemeinen Formel I umgesetzt werden, wobei R , R2, R3, X, Y und Z die im Anspruch 1 bzw. oben genannte Bedeutung besitzen,wherein R 1 , R 2 , R 3 , X, Y and Z have the meaning given in claim 1 or above and Hai is a halogen atom F, Cl, Br or iodine, are converted into compounds of the general formula I, where R, R 2 , R 3 , X, Y and Z have the meaning given in claim 1 or above,
b) für X = -(CH2)P-, -(CH2)P-0-. -(CH2)p-(C=0)-. -(CH2)p-(C=0)-NH-,b) for X = - (CH 2 ) P -, - (CH 2 ) P -0-. - (CH 2 ) p - (C = 0) -. - (CH 2 ) p - (C = 0) -NH-,
-(CH2)p-CHOH-, -CHOH-(CH2)p-, -(CH2)P-CH=CH-, -CH=CH-(CH2)p- mit p = 1...4 entsprechend Schema 2 verfahren wird, indem- (CH 2 ) p -CHOH-, -CHOH- (CH 2 ) p -, - (CH 2 ) P -CH = CH-, -CH = CH- (CH 2 ) p - with p = 1 ... 4 is proceeded according to scheme 2 by
Verbindungen der allgemeinen Formel III gegebenenfalls in Gegenwart einer Base, insbesondere Pyridin oder Natriumhydrid, und gegebenenfalls in Gegenwart eines Verdünnungsmittels, insbesondere Tetrahydrofuran oder Dimethylsulfoxid, mit Verbindungen der folgenden allgemeinen FormelnCompounds of the general formula III, if appropriate in the presence of a base, in particular pyridine or sodium hydride, and if appropriate in the presence of a diluent, in particular tetrahydrofuran or dimethyl sulfoxide, with compounds of the following general formulas
Hal-Y-R2, 0=C=N-(CH2)p-R2. [R2-(CH2)p-C=0]20 mit p = 0...5,Hal-YR 2 , 0 = C = N- (CH 2 ) p -R 2 . [R 2 - (CH 2 ) p -C = 0] 2 0 with p = 0 ... 5,
wobei R1, R2, R3, X, Y und Z die im Anspruch 1 bzw. oben genannte Bedeutung besitzen und Hai ein Halogenatom F. Cl. Br oder Jod bedeutet, zu Verbindungen der allgemeinen Formel I umgesetzt werden, wobei R1, R2, R3, X, Y und Z die im Anspruch 1 bzw. oben genannte Bedeutung besitzen, wobei Formel IM auch als tautomere Fom Formel IVwherein R 1 , R 2 , R 3 , X, Y and Z have the meaning given in claim 1 or above and Hai a halogen atom F. Cl. Br or iodine means to compounds of general formula I are implemented, wherein R 1 , R 2 , R 3 , X, Y and Z have the meaning given in claim 1 or above, wherein formula IM also as a tautomeric formula IV
Formel IVFormula IV
entsprechend Schema 3 vorliegen kann.according to Scheme 3.
7. Pharmazeutisches Mittel, dadurch gekennzeichnet, daß es als wirksamen Bestandteil mindestens eine Verbindung der Formel I nach den Ansprüchen 1 bis 3 und physiologisch verträgliche Träger- und/oder Verdünnungs- beziehungsweise Hilfsstoffe enthält.7. Pharmaceutical composition, characterized in that it contains at least one compound of the formula I as claimed in claims 1 to 3 and physiologically compatible carriers and / or diluents or auxiliaries as active ingredient.
8. Pharmazeutische Zubereitungen, dadurch gekennzeichnet, daß sie als wirksamen Bestandteil mindestens eine Verbindung der Formel I nach den8. Pharmaceutical preparations, characterized in that they are at least one compound of the formula I according to the active ingredient
Ansprüchen 1 bis 3 und einen geeigneten Trägerstoff enthalten.Claims 1 to 3 and contain a suitable carrier.
9. Pharmazeutische Präparate nach den Ansprüchen 1 , 2, 3, 7 und 8, dadurch gekennzeichnet, daß sie in Form von Tabletten. Dragees, Kapseln, Aerosolen, Pulverformulierungen, Pflastern, Lösungen, Ampullen oder Suppositorien verabreicht werden.9. Pharmaceutical preparations according to claims 1, 2, 3, 7 and 8, characterized in that they are in the form of tablets. Dragees, capsules, aerosols, powder formulations, plasters, solutions, ampoules or suppositories can be administered.
10. Verwendung der Verbindung der Formel I nach den Ansprüchen 1 bis 3 und/oder von pharmazeutischen Zubereitungen nach den Ansprüchen 7 und 8 als Mittel mit antiasthmatischen, antiallergischen, entzündungshemmenden und/oder immunmoduiierenden Wirkungen allein oder in Kombination untereinander oder in Kombination mit Trägerstoffen. 10. Use of the compound of formula I according to claims 1 to 3 and / or of pharmaceutical preparations according to claims 7 and 8 as agents with antiasthmatic, antiallergic, anti-inflammatory and / or immunomodulatory effects, alone or in combination with one another or in combination with carriers.
EP99950343A 1998-05-11 1999-04-01 Novel 1,2,5-trisubstituted 1,2-dihydro-indazol-3-ones with anti-asthmatic, anti-allergic, anti-inflammatory, immuno-modulating and neuro-protective effect, method for the production and use thereof as a medicament Withdrawn EP1077948A1 (en)

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DE19821003 1998-05-11
DE19821003A DE19821003A1 (en) 1998-05-11 1998-05-11 New dihydro-indazolone derivatives useful as antiasthmatic, antiallergic and neuroprotective agents and for treatment of inflammation and immune disorders
PCT/EP1999/002291 WO1999058504A1 (en) 1998-05-11 1999-04-01 Novel 1,2,5-trisubstituted 1,2-dihydro-indazol-3-ones with anti-asthmatic, anti-allergic, anti-inflammatory, immuno-modulating and neuro-protective effect, method for the production and use thereof as a medicament

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US6417189B1 (en) * 1999-11-12 2002-07-09 Gpi Nil Holdings, Inc. AZA compounds, pharmaceutical compositions and methods of use
US7253169B2 (en) 1999-11-12 2007-08-07 Gliamed, Inc. Aza compounds, pharmaceutical compositions and methods of use
WO2008141385A1 (en) * 2007-05-21 2008-11-27 Biota Scientific Management Pty Ltd Viral polymerase inhibitors
AU2012229172B2 (en) 2011-03-14 2017-02-09 Alkahest, Inc. Benzodioxane inhibitors of leukotriene production
WO2013012844A1 (en) 2011-07-19 2013-01-24 Boehringer Ingelheim International Gmbh Arylpyrazole ethers as inhibitors of leukotriene a4 hydrolase
AR090259A1 (en) 2012-03-06 2014-10-29 Boehringer Ingelheim Int BENZODIOXAN INHIBITORS OF LEUCOTRENE PRODUCTION FOR COMBINATION THERAPY
AR091315A1 (en) 2012-03-06 2015-01-28 Boehringer Ingelheim Int BENZODIOXAN INHIBITORS OF LEUCOTRENE PRODUCTION
WO2014014874A1 (en) 2012-07-17 2014-01-23 Boehringer Ingelheim International Gmbh Pyrazole derivatives which inhibit leukotriene production
JP2016523982A (en) 2013-07-15 2016-08-12 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Inhibitors of leukotriene production
JP6353899B2 (en) 2013-07-15 2018-07-04 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Inhibitors of leukotriene production
SG11201810580PA (en) * 2016-06-08 2018-12-28 Sunregen Healthcare Ag Lipids with odd number of carbon atoms and their use as pharmaceutical composition or nutritional supplement
CN113105409B (en) * 2021-04-06 2023-06-02 四川大学 2- (hydroxybenzyl) benzo [ d ] isothiazolone compound, preparation method and application thereof
AU2022376563A1 (en) 2021-11-01 2023-12-07 Alkahest, Inc. Benzodioxane modulators of leukotriene a4 hydrolase (lta4h) for prevention and treatment of aging-associated diseases

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3132916A1 (en) * 1981-08-20 1983-03-03 Kali-Chemie Pharma Gmbh, 3000 Hannover 1-PHENYLINDAZOL-3-ON COMPOUNDS, METHODS AND INTERMEDIATE PRODUCTS FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
US5179112A (en) * 1985-04-17 1993-01-12 Ici Americas Inc. Heterocyclic amide derivatives and pharmaceutical use
IL84944A (en) * 1987-01-19 1992-02-16 Ici Plc Pharmaceutical compositions containing 1,2-dihydro-3h-indazolone derivatives,some new such compounds and their preparation
US5036083A (en) * 1988-07-15 1991-07-30 Ici Pharma Heterocyclic agents
US5229408A (en) * 1988-07-15 1993-07-20 Ici Pharma 4-carbamoyl-1,2-dihydro-3H-indazol-3-one derivatives
DE19610882A1 (en) * 1996-03-20 1997-09-25 Dresden Arzneimittel New 1,3,5-trisubstituted indazole derivatives with antiasthmatic, antiallergic, anti-inflammatory and immunomodulating effects, processes for their preparation and their use as medicines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9958504A1 *

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