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Definitions

• the invention relates to substituted 7-azaindoles, processes for their preparation, pharmaceutical compositions containing these compounds and the pharmaceutical use of these compounds, which are inhibitors of phosphodiesterase 4, as active ingredients for the treatment of diseases associated with inhibition of phosphodiesterase 4 activity in particular in immunocompetent cells (eg macrophages and lymphocytes) are to be influenced by the compounds of the invention.
• Adenylate cyclase synthesizes the active cyclic AMP (cAMP) or cyclic GMP (cGMP) from AMP and GMP. These lead eg in smooth muscle cells to relaxation or in inflammatory cells to inhibit mediator release or synthesis.
• the degradation of the second messenger cAMP and cGMP occurs through the phosphodiesterases (PDE).
• PDE1-11 11 families of PDE enzymes (PDE1-11) are known that differ in their substrate specificity (cAMP, cGMP or both) and their dependence on other substrates (eg calmodulin).
• isoenzymes have different functions in the body and are different in the individual cell types (Beavo, J, Conti, M. and Heaslip, RJ, Multiple cyclic nucleotide phosphodiesterases, Mol Pharmacol 1994, 46: 399-405; Isoenzyme selective phosphodiesterase inhibitors: Potential clinical uses, Br. J. clin Pharmacol., 1993, 35: 1-7).
• Inhibition of the various PDE isoenzyme types leads to an accumulation of cAMP or cGMP in the cells, which can be used therapeutically (Torphy, TJ, Livi, GP, Christensen, SB Novel Phosphodiesterase Inhibitors for the Therapy of Asthma, Drug News and Perspectives 1993, 6: 203-214).
• the predominant PDE isoenzyme is type 4 (Torphy, JT and Undem, BJ, Phosphodiesterase inhibitors: new opportunities for the treatment of asthma, Thorax 1991, 46 : 512-523).
• PDE 4 The inhibition of PDE 4 by suitable inhibitors is therefore considered to be an important approach to the therapy of a variety of allergic-induced diseases (Schudt, Ch., Dent, G., Rabe, K., Phosphodiesterase Inhibitors, Academic Press London 1996).
• TNF ⁇ tumor necrosis factor ⁇
• TNF ⁇ tumor necrosis factor ⁇
• activated macrophages activated T lymphocytes, mast cells, basophils, fibroblasts, endothelial cells and astrocytes in the brain. It has a self-activating effect on neutrophils, eosinophils, fibroblasts and endothelial cells, releasing various tissue-destroying mediators.
• TNF ⁇ causes the increased production of other proinflammatory cytokines, such as GM-CSF (granulocyte macrophage colony-stimulating factor) or interleukin-8. Because of its proinflammatory and catabolic effects, TNF ⁇ plays a central role in a variety of diseases such as respiratory tract inflammation, inflammation of the joints, endotoxic shock, tissue rejection, AIDS and many other immunological disorders. Thus, inhibitors of phosphodiesterase 4 are also suitable for the therapy of such diseases associated with TNF ⁇ .
• COPD chronic obstructive pulmonary diseases
• COPD chronic obstructive pulmonary disease
• the current therapy is aimed only at alleviating the symptoms without causally interfering with the progression of the disease.
• long-acting beta2-agonists eg salmeterol
• muscarinic antagonists eg ipratropium
• cytokine TNF ⁇ tumor necrosis factor
• TNF ⁇ stimulates the formation of oxygen radicals by neutrophilic granulocytes
• PDE4 inhibitors can very effectively inhibit the release of TNF ⁇ from a variety of cells and thus suppress neutrophil granulocyte activity.
• the nonspecific PDE inhibitor pentoxifylline is able to inhibit both the formation of oxygen radicals and the phagocytosis capability of neutrophils (Wenisch, C, Zedtwitz-Liebenstein, K. Parschalk, B. and Graninger, W .: Effect of pentoxifylline in vitro on neutrophil reactive oxygen production and phagocytic ability assessed by flow cytometry, Clin. Drug Invest, 13 (2): 99- 104, 1997).
• PDE 4 inhibitors are already known. These are predominantly xanthine derivatives, rolipram analogs or nitraquazone derivatives (reviewed in: Karlsson, JA, Aldos, D., Phosphodiesterase 4 inhibitors for the treatment of asthma, Exp. Opin. Ther. Patents 1997, 7: 989-1003). None of these compounds has yet been brought to clinical use. It had to be stated that the known PDE4 inhibitors also have various side effects, such as nausea and emesis, which hitherto could not be sufficiently suppressed. Therefore, the discovery of new PDE4 inhibitors with better therapeutic latitude is required.
• Farmaco 22 (1967), 229-244 describes the preparation of 5-methoxyindol-3-ylglyoxylic acid amides. Again, the indole derivative used is reacted with oxalyl chloride and the resulting indole-3-ylglyoxylklarechlorid reacted with an amine.
• 7-Azaindol-3-yl-glyoxylic acid amides are known as PDE4 inhibitors from the patent application DE 100 53 275 A1, which also describes their preparation and use as therapeutics.
• the invention relates to substituted 7-azaindoles of the general formula I and their physiologically acceptable salts, wherein A, B, R ⁇ R 2 , R 3 and R 4 are as defined in claim 1.
• the compounds of the invention preferably include those compounds of formula 1, in which
• A is an N-oxide group and B is carbon (ie, a CH group or a CR 3 group as defined below) or nitrogen.
• (i) represents --C ⁇ o-alkyl, straight-chain or branched-chain, optionally mono- or polysubstituted with -OH, -SH, -NH 2 , -NHC, _ 6 -alkyl, -N (C 1.6 -alkyl) 2 , -NHC 6 . 14 -aryl, -N (C6. 14, aryl) 2> -N (C 1. 6, alkyl) (C.
• Heteroatoms which are preferably N, O and S, wherein the C 6 . 14 -aryl groups and the carbocyclic and heterocyclic substituents in turn optionally mono- or polysubstituted with -C ⁇ alkyl, -OH, -NH 2 , -NHC ⁇ alkyl, -NfC ⁇ -Alky! ,, , NO 2 , -CN, -F, -Cl, -Br, -I, -OC ⁇ -alkyl, -S-. g -alkyl, -SO 3 H,
• -COO-C ⁇ -alkyl or / and -O COJC ⁇ -alkyl may be substituted, and wherein the alkyl groups on the carbocyclic and heterocyclic substituent in turn optionally mono- or polysubstituted with -OH, -SH, -NH 2 , -F, -Cl, -Br, -I, -SO 3 H or / and -COOH may be substituted, or
• -N (C 1. 6, alkyl) (C 6.14 -aryl)
• -NO 2> is -CN, -F, -Cl, -Br, -I, -OC ⁇ alkyl
• 5- alkyl may be substituted, and wherein the alkyl groups on the carbocyclic and heterocyclic substituent in turn optionally mono- or polysubstituted with -OH, -SH, -NH 2 , -F, -Cl, -Br, -I, -SO 3 H and / or -COOH can be substituted,
• R 2 is hydrogen or C 1-3 -alkyl
• R 3 and R 4 may be the same or different and for
• compounds of the invention preferably include those N-oxides of the formula I in which
• -C ⁇ Q alkyl is straight or branched, optionally mono- or polysubstituted by -OH, -SH, -NH 2, -NHC., _ 6 alkyl,
• _ 5 alkyl may be substituted, and wherein the alkyl groups on the carbocyclic and heterocyclic substituents in turn optionally on or may be substituted several times with -OH, -SH, -NH 2 , -F, -Cl, -Br, -I, -SO 3 H or / and -COOH, or
• -N (C 1.6 -alkyl) (C. 6 l4 aryl), -NO 2> is -CN, -F, -Cl, -Br, -I, -OC ⁇ alkyl,
• -SO ⁇ alkyl, -OSO.C ⁇ alkyl, -COOH, - (COJC ⁇ alkyl, -COO-C, _ 5 alkyl and / or -O ⁇ OJC ⁇ alkyl may be substituted, and wherein. the alkyl groups on the carbocyclic and heterocyclic substituents in turn optionally mono- or polysubstituted with -OH, -SH, -NH 2 , -F, -Cl, -Br, -I, -SO 3 H or / and
• R 2 is hydrogen or -C ⁇ 3 alkyl
• R 3 and R 4 may be the same or different and for
• the compounds according to the invention include those N-oxides of the formula 1 in which
• a and B represent an N-oxide group. These are the compounds of the formula 1c according to the invention.
• (i) represents -C -.- Q- alkyl, straight-chain or branched-chain, optionally mono- or polysubstituted with -OH, -SH, -NH 2 , -NHC, _ 6 -alkyl,
• Heteroatoms which are preferably N, O and S, wherein the C g _ 14 aryl groups and the carbocyclic and heterocyclic substituents in turn optionally mono- or polysubstituted with -C ⁇ alkyl, -OH, -NH 2 , -NHC ⁇ -Alkyl, -N (C 1.6 -alkyl) 2 , -NO 2 , -CN, -F, -Cl, -Br, -I, -OC ⁇ -alkyl, -SC ⁇ -alkyl, -SO 3 H,
• -SO. .g- alkyl, -OSO 2 C, .6- alkyl, -COOH, - (CO) C can be substituted by 1.5- alkyl, -COO-C ⁇ -alkyl or / and -0 (CO) C ⁇ -alkyl, and wherein the alkyl groups on the carbocyclic and heterocyclic substituent in turn optionally mono- or polysubstituted with -OH, -SH, -NH 2 , -F, -Cl, -Br, -I, -SO 3 H or / and
• -COOH may be substituted, or
• alkyl may be substituted, and wherein the alkyl groups on the carbocyclic and heterocyclic substituent in turn may optionally be mono- or polysubstituted by -OH, -SH, -NH 2 , -F, -Cl, -Br, -I, -SO 3 H or / and -COOH .
• R 2 is hydrogen or -C ⁇ 3 alkyl
• R 3 and R 4 may be the same or different and for
• R 1 is an optionally substituted particularly preferred is a d-radical having a cyclic substituent.
• the cyclic substituents are preferably C 3-8 -cycloalkyl groups or Cs-io-aryl or heteroaryl groups, for example phenyl or naphthyl groups, which have at least one substituent selected from halogen, ie -F, -Cl, -Br or -I, -OH , -NO 2 , -CN, -CH 3 , -OCH 3 and -CF 3 .
• R 2 is preferably H or -CH 3 .
• At least one of R 3 and R 4 is preferably halogen, ie -F, -Cl, -Br, or -I.
• R 3 and R 4 are particularly preferably halogen, for example -Cl.
• the invention relates to the physiologically acceptable salts of the compounds according to formula 1.
• the physiologically acceptable salts are obtained in a customary manner by neutralization of the bases with inorganic or organic acids or by neutralization of the acids with inorganic or organic bases.
• inorganic acids are hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid, as organic acids, for example carboxylic, sulfonic or sulfonic acids, 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, citric acid, malic acid, salicylic acid, 3-aminosalicylic acid, ascorbic acid, embonic acid, nicotinic acid, isonicotinic acid, oxalic acid, amino acids, methanesulfonic acid, ethanesul
• inorganic bases are sodium hydroxide solution, potassium hydroxide solution, ammonia and, as organic bases, amines, but preferably tertiary amines, such as trimethylamine, triethylamine, pyridine, N, N-dimethylaniline, quinoline, isoquinoline, ⁇ -picoline, ⁇ -picoline, ⁇ -picoline , Quinaldine or pyrimidine, in question.
• physiologically acceptable salts of the compounds according to formula 1 can be obtained by converting derivatives having tertiary amino groups into the corresponding quaternary ammonium salts in a manner known per se with quaternizing agents.
• quaternizing come for example Alkyl halides, such as methyl iodide, ethyl bromide and n-propyl chloride, but also arylalkyl halides, such as benzyl chloride or 2-phenylethyl bromide, in question.
• the invention relates to the compounds of formula 1 which contain an asymmetric carbon atom, the D-form, the L-form and D, L mixtures and, in the case of several asymmetric carbon atoms, the diastereomeric forms.
• Those compounds of formula 1 which contain asymmetric carbon atoms and are generally 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 the end product obtained is a corresponding optically active or diastereomeric compound.
• the compounds according to the invention are phosphodiesterase 4 inhibitors. It is therefore an object of this invention that the compounds according to formula I and their salts as well as pharmaceutical preparations containing these compounds or their salts can be used for the treatment of diseases in which an inhibition of the Phosphodiesterase 4 is useful.
• These diseases include, for example, joint inflammation including arthritis and rheumatoid arthritis as well as other arthritic diseases such as rheumatoid spondylitis and osteoarthritis. Further applications are the treatment of patients suffering from osteoporosis, sepsis, septic shock, gram negative sepsis, toxic Shock syndrome, respiratory distress syndrome, asthma or other chronic pulmonary disease, bone resorption disease or transplant rejection or other autoimmune diseases such as lupus erythematosus, multiple sclerosis, glomerulonephritis and uveitis, insulin-dependent diabetes mellitus, and chronic demyelination.
• the compounds according to the invention can also be used for the therapy of infections, such as viral infections and parasite infections, for example for the treatment of malaria, leishmaniasis, infection-related fever, infection-related muscle pain, AIDS and cachexia, as well as non-allergic rhinitis.
• infections such as viral infections and parasite infections
• malaria such as malaria, leishmaniasis, infection-related fever, infection-related muscle pain, AIDS and cachexia, as well as non-allergic rhinitis.
• the compounds according to the invention can likewise be used for the therapy of hyperproliferative disorders, in particular of cancers, for example for the therapy of melanomas, breast cancer, lung cancer, colon cancer, skin cancer and leukemia.
• the compounds of the invention may also be used as bronchodilators and for the treatment of asthma, e.g. used for asthma prophylaxis.
• the compounds according to formula 1 are further inhibitors of the accumulation of eosinophils and their activity. Accordingly, the compounds of the invention can also be used in diseases in which eosinophils play a role. These diseases include, for example, inflammatory respiratory diseases such as bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, eczema, allergic angiitis, eosinophil mediated inflammation such as eosinophilic fasciitis, eosinophilic pneumonia and PIE syndrome (pulmonary infiltration with eosinophilia), urticaria.
• inflammatory respiratory diseases such as bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, eczema, allergic angiitis, eosinophil mediated inflammation such as eosinophilic fasciitis, eosinophilic pneumonia and PIE syndrome (pulmonary infiltration with e
• the object of this invention is that the compounds according to formula 1 and their salts can also inhibit LPS-induced pulmonary neutrophil infiltration in rats in vivo.
• the pharmacologically important properties found prove that the compounds according to formula 1 and their salts as well as pharmaceutical preparations containing these compounds or their salts can be used therapeutically for the treatment of chronic obstructive pulmonary diseases.
• the compounds of the invention also possess neuroprotective properties and can be used to treat diseases in which neuroprotection is useful. Such disorders include senile dementia (Alzheimer 's disease), memory loss, Parkinson 's disease, depression, strokes and intermittent claudication.
• prostate diseases such as, for example, benign prostatic hyperplasia, pollakiuria, nocturia, and the treatment of incontinence, colic caused by urinary stones, and male and female sexual dysfunctions.
• the compounds according to the invention can likewise be used for inhibiting the development of a drug dependence with repeated use of analgesics, such as, for example, morphine, and for reducing the development of tolerance in the repeated use of these analgesics.
• analgesics such as, for example, morphine
• an effective dose of the compounds according to the invention or salts thereof is used.
• the dosage of the active ingredients may vary depending on the route of administration, age, weight of the patient, and type The severity of the diseases to be treated and similar factors vary.
• the daily dose may be given as a single dose to be administered once, or divided into 2 or more daily doses, and is usually 0.001-100 mg. Particularly preferred daily dosages of 0.1-50 mg are administered.
• the form of administration can be oral, parenteral, intravenous, transdermal, topical, inhalative and intranasal preparations. Particular preference is given to using topical, inhalative and intranasal preparations of the compounds according to the invention.
• the usual pharmaceutical preparation forms such as tablets, dragees, capsules, dispersible powders, granules, aqueous solutions, aqueous or oily suspensions, syrups, juices or drops, are used.
• Solid dosage forms may contain inert ingredients and carriers, e.g. Calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatin, guar gum, magnesium or aluminum stearate, methyl cellulose, talc, fumed silica, silicone oil, higher molecular weight fatty acids (such as stearic acid), gelatin, agar-agar or vegetable or animal Fats and oils, solid high molecular weight polymers (such as polyethylene glycol); If desired, preparations suitable for oral administration may contain additional flavorings and / or sweeteners.
• inert ingredients and carriers e.g. Calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatin, guar gum, magnesium or aluminum stearate, methyl cellulose, talc, fumed silica, silicone oil, higher molecular weight fatty acids (such as stearic acid), ge
• Liquid dosage forms may be sterilized and / or optionally contain excipients, such as preservatives, stabilizers, wetting agents, penetrating agents, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols, for controlling the osmotic pressure or for buffering and / or viscosity regulators.
• excipients such as preservatives, stabilizers, wetting agents, penetrating agents, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols, for controlling the osmotic pressure or for buffering and / or viscosity regulators.
• Such additives include tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediamine tetraacetic acid and its non-toxic salts).
• high molecular weight polymers in Question such as liquid polyethylene oxide, microcrystalline celluloses, carboxymethylcelluloses, polyvinylpyrrolidones, dextrans or gelatin.
• Solid carriers are, for example, starch, lactose, mannitol, methylcellulose, talc, highly disperse silicas, higher molecular weight fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular weight polymers such as polyethylene glycol.
• Oily suspensions for parenteral or topical applications may include vegetable synthetic or semisynthetic oils, such as, for example, fatty fatty acid esters each having 8 to 22 C atoms in the fatty acid chains, for example palmitic, lauric, tridecyl, margarine, stearic, arachin , Myristic, behenic, pentadecyl, linoleic, elaidic, brasidic, erucic or oleic acid, which are reacted 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 are esterified.
• vegetable synthetic or semisynthetic oils such as, for example, fatty fatty acid esters each having 8 to 22 C atoms in the fatty acid chains, for example palmitic, lauric, tridecyl
• Such fatty acid esters are, for example, commercial miglyols, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG 6 capric acid, caprylic / capric acid esters of saturated fatty alcohols, polyoxyethylene glycerol trioleates, ethyl oleate, waxy fatty acid esters, such as artificial duckbald gland fat, isopropyl coconut fatty acid,
• Oleic acid oleyl ester oleic acid dicylate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol fatty acid esters, and the like.
• silicone oils of different viscosity or fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or oleyl alcohol, fatty acids, such as oleic acid.
• vegetable oils such as castor oil, almond oil, olive oil, sesame oil, cottonseed oil, peanut oil or soybean oil may be used.
• Suitable solvents, gelling agents and solubilizers are water or water-miscible solvents.
• Suitable examples are alcohols, such as, for example, ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, Glycerol, di- or tripropylene glycol, waxes, methyl cellosolve, cellosolve, esters, morpholines, dioxane, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, etc.
• alcohols such as, for example, ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, Glycerol, di- or tripropylene glycol, waxes, methyl cellosolve,
• Cellulose ethers which can dissolve or swell both in water and in organic solvents, such as, for example, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose or soluble starches, can be used as film formers.
• gel and film formers are also possible.
• ionic macromolecules such as Sodium carboxymethyl cellulose, polyacrylic acid, polymethacrylic acid and its salts, sodium amylopectin monoglycolate, alginic acid or propylene glycol alginate as the sodium salt, gum arabic, xanthan gum, guar gum or carrageenan.
• formulation auxiliaries may be used: glycerol, paraffin of different viscosity, triethanolamine, collagen, allantoin, novantisolic acid.
• surfactants emulsifiers or wetting agents may also be necessary for the formulation, e.g. of Na lauryl sulfate, fatty alcohol ether sulfates, di-Na-N-lauryl-.beta.-iminodipropionate, polyoxyethylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (eg Tween), cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ethers, cetyltrimethyl ammonium chloride or mono- / Dialkyipolyglykoletherorthophosphorklare- monoethanolamine salts.
• surfactants e.g. of Na lauryl sulfate, fatty alcohol ether sulfates, di-Na-N-lauryl-.beta.-iminodipropionate, polyoxyeth
• Stabilizers such as montmorillonites, or colloidal silicas for stabilizing emulsions or preventing the degradation of active substances, such as antioxidants, for example tocopherols or butylated hydroxyanisole, or preservatives, such as p-hydroxybenzoic acid. acid esters, may also be necessary to prepare the desired formulations.
• Preparations for parenteral administration may be in separate dosage unit forms, such as e.g. Ampoules or vials are present.
• solutions of the active ingredient are used, preferably aqueous solutions and especially isotonic solutions but also suspensions.
• injection forms can be provided as a finished preparation or just before use by mixing the active compound, e.g. of the lyophilizate, optionally with further solid carriers, with the desired solvent or suspending agent.
• Intranasal preparations may be present as aqueous or oily solutions or as aqueous or oily suspensions. They may also be present as lyophilisates, which are prepared before use with the appropriate solvent or suspending agent.
• the preparation, filling and sealing of the preparations is carried out under the usual antimicrobial and aseptic conditions.
• the invention further relates to processes for the preparation of the compounds of the invention.
• the solvent mixture is distilled off in vacuo and the residue recrystallized from isopropanol.
• the solvent mixture is distilled off in vacuo and the residue is recrystallized from ethanol.
• the solvent mixture is distilled off in vacuo and the residue is recrystallized from ethanol.
• the compounds according to the invention are potent inhibitors of phosphodiesterase 4. Their therapeutic potential is demonstrated in vivo, for example, by the inhibition of the asthmatic late-phase reaction (eosinophilia) and by the inhibition of LPS-induced neutrophilia in rats.
• PDE4 activity is determined with enzyme preparations from human polymorphonuclear lymphocytes (PMNL).
• PMNL human blood (buffy coats) was anticoagulated with citrate. Centrifugation at 700 xg for 20 minutes at room temperature (RT) separates the platelet-rich plasma in the supernatant from the erythrocytes and leukocytes.
• the PMNLs for the PDE4 determination are characterized by a following dextran sedimentation and subsequent gradient centrifugation with Ficoll-Paque isolated.
• the still intact PMNLs are washed twice with PBS and lysed by ultrasound.
• the supernatant from a one-hour centrifugation at 4 ° C at 48,000 xg contains the cytosolic fraction of PDE 4 and is used for the PDE4 measurements.
• the phosphodiesterase activity is determined by a modified method of Amersham Pharmacia Biotech, a SPA (Scintillation Proximity Assay).
• the reaction mixtures contain buffer (50 mM Tris-HCl (pH 7.4), 5 mM MgCl 2 , 100 ⁇ M cGMP), the inhibitors in variable concentrations and the corresponding enzyme preparation.
• buffer 50 mM Tris-HCl (pH 7.4), 5 mM MgCl 2 , 100 ⁇ M cGMP
• the inhibitors in variable concentrations and the corresponding enzyme preparation.
• Test substances are prepared as stock solutions in DMSO.
• the DMSO DMSO
• IC 5 O values in the range from 10 -10 to 10 5 M were determined with respect to the inhibition of phosphodiesterase 4.
• the selectivity to PDE types 3, 5 and 7 is from 100 to 10,000.
• the results for the inhibition of PDE4 were summarized in the following table for selected application examples:
• OVA ovalbumin
• Sensitization is by subcutaneous injection of a suspension of 10 ⁇ g OVA together with 20 mg of aluminum hydroxide as adjuvant in 0.5 ml of physiological saline per animal on days 1, 14 and 21.
• the animals will receive Bordetella pertussis vaccine dilution at the same times Animal injected 0.25 ml ip.
• the animals are placed individually in open 1 l Plexiglas boxes connected to a head-nose exposure device.
• the animals are exposed to an aerosol of 1, 0% Ovalbuminsuspension (allergen Challenge).
• the ovalbumin aerosol is generated by a compressed air (0.2 MPa) nebulizer (Bird micro nebulizer, Palm Springs CA, USA). Exposure time is 1 hour, with normal controls aerosolized with 0.9% saline also nebulized for 1 hour. 48 hours after the allergen challenge, massive eosinophilic granulocyte migration into the lungs occurs.
• the animals are anesthetized with an overdose of ethyl urethane (1, 5 g / kg body weight ip) and a bronchoalveolar lavage (BAL) with 3 x 4 ml Hank's Balanced solution.
• BAL bronchoalveolar lavage
• the total cell number and the number of eosinophilic granulocytes of the pooled BAL fluid are then determined with an automatic cell differentiation device (Bayer Diagnostics Technicon H1E).
• control groups nebulization with saline and nebulization with OVA solution.
• the percent inhibition of eosinophilia of the substance-treated experimental group is calculated according to the following formula:
• test substances are administered intraperitoneally or orally as a suspension in 10% polyethylene glycol 300 and 0.5% 5-hydroxyethyl cellulose 2 hours before the allergen challenge.
• the control groups are treated according to the application form of the test substance with the vehicle.
• the compounds according to the invention inhibit the late phase eosinophilia after intraperitoneal administration of 10 mg / kg by 30% to 100% and after oral administration of 30 mg / kg by 30% to 80%.
• the compounds of the invention are therefore particularly suitable for the preparation of medicaments for the treatment of diseases associated with the action of eosinophils.
• Example 7 Inhibition of lipopolysaccharide (LPS) -induced lung neutrophilia in Lewis rats
• the inhibition of pulmonary neutrophil infiltration by the substances according to the invention is tested on male Lewis rats (250-350 g).
• the animals are placed individually in open 1 l Plexiglas boxes connected to a head-nose exposure device.
• the animals are exposed to an aerosol from a lipopolysaccharide suspension (100 ⁇ g LPS / ml 0.1% hydroxylamine solution) in PBS (LPS provocation).
• the LPS / hydroxylamine aerosol is generated by a nebulizer (Bird micro nebulizer, Palm Springs CA, USA) operated with compressed air (0.2 MPa). Exposure time is 40 minutes, normal controls being aerosolized with 0.1% hydroxylamine solution aerosol in PBS also for 40 minutes.
• control groups nebulization with 0.1% hydroxylamine solution in PBS and nebulization with 100 ⁇ g LPS / ml 0.1% hydroxylamine solution in PBS are carried.
• the percentage inhibition of neutrophilia of the substance-treated experimental group is calculated according to the following formula:
• SC vehicle treated and challenged with 0.1% hydroxylamine solution
• LPSC vehicle treated and challenged with LPS (100 ⁇ g / ml 0.1% hydroxylamine solution) control group
• LPSD substance-treated and challenged with LPS (100 ⁇ g / ml 0.1% hydroxylamine solution) experimental group.
• test substances are administered orally as a suspension in 10% polyethylene glycol 300 and 0.5% 5-hydroxyethyl cellulose 2 hours before the LPS provocation.
• control groups are treated according to the application form of the test substance with the vehicle.
• the compounds of the invention inhibit the neutrophilia after oral administration of 1 mg / kg by 30% to 90% and are therefore particularly suitable for the preparation of medicaments for the treatment of diseases associated with the action of neutrophils.

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