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Definitions

• the invention relates to substituted 5-hydroxyindoles with N-oxide groups, processes for their preparation, pharmaceutical preparations which contain these compounds and the pharmaceutical use of these compounds which are inhibitors of phosphodiesterase 4, as active ingredients for the treatment of diseases which inhibit the Phosphodiesterase 4 activity in particular in immunocompetent cells, for example Macrophages and lymphocytes) are to be influenced by the compounds according to the invention.
• Adenylate cyclase synthesizes the effective cyclic AMP (cAMP) and cyclic GMP (cGMP) from AMP and GMP. These lead to relaxation in smooth muscle cells, for example, and inhibition of mediator release or synthesis in inflammatory cells.
• the "second messenger” cAMP and cGMP are degraded by the phosphodiesterases (PDE). So far, 11 families of PDE enzymes (PDE1-11) are known, which differ in their substrate specificity (cAMP, cGMP or both) and the dependence on other substrates (eg calmodulin).
• 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, which releases various tissue-destroying mediators.
• TNF ⁇ causes the increased production of further pro-inflammatory cytokines, such as GM-CSF (Granulocyte-macrophage colony-stimulating factor) or Interleukin-8. Due to its inflammatory and catabolic effects, TNF ⁇ plays a central role in a variety of diseases, such as inflammation of the respiratory tract, inflammation of the joints, endotoxic shock, tissue rejection, AIDS and numerous other immunological diseases. Inhibitors of phosphodiesterase 4 are therefore also suitable for the therapy of such diseases associated with TNF ⁇ . Chronic obstructive pulmonary diseases (COPD) are widespread in the population and are also of great economic importance.
• COPD chronic obstructive pulmonary diseases
• COPD diseases For example, about 10-15% of all medical expenses in developed countries and about 25% of all deaths in the United States are caused by COPD diseases (Norman, P .: COPD: New developments and therapeutic opportunities, Drug News Perspect. 11 (7), 431-437, 1998). The WHO estimates that COPD will be the third leading cause of death within the next 20 years.
• COPD chronic obstructive pulmonary diseases
• beta2 agonists e.g. salmeterol
• muscarinergic antagonists e.g. ipratropium
• neutrophilic granulocytes Regardless of the bacterial infections complicating the disease, there is a chronic inflammation in the bronchi, which is dominated by neutrophilic granulocytes.
• the mediators and enzymes released by neutrophilic granulocytes are responsible for the observed structural changes in the airways (emphysema). Inhibiting neutrophil granulocyte activity is thus a rational approach to prevent or slow the progression of COPD (deterioration in lung function parameters).
• An important stimulus for the activation of the granulocytes is the pro-inflammatory cytokine TNF ⁇ (tumor necrosis factor).
• TNF ⁇ stimulates the formation of oxygen radicals by neutrophilic granulocytes
• PDE4 inhibitors can be very effective in releasing TNF ⁇ from a variety of Inhibit cells and thus suppress the activity of the neutrophil granulocytes.
• the non-specific PDE inhibitor pentoxifylline is able to inhibit both the formation of oxygen radicals and the phagocytosis ability of neutrophil granulocytes (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 primarily xanthine derivatives, rolipram analogs or nitraquazone derivatives (overview in: Karlsson, JA, Aldos, D., Phosphodiesterase 4 inhibitors for the treatment of asthma, Exp. Opin. Ther. Patents 1997, 7: 989-1003). So far, none of these compounds has been brought to clinical use. It had to be found that the known PDE4 inhibitors also have various side effects, such as nausea and emesis, which have not been adequately suppressed so far. It is therefore necessary to discover new PDE4 inhibitors with a better therapeutic index.
• Patents US 2,825,734 and US 3,188,313 describe various indol-3-ylglyoxylic acid amides which are prepared in the manner shown in Scheme 1. These compounds were used as intermediates for the production of indole derivatives resulting from reductions. Patent US 3,642,803 also describes indol-3-ylglyoxylamides.
• 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 indol-3-ylglyoxylic acid chloride is reacted with an amine.
• the invention relates to substituted hydroxyindoles of the general formula 1,
• (i) represents -C ⁇ .- alkyl, straight-chain or branched-chain, optionally mono- or polysubstituted with -OH, -SH, -NH 2 , -NHC ⁇ -alkyl, -N (C 1.6 -alkyl) 2 , - NHC - ⁇ - aryl, -N (C 6.14 aryl) 2 ,
• Heteroatoms which are preferably N, O and S, are, wherein the C-_ 14 aryl groups and the carbocyclic and heterocyclic substituents, in turn, optionally one or more times 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.C ⁇ g alkyl, -OSO ⁇ alkyl, -COOH, - (CO C ⁇ - alkyl, -COO-C,.
• alkyl and / or -O ⁇ OJC ⁇ alkyl may be substituted and wherein the alkyl groups on the carbocyclic and heterocyclic substituents for their part may optionally be mono- or polysubstituted by -OH, -SH, -NH 2 , -F, -Cl, -Br, -I, -SO 3 H or / and
• -COOH can be substituted, or
• (ii) represents -C 2.10 alkenyl, mono- or polyunsaturated, straight-chain or branched-chain, optionally mono- or polysubstituted with -OH, -SH, -NH 2 ,
• alkyl, -COOH, - (CO C ⁇ alkyl, -O ⁇ OJC ⁇ alkyl or / and -COO-C ⁇ alkyl may be substituted, and wherein the alkyl groups on the carbocyclic and heterocyclic substituents, in turn, may optionally be substituted one or more times with -OH, -SH, -NH 2 , -F, -Cl, -Br, -I, -S0 3 H or / and -COOH,
• R 2 represents hydrogen or -C ⁇ -3 alkyl
• R 3 represents a hydroxy group
• R 4 and R 5 may be the same or different and represent hydrogen, -C ⁇ -6- alkyl, -OH, -SH, -NH 2 , -NHC ⁇ -6 -alkyl, -N (C ⁇ - 6 -alkyl) 2 ,
• Alkyl substituents in turn, optionally one or more times with -OH,
• -SH, -NH 2 , -F, -Cl, -Br, -I, -SO 3 H, -SO 3 C ⁇ -3 -alkyl, -COOH, -COOC 1-3 -alkyl, -O-C ⁇ -3 -Alkyl, -S-C ⁇ -3-alkyl or / and -0 (CO) -C ⁇ - 3 alkyl may be substituted.
• Preferred compounds of formula 1 are those in which R 1 is an optionally substituted one ad radical with a cyclic substituent is particularly preferred.
• the cyclic substituents are at least one substituent selected from halogen, ie, -F, -Cl, -Br or -I, -OH, -N0 2 is preferably C 3- 8-Cycloalkylgrupppen or C 5-6 aryl or heteroaryl groups, -CN and -CF 3 can wear.
• the invention preferably relates to those compounds in which R 2 represents hydrogen or a methyl group.
• the invention preferably relates to those compounds in which at least one of R 4 and R 5 represents a halogen atom.
• R 4 and R 5 are particularly preferably halogen atoms.
• the compounds mentioned in the experimental examples are also particularly preferred.
• the invention further relates to the physiologically tolerable salts of the compounds of the formula
• the physiologically tolerable 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
• organic acids are, for example, carboxylic 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, ethanesulfonic acid, 2-
• Hydroxyethanesulfonic acid ethane-1, 2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid or naphthalene-2-sulfonic acid.
• inorganic bases sodium hydroxide solution, potassium hydroxide solution, ammonia and organic bases are amines, but preferably tertiary amines, such as trimethylamine, triethylamine, pyridine, N, N-dimethylaniline, quinoline, isoquinoline, ⁇ -picoline, ⁇ -picoline, ⁇ -picoline , Quinaldine or pyrimidine.
• physiologically tolerable salts of the compounds of the formula 1 can be obtained by using derivatives which have tertiary amino groups in a manner known per se Quaternizing agents are converted into the corresponding quaternary ammonium salts.
• suitable quaternizing agents are alkyl halides, such as methyl iodide, ethyl bromide and n-propyl chloride, but also aryl alkyl halides, such as benzyl chloride or 2-phenylethyl bromide.
• the invention further relates to the compounds of the 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 which are generally obtained as racemates can be separated into the optically active isomers in a manner known per se, for example using an optically active acid.
• an optically active starting substance from the outset, in which case a corresponding optically active or diastereomeric compound is obtained as the end product.
• the compounds according to the invention are inhibitors of phosphodiesterase 4. It is therefore the object of this invention that the compounds of the formula 1 and their salts and pharmaceutical preparations which contain 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, and others arthritic diseases such as rheumatoid spondylitis and osteoarthritis.
• Other possible uses 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 diseases, bone resorption diseases or graft
• 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 therapy of malaria, leishmaniasis, infection-related fever, infection-related muscle pain, AIDS and cachexia, and non-allergic rhinitis.
• infections such as viral infections and parasite infections
• malaria for example for the therapy of malaria, leishmaniasis, infection-related fever, infection-related muscle pain, AIDS and cachexia, and non-allergic rhinitis.
• the compounds according to the invention can also be used for the therapy of hyperproliferative diseases, in particular cancer diseases, for example for the therapy of melanomas, breast cancer, lung cancer, colon cancer, skin cancer and leukemia.
• the compounds according to the invention can also be used as bronchodilators and for the treatment of asthma, e.g. for asthma prophylaxis.
• the compounds according to formula 1 are also 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 ones
• Respiratory diseases such as bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, eczema, allergic angiitis, inflammation mediated by eosinophils, such as eosinophilic fasciitis, eosinophilic pneumonia and PIE syndrome (pulmonary infiltration with eosinophilia), urticaria, ulcerative colitis, the Crohn's disease or psoriasis, like psoriasis, and proliferative disorders ,
• eosinophils such as eosinophilic fasciitis, eosinophilic pneumonia and PIE syndrome (pulmonary infiltration with eosinophilia), urticaria, ulcerative colitis, the Crohn's disease or psoriasis, like psoriasis, and proliferative disorders .
• the object of this invention is that the compounds of formula 1 and their salts can also inhibit LPS-induced pulmonary neutrophil infiltration in rats in vivo.
• the pharmacologically significant properties found prove that the compounds of the formula 1 and their salts and pharmaceutical preparations which contain these compounds or their salts can be used therapeutically for the treatment of chronic obstructive pulmonary diseases.
• the compounds of the invention also have neuroprotective properties and can be used to treat diseases in which neuroprotection is useful.
• diseases include senile dementia (Alzheimer 's disease), memory loss, Parkinson's disease, depression, strokes and intermittent claudication.
• prostate diseases such as, for example, benign prostate 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 also be used to inhibit the development of drug addiction with repeated use of analgesics, such as, for example, morphine, and to reduce the development of tolerance when using these analgesics repeatedly.
• analgesics such as, for example, morphine
• 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 patient, type and severity of the diseases to be treated and similar factors.
• the daily dose can 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. Daily doses of 0.1-50 mg are particularly preferably administered.
• Topical, inhalative and intranasal preparations of the compounds according to the invention are particularly preferably used.
• the usual galenical forms of preparation are used, such as tablets, dragees, capsules, dispersible powders, granules, aqueous solutions, aqueous or oily suspensions, syrups, juices or drops.
• 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 silicas, silicone oil, higher molecular fatty acids (such as Stearic acid), agar or vegetable or animal fats and oils, solid high-molecular polymers (such as polyethylene glycol); Preparations suitable for oral administration can optionally contain additional taste and / or sweeteners.
• 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 silicas, silicone oil, higher molecular fatty acids (such as Stearic acid), agar or vegetable or animal fats and oils, solid high-
• Liquid pharmaceutical forms can be sterilized and / or optionally contain auxiliaries, such as preservatives, stabilizers, wetting agents, penetrants, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols, for regulating the osmotic pressure or for buffering and / or viscosity regulators.
• auxiliaries such as preservatives, stabilizers, wetting agents, penetrants, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols, for regulating the osmotic pressure or for buffering and / or viscosity regulators.
• Such additives are e.g. 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 can be used, such as liquid polyethylene oxide, microcrystalline celluloses, carboxymethyl celluloses, polyvinylpyrrolidones, dextrans or gelatin.
• Solid carriers are e.g.
• Starch lactose, mannitol, methyl cellulose, talc, highly disperse silicas, higher molecular fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular polymers, such as polyethylene glycol.
• Oily suspensions for parenteral or topical applications can include 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, laurin, tridecyl, margarine, stearin, arachine, Myristic, behenic, pentadecyl, linoleic, elaidic, brasidic, erucic or oleic acid, which are monohydric to trihydric alcohols containing 1 to 6 carbon atoms, such as methanol, ethanol, propanol, butanol, pentanol or whose isomers, glycol or glycerol are esterified.
• 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, laurin, tridecyl, margarine, stearin, arachine, My
• Such fatty acid esters are, for example, commercially available 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 duckburzeldosoleic acid, fatty acid ethyl ester, oleic acid ethyl ester, oleic acid ethyl ester, oleic acid ethyl ester, oleic acid ethyl ester, oleic acid ethyl ester,
• silicone oils of various viscosities 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 can also be used.
• Suitable solvents, gelling agents and solubilizers are water or water-miscible solvents. Suitable are e.g. Alcohols, such as ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerol, di- or tripropylene glycol, waxes, methyl cellosolve, cellosolve, ester, morpholine, dioxane, dimethyl sulfoxide, dimethyl formrofuran, tetrahydrofuran
• Alcohols such as ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerol, di- or tripropylene glycol, waxes, methyl cellosolve, cellosolve, ester, morpholine
• Cellulose ethers which can dissolve or swell both in water and in organic solvents, such as, for example, hydroxypropylmethyl cellulose, methyl cellulose, ethyl cellulose or soluble starches, can be used as film formers.
• Ionic macromolecules are primarily used here, e.g. Sodium carboxymethyl cellulose, polyacrylic acid, polymethacrylic acid and its salts, sodium amylopectin semiglycolate, alginic acid or propylene glycol alginate as the sodium salt, gum arabic, xanthan gum, guar gum or carrageenan.
• auxiliaries that can be used are: glycerol, paraffin of different viscosities, triethanolamine, collagen, allantoin, novantisol acid.
• surfactants such as, for example, sodium lauryl sulfate, fatty alcohol ether sulfates, di-Na-N-lauryl- ⁇ -iminodipropionate, polyoxy- ethylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (e.g. Tween), cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ether, cetyltrimethylammonium chloride or mono- / dialkylpolyglycol ether orthophosphoramic acid.
• sodium lauryl sulfate such as sodium lauryl sulfate, fatty alcohol ether sulfates, di-Na-N-lauryl- ⁇ -iminodipropionate, polyoxy- ethylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorb
• Stabilizers such as montmorillonites, or colloidal silicas to stabilize emulsions or to prevent the breakdown of active substances, such as antioxidants, for example tocopherols or butylhydroxyanisole, or preservatives, such as p-hydroxybenzoic acid esters, may also be necessary for the preparation of the desired formulations.
• Preparations for parenteral administration can be in separate dosage unit forms, e.g. Ampoules or vials. Solutions of the active ingredient are preferably used, preferably aqueous solutions and above all isotonic solutions but also suspensions. These injection forms can be provided as a ready-to-use preparation or only directly before use by mixing the active compound, e.g. of the lyophilisate, optionally with other solid carriers, can be prepared with the desired solvent or suspending agent.
• Intranasal preparations can be present as aqueous or oily solutions or as aqueous or oily suspensions. They can also be in the form of lyophilisates which are prepared with the appropriate solvent or suspending agent before use.
• the preparation, filling and sealing of the preparations takes place under the usual antimicrobial and aseptic conditions.
• the invention further relates to processes for the preparation of the compounds according to the invention.
• the compounds of general formula 1 are prepared with the meanings of R 1 , R 2 , R 3 , R 4 and R 5 shown above,
• R 3 is -OR 6 and R 6 is a leaving group, for example alkyl, cycloalkyl, arylalkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, N-substituted aminocarbonyl, silyl, sulfonyl Groups and complexing agents, such as, for example, compounds of boric acid, phosphoric acid and covalently or coordinatively bound metals, such as zinc, aluminum or copper, are available in a manner known per se by treatment with an oxidizing agent, for example an organic peracid, preferably with m-chloroperbenzoic acid acid or / and peracetic acid, to the Compounds of formula 1- according to the invention in which R 3 is -OR 6 are oxidized.
• an oxidizing agent for example an organic peracid, preferably with m-chloroperbenzoic acid acid or / and peracetic acid
• the compounds of formula 1 according to the invention are released by splitting off the leaving group R 6 still contained in R 3 .
• both acids and bases such as, for example, hydrobromic acid, hydrochloric acid or hydroiodic acid or sodium hydroxide solution, potassium hydroxide solution and sodium or potassium carbonate, but also activating Lewis acids, such as, for example, AICI 3 , BF 3 , BBr 3 or LiCI used.
• the cleavage reaction takes place in the absence or in the presence of additional activators, such as ethane-1, 2-dithiol or benzyl mercaptan, and ether cleavages, by means of hydrogen, under elevated pressure or under atmospheric pressure, in the presence of a suitable catalyst, such as, for example, palladium or iridium catalysts.
• the compounds according to the invention are strong inhibitors of phosphodiesterase 4. Their therapeutic potential is demonstrated in vivo, for example by inhibiting the late phase asthmatic reaction (eosinophilia) and by inhibiting LPS-induced neutrophilia in rats.
• Example 2
• PDE4 activity is determined using enzyme preparations from human polymorphonuclear lymphocytes (PMNL). Human blood (buffy coats) was anticoagulated with citrate. The platelet-rich plasma in the supernatant is separated from the erythrocytes and leukocytes by centrifugation at 700 ⁇ g for 20 minutes at room temperature (RT). The PMNLs for PDE4 determination are isolated by a subsequent dextran sedimentation and subsequent gradient centrifugation with Ficoll-Paque.
• PMNL polymorphonuclear lymphocytes
• the still intact PMNLs are washed twice with PBS and lysed using ultrasound.
• the supernatant from a one hour centrifugation at 4 ° C at 48000 xg contains the cytosolic fraction of the PDE4 and is used for the PDE4 measurements.
• the phosphodiesterase activity is determined using a modified method from 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.
• the reaction is started by adding the substrate, 0.5 ⁇ M [ 3 H] -cAMP.
• the final volume is 100 ⁇ l.
• Test substances are prepared as stock solutions in DMSO.
• the DMSO concentration in the reaction mixture is 1% v / v. At this DMSO concentration, the PDE activity is not affected.
• the samples are incubated at 37 ° C. for 30 minutes. By adding a defined amount of SPA beads, the reaction is stopped and the samples after one hour in the Beta counter measured.
• the non-specific enzyme activity (the blank) is determined in the presence of 100 ⁇ M rolipram and subtracted from the test values.
• the incubation batches of the PDE4 assay contain 100 ⁇ M cGMP in order to inhibit any contamination by the PDE 3.
• IC 5 o values were determined in the range of 10 "9 to 10" 5 M with respect to.
• the selectivity for PDE types 3, 5 and 7 is a factor of 100 to 10,000.
• the inhibition of pulmonary eosinophil infiltration by the substances according to the invention is tested on male Brown Norway rats (200-250 g) which are actively sensitized to ovalbumin (OVA).
• OVA ovalbumin
• the sensitization is carried out by subcutaneous injections of a suspension of 10 ⁇ g OVA together with 20 mg aluminum hydroxide as adjuvant in 0.5 ml physiological saline per animal on day 1, 14 and 21.
• the animals receive Bordetella pertussis vaccine dilution pro at the same times Animal 0.25 ml ip injected.
• the animals are placed individually in open 1 liter plexiglass boxes which are connected to a head and nose exposure device.
• the animals are exposed to an aerosol from 1.0% ovalbumin suspension (allergen challenge).
• the ovalbumin aerosol is generated by a nebulizer operated with compressed air (0.2 MPa) (Bird micro nebulizer, Palm Springs CA, USA).
• the exposure time is 1 hour, whereby normal controls are also nebulized with an aerosol from 0.9% saline solution for 1 hour.
• 48 hours after the allergen challenge there is a massive immigration of eosinophilic granulocytes into the lungs of the animals.
• the animals are anesthetized with an overdose of ethyl urethane (1.5 g / kg body weight ip) and bronchoalveolar lavage (BAL) is carried out using 3 ⁇ 4 ml of Hank's balanced solution.
• BAL bronchoalveolar lavage
• the total cell number and the number of eosinophilic granulocytes in the pooled BAL fluid are then determined using an automatic cell differentiation device (Bayer Diagnostics Technicon H1E).
• 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.
• control groups are treated with the vehicle according to the application form of the test substance.
• the compounds according to the invention inhibit late-phase eosinophilia by 30% to 100% after intraperitoneal application of 10 mg / kg and by 30% to 75% after oral application of 30 mg / kg.
• 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 action of eosinophils.
• LPS lipopolysaccharide
• Plexiglass boxes set which are connected to a head-nose exposure device. The animals become an aerosol from a
• Aerosol is generated by a nebulizer operated with compressed air (0.2 MPa)
• Exposure time is 40 minutes, with normal controls using a
• Aerosol from 0.1% hydroxylamine solution in PBS should also be nebulized for 40 minutes.
• Two control groups nebulization with 0.1% hydroxylamine solution in PBS and nebulization with 100 ⁇ g LPS / ml 0.1% hydroxylamine solution in PBS) are included in each test.
• the percentage inhibition of neutrophilia in the test group treated with the substance is calculated using the following formula:
• SC Vehicel treated control group challenged with 0.1% hydroxylamine solution
• LPSC Vehicel treated control group challenged with LPS (100 ⁇ g / ml 0.1% hydroxylamine solution)
• LPSD substance-treated test group which had been challenged with LPS (100 ⁇ g / ml 0.1% hydroxylamine solution).
• test substances are administered orally as a suspension in 10% polyethylene glycol 300 and 0.5% 5-hydroxyethyl cellulose 2 hours before the LPS challenge.
• control groups are treated with the vehicle according to the application form of the test substance.
• the compounds according to the invention inhibit neutrophilia by 30% to 90% after oral administration of 10 mg / kg and are therefore particularly suitable for the production of medicaments for the treatment of diseases which are associated with the action of neutrophils.

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