MXPA00010514A - New hydroxyindoles, their use as phosphodiesterase 4 inhibitors and method for producing same - Google Patents

Abstract

The invention relates to hydroxyindoles of formula (1), where R1 and R5 are -C1...12-alkyl, -C2... 12-alkenyl, mono-, bi- or tricyclic carbocycles, mono-, bi- or tricyclic heterocycles, carbo- or heterocyclic spirocycles, and R2 and R3 can be hydrogen or -OH, whereby at least one of the two substituents must be -OH. The invention also relates to their use as phosphodiesterase 4 inhibitors and to a method for producing them.

Description

NEW HYDROXY INDONES, THEIR USE AS INHIBITORS OF PHOSPHODIESTERASE 4 AND METHOD FOR PRODUCING THEM Description of the invention Technical Field The invention relates to substituted hydroxyindoles of the general formula 1, to methods for their production, to pharmaceutical preparations containing these compounds as well as to the pharmaceutical use of these compounds which are inhibitors of phosphodiesterase 4, as active ingredients for the treatment of diseases in which it can be influenced by an inhibition of the activity of the phosphodiesterase 4 in immunocompetent cells by the compounds according to the invention.

STATE OF THE ART The activation of cell membrane receptors, by means of transmitters, leads to the activation of the "second messenger" system. Adenyl cyclase synthesizes the active cyclic MFA (cMFA) and cyclic MFG (cGMP) from MFA and MFG. These, for example, in smooth muscle cells lead to relaxation, and in inflammatory cells to the inhibition of the release or synthesis of the mediator. The disintegration of the "second messengers" cMFA and cMFG is effected by the phosphodiesterases (PDE). Up to now, 7 families of PDE enzymes (PDE 1-7) are known, which differ by the specificity of their substrate (cMFA, cMFG or both) and the dependence of other substances (e.g., calmodulin). These isoenzymes have different functions in the body and are expressed differently in the individual cell classes (Beavo JA, Conti M and Heaslip RJ.Multiple cyclic nucleotide phosphodiesterases.Mol.Pharmacol., 1994, 46: 399-405; Hall IP. Isoenzyme selective phosphodiesterase inhibitors: potential clinical uses, Br. J. Clin. Pharmacol., 1993, 35: 1-7). By inhibiting the various types of PDE isoenzymes, an accumulation of cMFA or cMFG occurs in the cells, which can be used therapeutically (Torphy TJ, Livi GP, Christensen SB, Novel Phophodiesterase Inhibitors for the Therapy of Asthma, Drug News and Perspectives 1993, 6: 203-214). In cells important for allergic inflammation (lymphocytes, mast cells, eosinophilic granulocytes, macrophages), the prevailing PDE isoenzyme is type 4 (Torphy, JT and Undem BJ Phosphordiesterase inhibitors: new opportunities for the treatment of asthma, Thorax 1991, 46 : 512-523). The inhibition of PDE 4 by suitable inhibitors is therefore considered as an important approach for the therapy of a multitude of diseases (Schudt Ch, Dent G, Rabe K, Phosphodiesterase inhibitors, Academic Press London 1996). An important property of Phosphodiesterase 4 inhibitors is the inhibition of tumor necrosis factor (TNFa) release from inflammatory cells. TNFa is a significant pro-inflammatory cytosine that influences a multitude of biological processes. TNFa is released, for example, from activated macrophages, activated T lymphocytes, mast cells, basophils, fibroblasts, endothelial cells and astrocytes in the brain. By itself, it activates neutrophils, eosinophils, fibroblasts and endothelial cells, through which various tissue-mediating mediators are released. In monocytes, macrophages and T lymphocytes, TNFα causes the increased production of other proinflammatory cytokines such as FE-CGM (granulocyte-macrophage colony stimulation factor) or interleukin-8. By virtue of its catabolic activity and promotion of inflammation, TNFa plays a central role in a multitude of diseases, such as inflammation of the airways, inflammation of the joints, endotoxic shock, tissue rejection, AIDS and numerous other immunological diseases. Accordingly, phosphodiesterase 4 inhibitors are also suitable for the therapy of this type of diseases linked to TNFa. Chronic obstructive pulmonary diseases (COPD) are widely reported in the population and also have great economic significance. Thus, for example, COPD diseases cause approximately 10-15% of all costs for illness in developed countries and approximately 25% of all deaths in the United States. are due to this cause (Norman P .: COPD: New developments and therapeutic opportunities, Drug News Perspec. 11 (7); 431-437, 1998), although certainly patients are over 55 at the time of death (Nolte D.: Chronische Bronchitis - eine Volkskrankheit multifaktorieller Genese, Atemw.-Lungenkrkh, 20 (5), 260-267, 1994). The WHO estimates that within the next 20 years, COPD will be the third most frequent cause of death. Within the clinical picture of chronically obstructive pulmonary diseases (COPD), several chronic bronchitis symptoms are grouped with the symptoms of cough and expectoration, as well as a progressive and irreversible deterioration of pulmonary function (expiration is particularly affected). The course of the disease is in the form of outbreaks, and is often complicated by microbial infections (Rennard SI: COPD: Overview of definitions, Epidemiology, and factors influencing its development.) Chest, 113 (4) Suppl., 235S-241S, 1998). During the course of the disease pulmonary function is continuously reduced, the lung becomes increasingly emphysematous, and dyspnea becomes apparent. This disease significantly affects the quality of life of patients (panting, little resistance) and significantly curtails their life expectancy. The main risk factor, in addition to environmental factors, is smoking (Kummer F.: Asthma und COPD, Atemw, Lungenkrkh, 20 (5), 299-302, 1994) (Rennard SI: COPD: Overview of definitions, Epidemiology, and factors influencing its development, Chest, 113 (4) Suppl., 235S-241S, 1998), and therefore, men are notoriously affected more frequently than women, however, this picture will suffer a shift in the future due to the change in life habits, and the increase in the number of smokers.The current therapy only contemplates mitigating the symptoms without intervening causally in the progression of the disease.The application of beta2 agonists (eg Salmeterol), optionally in combination with muscarinérgicos antagonists (eg Ipratropium) improves lung function by bronchodilation, and is routinely applied (Norman P .: COPD: New developments and therapeutic opportunities, Drug News Perspec., 11 (7), 431-437, 1998). A very im paper In the case of COPD outbreaks, it is represented by microbial infections that must be treated with antibiotics (Wilson R.: The role of infection in COPD, Chest, 113 (4) Suppl., 242S-248S, 1998; Grossman R.F .: The value of antibiotics and the outcomes of antibiotic therapy in exacerbations of COPD. Chest, 113 (4) Suppl., 249S-255S, 1998). Until now the therapy of this disease continues to be unsatisfactory, especially in attention to the constant reduction of lung function. New approaches in therapy that attack mediators of inflammations, proteases or adhesion molecules can be very promising (Barnes P.J .: Chronic obstructive disease: new opportunities for drug development, TiPS 10 (19), 415-423, 1998).

Regardless of the microbial infections that complicate the disease, in the bronchi is a chronic inflammation dominated by neutrophil granulocytes. Of the structural changes observed in the respiratory tract (emphysema), they are responsible, among others, for the mediators and enzymes released by neutrophil granulocytes. Therefore, the inhibition of the activity of neutrophil granulocytes is a rational approach to prevent or delay an advance of COPD (deterioration of lung function parameters). An important stimulus for the activation of granulocytes is the cytosine TNFa (tumor necrosis factor) pro-inflammatory. It is known, for example, that TNFa stimulates the formation of oxygen radicals by neutrophil granulocytes (Jersmann, HPA, Rathjen, DA and Ferrante A.: Enhancement of LPS-induced neutrophil oxygen radical production by TNFa, Infection and Immunity, 4 , 1744-1747, 1998). PDE4 inhibitors can very effectively inhibit the release of TNFa from a multitude of cells, and therefore suppress the activity of neutrophil granulocytes. The nonspecific PDE inhibitor pentoxifylline is able to inhibit both the formation of oxygen radicals as well as the phagocytosis faculty of neutrophil granulocytes (Wenisch, C, Zedwitz-Liebenstein, K., Parschalk, B. and Graninger,.: 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). Various PDE inhibitors are already known. It is primarily treated with Xanthine derivatives, Rolipram analogs or Nitraquazon derivatives (Summary in: Karlsson J-A, Aldos D Phosphodiesterase 4 inhibitors for the treatment of asthma, Exp. Opin. Ther.Patents 1997, 7: 989-1003). Until now, it has not been possible to reach clinical application with any of these compounds. It was found that the known PDE 4 inhibitors also have various side effects such as nausea and emesis, which until now have not been sufficiently repressed. Therefore, the discovery of new inhibitors of PDE 4 with a better therapeutic amplitude is necessary. Although the characters have for many years played an important role in the development of new active ingredients for various indications, the hydroxyindoles, on the other hand, are totally unknown as inhibitors of PDE 4. Description of the invention The invention relates to substituted hydroxyindoles of the general formula 1, wherein R1, R5 represents Ci.C.sub.2 -C.sub.2 alkyl, straight chain or branched chain, optionally mono- or polysubstituted with -OH, -SH, NH.sub.2, -NH-alkylC? .. C6, -N- (C .. C6) 2, -NH- arylCβ-. C? 4, -N- (arylC.sub.β • C?) 2, -N- (alkylC .. Cd) - (arylC6..C? 4), -NHCOR6, -N02, -CN, -F, -Cl, -Br, -I, O- alkylCj -O-arylCß- .C14, 0 (CO) Re -S- alkylCi..C6, -S-arylC6 .. Ci4, -SOR6, -S03H, -S02R6, - OS02- alkylC? .. C6, -OS02-arylC6 .. Ci4, - (CS) R6, -COOH, - (CO) R6, mono, bi or tricyclic carbocycles saturated or mono- or polyunsaturated, with 3 ... 14 ring members , mono, bi or tricyclic saturated or mono- or polyunsaturated heterocycles, with 5 ... 15 ring members and 1 ... 6 heteroatoms, which preferably are N, O and S, with the C6..C? 4 aryl groups being and the carbocyclic and heterocyclic substituents enclosed may themselves be optionally mono- or polysubstituted with straight-chain or branched chain mono- or polyunsaturated R4, C2- or C2-alkenyl, optionally mono- or polysubstituted with -OH, -SH, -NH2 , -NH-alkylC? .. C6, -N- (Ci.C6 alkyl) 2, -NH-arylCβ-. Ci4, -N- (arylC6 .. C? 4) 2, -N- (alkyl d..C6) (arylCg..Ci4), -NHCOR6, -N02, -CN, -F, -Cl, -Br, - I, O-alkylCi..C6, -0-arylC6 .. C? , 0 (CO) R6, -S-Ci.C6 alkyl, -S-arylC6 .. C14, -SOR6, -S03H, -S02R6, -OS02-alkylC? .. C6, -OS02-arylC6 .. C14, - (CS) R6, -COOH, - (CO) R6, mono, bi or tricyclic carbocycles, saturated or mono or polyunsaturated, with 3 ... 14 ring members, mono, bi or tricyclic saturated or mono- or polyunsaturated heterocycles, with 5 ... 15 ring members and 1 ... 6 heteroatoms, which preferably are N, O and S, being that the aryl groups Cß..C? and the enclosed carbocyclic and heterocyclic substituents may in turn be optionally mono- or polysubstituted with R4, mono-, bi- or tricyclic, saturated or mono- or poly-unsaturated carbocycles, with 3 ... 14 ring members, optionally mono- or polysubstituted with -OH, -SH, NH2, -NH-C1-6alkyl, -N- (Ccy6alkyl) i, -NH-arylC6..C? 4, -N- (arylC6.C1) 2, -N- (C1-6alkyl) .. C6) - (arylCg..Ci4), -NHCOR6, -N02, -CN, -F, -Cl, -Br, -I, O-alkylCi..C6, -0-arylC6 .. C? 4, 0 (CO) R 6, -S-Ci.C6 alkyl, -S-arylC6 .. Ci4, -SOR6, -S03H, -S02R6, -OS02-alkylC? .. C6, -OS02-arylC6 .. C14, - ( CS) R6, -COOH, - (CO) R6, mono, bi or tricyclic carbocycles saturated or mono or polyunsaturated, with 3 ... 14 ring members, mono, bi or tricyclic saturated monocyclic or mono or polyunsaturated heterocycles, with 5. .. 15 ring members and 1 ... 6 heteroatoms, which preferably are N, O and S, wherein the C6..C.sub.4 aryl groups and the carbocyclic and heterocyclic substituents enclosed can in turn, they are optionally mono or polysubstituted with R 4, mono, bi or tricyclic, saturated or mono- or poly-unsaturated heterocycles, with 5 ... 15 ring members and 1 ... 6 heteroatoms, which preferably are N, 0 and S, optionally mono or polysubstituted with -OH, -SH, -NH2, -NH-Ccy..C6 alkyl, -N- (Ccy.C6 alkyl) 2, -NH-arylC6..C? 4, -N- (arylC .. C? ) 2, -N- (Ci- C6alkyl) - (arylCe- .CX4), -NHCOR6, -N02, -CN, -F, -Cl, -Br, -I, 0-alkylCi..C6, -0 -arylC6 .. Ci4, 0 (C0) R6, -S-Ci.C6 alkyl, -S-arylC6 .. Ci4, -SOR6, -S03H, -S02R6, -OS02-alkylC-L..C6, -OS02- arylC6 .. C14, - (CS) R6, -COOH, - (C0) R6, mono, bi or tricyclic carbocycles saturated or mono or polyunsaturated, with 3 ... 14 ring members, mono, bi or tricyclic saturated heterocycles or mono or polyunsaturated, with 5 ... 15 ring members and 1 ... 6 heteroatoms, which preferably are N, O and S, being that the C6..Ci4 aryl groups and the carbocyclic and heterocyclic substituents enclosed can in turn possibly mono or polysubstituted with R4, carbo or heterocyclic saturated or mono- or polyunsaturated spirocycles, with 3 ... 10 ring members, the heterocyclic systems containing 1 ... 6 heteroatoms, preferably being N, O and S, optionally mono- or polysubstituted with -OH, -SH, NH2, -NH-C1-6alkyl, -N- (C1-6alkyl) 2, -NH- arylCβ .. C14, -N- (arylC6 .. Ci4) 2, -N- (alkylC .. C6) - (arylC6.-C? 4), -NHCOR6, -N02, -CN, -F , -Cl, -Br, -I, 0- alkylCi..C6, -0-arylC6 .. Ci4, 0 (C0) R6, -S- alkylCi..C6, -S-arylC6 .. Ci4, -SOR6, -S03H, -S02R6, -OS02-C1alkyl? C6, -OS02-arylC6 .. Ci4, - (CS) R6, -COOH, - (CO) R6, mono, bi or tricyclic carbocycles saturated or mono- or polyunsaturated, with 3 ... 14 ring members, mono, bi or tricyclic saturated mono- or polyunsaturated heterocycles, with 5 ... 15 ring members and 1 ... 6 heteroatoms, which preferably are N, O and S, being the aryl C groups? ..C? 4 and the carbocyclic and heterocyclic substituents enclosed may in turn be optionally mono or polysubstituted with R4, where R1 and R5 may be the same or different; R2, R3 can be hydrogen or -OH, where at least one of the two substituents must be OH, R4 represents -H, -OH, -SH, -NH2, -NH-Ccy..C6 alkyl, -N- (Ci- ..C 2, -NH-arylC6 .. C14, -N- (arylCg .. Ci4) 2, - N- (alkylC .. C6) - (arylC6..Ci4), -NHCOR6, -N02, -CN, - COOH, - (C0) R6, [CS) R6, -F, -Cl, -Br, -I, 0-alkylC .. C6, -0-arylC6. -C? 4, 0 (CO) R, Ci.C6 alkyl, -S-arylC6 .. Ci, -SOR6, -S02R6. R ° can mean -H, -NH2, -NH-C1-6alkyl, -N- (C1-6alkyl) 2, -NH- arylC5..C? 4, -N- (arylC6.CX) 2, -N- (alkylC .. C6) - (arylC6..C? 4), O-alkylCi .. C6, -0-arylC6 .. Ci4, -S- alkylCi .. Ce, -S-arylCβ-. C? , straight-chain or branched chain alkyl, CiC..C.sub.2, C2.C2 alkenyl, mono- or polyunsaturated, straight-chain or branched chain, mono-, bi- or tricyclic, saturated or mono- or poly-unsaturated carbocycles, with 3 .. .14 ring members, mono, bi or tricyclic saturated mono- or polyunsaturated heterocycles, with 5 ... 15 ring members and 1. ..6 heteroatoms, which preferably are N, O and S. A represents either a bond or, - (CH2) m-, - (CH2) m- (CH = CH) n- (CH2) p-, - (CH0Z) m-, - (C = 0) -, - (C = S) -, - (C = NZ) -, -O-, -S-, -NZ-, since they are m, p = 0 ... 3 and n = 0..2, and Z represents -H, or -alkylCi .. Ci2, straight chain or branched chain, C2, C2, alkenyl, mono or polyunsaturated, straight-chain or branched chain, carbocycles mono, bi or tricyclic, saturated or mono or polyunsaturated, with 3 ... 14 ring members, mono, bi or tricyclic, saturated or mono or polyunsaturated heterocycles, with 5 ... 15 ring members and 1. ..6 heteroatoms, which preferably are N, O and S.

B can be either carbon or sulfur, or signify - (S = 0) -, D can be oxygen, sulfur, CH2, or N-Z, where D can only be S or CH2 if B means carbon. E can represent a bond, or represent - (CH2) m-, -O-, -S-, - (N-Z) -, where m and Z have the meaning already described above. The invention also relates to the physiologically tolerable salts of the compounds according to formula 1.

The physiologically 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. Suitable as inorganic acids, for example, hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid, such as organic acids, for example, carboxylic acids, sulfo acids or sulfonic acids such as acetic acid, tartaric acid, lactic acid, propionic acid, acid glycolic, 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. Suitable as inorganic bases, for example, sodium hydroxide, caustic potash, ammonia, as well as organic bases, the amines, but preferably preferably tertiary amines such as trimethylamine, triethylamine, pyridine, N, N-dimethylaniline, quinoline, isoquinolone. , α-picoline, β-picoline, β-picoline, quinaldine or pyrimidine. In addition, the physiologically acceptable salts of the compounds according to formula 1 can be obtained by converting derivatives containing tertiary amino groups into the quaternary ammonium salts, in a manner known per se with quaternizing agents. Suitable quaternizers are, for example, alkyl halides such as methyloduro, ethyl bromide, and n-propylchloride, but also arylalkyl halides such as benzyl chloride or 2-phenylethylbromide. The invention also relates to compounds of formula 1 which contain an asymmetric carbon atom, with the mixtures with D-form, L-form and mixtures D, L, as well as with the diastereomeric forms in the case of several asymmetric carbon atoms. Those compounds of the formula _! containing asymmetric carbon atoms and which as a rule are 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 beginning, since a corresponding optically active compound or diastereomer is obtained as a final product.

For the compounds according to the invention pharmacologically significant therapeutically usable properties were discovered. The compounds according to the invention are inhibitors of TNFa release. It is therefore object of this invention that the compounds according to formula 1 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 is useful. of TNFa. These diseases include, for example, inflammations of the joints, including arthritis and rheumatoid arthritis, as well as other arthritic diseases such as arthritic spondylitis and osteoarthritis. Other additional possibilities of application are the treatment of patients suffering from septicemia, septic shock, gram-negative septicemia, toxic shock syndrome, dyspnea syndrome, asthma or other chronic pulmonary diseases, bone resorption diseases, or rejection reactions to transplants or other autoimmune diseases, such as lupus erythematosus, multiple sclerosis, glomerulonephritis and uveitis, insulin dependent diabetes mellitus as well as chronic demyelination. The compounds according to the invention can also be applied for the therapy of infections such as infections by viruses, parasites, for example for malaria therapy, fevers caused by infection, myalgia caused by infection, AIDS and cachexia. The compounds according to the invention are inhibitors of phosphodiesterase 4. Accordingly, it is the object of the invention that the compounds according to formula 1 and their salts, as well as pharmaceutical preparations containing these compounds or their salts, they can be used for the treatment of diseases in which an inhibition of phosphodiesterase is useful. Thus, for example, the compounds according to the invention can be applied as bronchodilators and for the prophylaxis of asthma. The compounds according to formula 1 are also inhibitors of the accumulation of eosinophils and their activity. Accordingly, the compounds according to the invention can also be applied in the case of diseases in which eosinophils play a role. These diseases include, for example, inflammatory diseases of the respiratory tract such as bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, eczema, allergic angiitis, inflammations caused by eosinophils such as eosinophilic fasciitis, eosinophilic pneumonia and IPE syndrome (infiltration). pulmonary with eosinophils), urticaria, ulcerative colitis, Crohn's disease and proliferative diseases of the skin, such as psoriasis or keratosis. The object of the invention is that the compounds according to formula 1 and their salts can inhibit both the release of TNFα in human blood induced by lipopolysaccharides (LPS) in vi tro, as well as the pulmonary infiltration of neutrophils induced by LPS in mustelas and guinea pigs in vivo. All of these pharmacologically significant properties prove that the compounds according to formula 1 and their salts, as well as the pharmaceutical preparations containing these compounds or their salts, can be used therapeutically for the treatment of chronically obstructive lung diseases. The compounds according to the invention also possess neuroprotective properties, and can be used for the therapy of diseases in which neuroprotection is useful. These diseases are, for example, senile dementia (Alzheimer's disease), memory loss, Parkinson's disease, depressions, strokes, intermittent lameness. Other possibilities of application of the compounds according to the invention are the prophylaxis and therapy of diseases of the prostate, such as benign hyperplasia of the prostate, frequency, nocturia, as well as for the treatment of urinary incontinence and cramps triggered by urinary stones. Finally, the compounds according to the invention can also be used to inhibit the pathogenesis of a drug dependence in the case of the repeated application of analgesics such as, for example, morphine, as well as to reduce the development of tolerance in the case of the repeated application of these analgesics. For the production of the medicaments, in addition to the usual adjuvants, vehicles and fillers, an active dose of the compounds according to the invention or their salts is used. The dosage of the active ingredients can be varied according to the route of administration, the age, the weight of the patient, the type and severity of the diseases to be treated, and similar factors. The daily dose can be administered as a single dose to be administered once, or subdivided into 2 or more daily doses, and is usually 0.001-100 mg.

As forms of application, oral, parenteral, intravenous, transdermal, topical, inhalative and intranasal preparations are considered. The usual galenic preparation forms are administered, such as tablets, dragees, capsules, dispersible powders, granules, aqueous solutions, aqueous or oily suspensions, syrup, juices or drops. The solid forms of medicament may have adjuvants and inert carriers, such as, for example, calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatin, guar gum, magnesium or aluminum stearate, methylcellulose, talc, acids highly dispersed silicas, silicone oil, high molecular weight fatty acids (such as stearic acid), gelatins, agar-agar or fats and oils of vegetable and animal origin, solid polymers of high molecular weight (such as polyethylene glycol); preparations suitable for oral administration may contain, if desired, additional flavors and / or sweeteners. The liquid medicament forms can be sterilized and / or optionally contain adjuvants such as preservatives, stabilizers, crosslinkers, penetration aids, emulsifiers, debonding agents, dissolution promoters, salts, sugar or sugar alcohols to regulate the osmotic pressure and / or for regulation and / or viscosity regulators. Such additives are, for example, tartrate and citrate regulator, ethanol, complexing agents (such as tetraacetic acid of ethylenediamine and its non-toxic salts). To regulate the viscosity, high molecular weight polymers are suitable, such as, for example, liquid polyethylene oxide, microcrystalline celluloses, carboxymethyl celluloses, polyvinyl pyrrolidones, dextrans or gelatin. Solid carriers are, for example, starch, lactose, mannitol, methylcellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatins, agar-agar, calcium phosphate, magnesium stearate, fats. of animal and vegetable origin, solid polymers of high molecular weight, such as polyethylene glycol. Oily suspensions for parenteral or topical applications can be synthetic or semi-synthetic oils of vegetable type, such as for example liquid esters of fatty acids with respectively 8 to 22 C atoms in the fatty acid chains, for example palmitic acid, lauric acid, tridecanic acid, margaric acid, stearic acid, aracaric acid, myristic acid, behenic acid, pentadecanoic acid, linolic acid, elaidinic acid, brasidinic acid, erucic acid or oleic acid, esterified with primary to tertiary alcohols with 1 to 6 carbon atoms, such as, for example, methanol, ethanol, propanol, butanol, pentanol or its isomers, its isomers glycol and glycerin. This type of esters of fatty acids are, for example, commercial miglioles, isopropylmyristate, isopropylpalmitate, isopropyl stearate, 6-caprinic acid of PEG, ethyl esters of caprylic / capric acids of saturated fatty alcohols, polyoxyethylene glycerol trioleates, ethyl oleate, esters ethyl esters of waxy fatty acids such as synthetic fat from the tail glands of ducks, isopropyl ester of coconut fatty acid, oleic esters of oleic acids, decyl esters of oleic acids, ethyl ester of lactic acid, dibutyl phthalate, isopropyl ester of adipic acid, fatty acid esters of polyols and others. Also suitable are silicone oils of various viscosities or fatty alcohols such as isotridecylalcohol, 2-octyldodecanol, cetylstearyl alcohol or oleyl alcohol, fatty acids such as, for example, oleic acid. It is also possible to use vegetable oils such as castor oil, almond oil, olive oil, sesame oil, cottonseed oil, peanut oil or soybean oil. Suitable solvents, binders and promoters of the solution are water or miscible solvents with water. They are suitable, for example, alcohols such as ethanol or isopropyl alcohol, benzylalcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerin, di- or tri-propylene glycol, waxes, methyl Cellosolv, Cellosolv, esters, morpholines, dioxane, dimethylsulfoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, etc. As the film formers, cellulose ethers which dissolve or can be swollen can be used, both in water and in organic solvents, such as, for example, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose or soluble starches. Mixed forms between gel and film formers are also quite possible. In this case, they are primarily used as ionic macromolecules, for example sodium carboxymethylcellulose, polyacrylic acid, polymethacrylic acid and their salts, sodium amylopectin semigyllate, alginic acid or propylene glycol alginate such as sodium salt, gum arabic, xanthan gum, guar gum or carrageenan. . Additional adjuvants of the formulation can be used: glycerin, paraffin of various viscosities, triethylamine, collagen, allantoin, novantisolic acid. It may also be necessary for the formulation to use surfactants, emulsifiers or crosslinkers, such as sodium lauryl sulfate, fatty alcohol ether sulfates, Di-Na-N-lauryl-β-iminodipropionate, polyoxyethylated castor oil, or monooleate sorbitol, sorbitol monostearate, polysorbates (eg Tween), cetylalcohol, lecithin, glycerin monostearate, polyoxyethylenestearate, alkylphenol polyglycol ether, cetyltrimethylammonium chloride or monoethanolamine salts - mono / dialkyl polyglycol ether orthophosphoric acid. For the preparation of the desired formulations, stabilizers such as montmorillonite or colloidal silicic acids to stabilize emulsions, or antioxidants such as, for example, tocopherols or butylhydroxyanisole to prevent the decomposition of the active ingredients, or preservatives such as p-acid ester may also be necessary. -hydroxybenzoic Preparations for parenteral application can exist in the form of individual dosage units, such as ampoules or small vials. Preference is given to using active-substance solutions, preferably aqueous solutions, and above all isotonic solutions, but also suspensions. These injectable forms can be made available ready-to-use or can be prepared immediately before use by mixing the active compound, for example the lyophilisate, optionally with other solid carriers, with the desired solvent or suspension agent. Intranasal preparations can exist as aqueous or oily solutions or as aqueous or oily suspensions. They can also exist as lyophilisates which, prior to use, are prepared with the solvent or suitable suspension agent. The production, filling and closing of the preparations is carried out under the usual antimicrobial and aseptic conditions. The invention also relates to processes for the preparation of the compounds according to the invention. According to the invention, the compounds of the general formula 1 with the meanings of R1, R2, R3, R4, R5, A, B, D and E previously described are prepared by transforming, by cleavage of R7, the compounds according to formula 1 for which R2 or R3 or R2 and R3 mean = -O-R7, in the compounds according to the invention.

In this, R7 represents suitable substituents as a leaving group, such as, for example, alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl, acyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, substituted N-aminocarbonyl, silyl, sulfonyl groups, as well as complexing agents, such as, for example, of boric acid, phosphoric acid as well as metals covalently or coordinately bound as zinc, aluminum or copper. An especially preferred reaction for splitting R7 in the sense of the production processes according to the invention are saponifications with suitable bases, such as for example sodium hydroxide, caustic potash or sodium carbonate and potassium carbonate. These saponifications are preferably used for R7 = acyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, substituted N-aminocarbonyl, silyl, sulfonyl groups, as well as complexing agents, such as, for example, boric acid, phosphoric acid compounds and coordinatively bound metals such as zinc , aluminum or copper. An especially preferred reaction for splitting R7 in the sense of the production processes according to the invention, starting from the compounds in which R7 is an alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl group, is the cleavage of ether, for example by means of hydrobromic acid, hydrochloric acid, hydroiodic acid as well as activated Lewis acids, such as for example A1C13, BF3, BBr or LiCl, in each case in the absence or in the presence of additional activators, such as, for example, ethane-1,2-dithiol or benzyl mercaptan, as well as cleavage of ether by hydrogen, under high pressure or under normal pressure, in the presence of a suitable catalyst, such as for example palladium or iridium catalysts. According to the invention, the compounds of the general formula 1. with the previously described meanings of R 1, R 2, R 3, R 4, R 5, A, B, D and E are also prepared by converting compounds of the formula 1 into other compounds of the formula 1 through transformations of the partial structure = -t k-B, by means of known reactions. Especially preferred conversion reactions with compounds of formula 1 according to the invention are, for example, for A = - (C = 0) reductions to obtain A = - (CH-OH) - or A = -CH2- by reducing agents known per se, such as sodium borohydride or hydrogenations, which can also be carried out stereoselectively. Other preferred transformation reactions are the transformation of compounds in which D and E means oxygen, to obtain compounds in which only D means oxygen and instead E represents - (N-Z) -, where Z has the meaning already explained. EXEMPLIFICATION EMBODIMENTS Exemplary processing processes for the compounds of the formula 1 according to the invention starting from the starting substances of the type described in which R7 is an alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl group: Example 1: N - (3, 5-dichloropyridin-4-yl) -2- [l- (4-fluorobenzyl) -5-hydroxy-indol-3-yl] -2-oxo-acetamide (1) 1.4 g of N- (3 , 5-dichloropyridin-4-yl) -2- [l- (4-fluorobenzyl) -5-methoxy-indol-3-yl] -2-oxo-acetamide (3 mmol) are dissolved in 100 ml of dichloromethane. The solution is heated to reflux and mixed under stirring with a solution of 14 mmol of BBr 3 in 15 ml of dichloromethane. The reaction mixture is boiled for 3 hours at reflux. After cooling the solution is stirred vigorously for 3 hours at 20 ° C with 200 ml of an aqueous solution of sodium hydrocarbonate. By doing this, the product crystallizes. Isolate, dry at 60 ° C and recrystallize with 80 ml of ethanol. Yield: 1.1 g (80% of the theory) Melting point: 213-214 ° C. Example 2 N- (3, 5-dichloropyridin-4-yl) -2- [l- (4-fluorobenzyl) -5-hydroxy-indol-3-yl] -2-oxo-acetamide (1) 5 g (38 mmol) of aluminum chloride Anhydrous are prepared in 50 ml of ethane-1,2-dithiol. At 0 ° C a solution of 4.7 g of N- (3,5-dichloropyridin-4-yl) -2- [1- (4-fluorobenzyl) -5-methoxy-indol-3-yl] -2- is added. oxo-acetamide (10 mmol) in 50 ml of dichloromethane. The mixture is stirred for 4 hours at 0 ° C. Under stirring, 50 ml of 10% hydrochloric acid are added dropwise at 0-10 ° C. The product that crystallizes is isolated, washed with water and dried at 20 ° C. Recrystallization from ethanol (180 ml) gives a pure product. Yield: 3.1 g (67% of the theory) Melting point: 212-214 ° C Exemplary process for preparing the compounds of the formula 1 according to the invention from starting substances of the type described in which R7 is an acyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, substituted N-aminocarbonyl, silyl, sulfonyl group: Example 3 N- (3,5-dichloropyridin-4-yl) -2- [1- (4-fluorobenzyl) sodium salt -5-hydroxy-indol-3-yl] -2-oxo-acetamide (2) 5 g of N- (3,5-dichloropyridin-4-yl) -2- [5-acetoxy-l- (4-fluorobenzyl ) -indol-3-yl] -2-oxo-acetamide (10 mmol) are stirred in 50 ml of dilute sodium hydroxide for 1 hour at 40-50 ° C. The solution is neutralized with hydrochloric acid (10%) under ice-cooling and concentrated to dryness. The residue is dissolved in 80 ml of acetone. The insoluble components are separated. The clear solution is mixed with a solution of 0.4 g of NaOH in 3 ml of water and stirred for 2 hours at 20 ° C. The crystallized product is isolated, washed with acetone and dried at 60 ° C. Yield: 2.44 g (51% of the theory) Melting point: 265 ° C Exemplary process for preparing the compounds of the formula _1 according to the invention from other compounds of the formula 1_ according to the invention: Example 4 N- (3,5-dichloropyridin-4-yl) -2- [l- (4-fluorobenzyl) -5-hydroxy-indol-3-yl] -2-hydroxyacetamide (2) 1 g of N- (3 , 5-dichloropyridin-4-yl) -2- [l- (4-fluoro-benzyl) -5-hydroxy-indol-3-yl] -2-oxo-acetamide (1.2 mmol) are suspended in 75 ml of methanol . After adding a solution of 0.2 g of sodium borohydride in 3 ml of dilute sodium hydroxide, the reaction mixture is stirred for 6 hours at 20 ° C. After the solvent has been distilled off, the residue is recrystallized with water. ml of ethanol Yield: 0.5 g (50% of the theory) Melting point: 205-207 Numerous additional compounds of the formula 1 can be produced using the indicated exemplary variants of which the following are listed by way of example: The compounds according to the invention are strong inhibitors of phosphodiesterase 4 and the release of TNFa. Its therapeutic potential is tested in vivo, for example, by inhibiting the reaction of the late asthmatic phase (eosinophilia) in the guinea pig, as well as by influencing allergy-induced vascular permeability in actively sensitized Brown-Norway rats. Inhibition of phosphodiesterase PDE 4 activity is determined in enzyme preparations of polymorph nucleus human lymphocytes (PMNL), PDE activity 2, 3 and 5 with PDE of human thrombocytes. Human blood was coagulated with citrate. Centrifugation of the erythrocyte and leukocyte supernatant is separated by thrombocyte-rich plasma at 700 x g for 20 minutes at room temperature. Thrombocytes are lysed by ultrasound and placed in the PDE 3 and PDE 5 assay. To determine PDE 2 activity, the cytosolic thrombocyte fraction is purified on an anion exchange column by NaCl gradient, and the peak is obtained PDE 2 for the test. The PMNLs for the determination of PDE 4 are isolated by a subsequent sedimentation of dextran and successive gradient centrifugation with ficoll packing. After washing the cells 2 times, the erythrocytes still contained are subjected to lysis within a 6 minute interval at 4 ° C, by the addition of 10 ml of hypotonic buffer (155 mM NH4C1, 10 mM NaHCO3, 0.1 mM of EDTA, pH = 7.4). The still intact PMNLs are washed twice more with PBS and lysed by ultrasound. The supernatant of one hour centrifugation at 4 ° C at 48,000 x g contains the cytosolic fraction of PDE 4 and is applied to PDE 4 measurements. Phosphodiesterase activity is determined with some modifications according to the method described by Thompson et al. (Thompson, J., Appleman, M.M., Assay of cyclic nucleotide phosphodiesterase and resolution of multiple molecular forms of the enzyme Adv. Cycl. Nuci, Res. 1979, 10.69-92). The reaction mixtures contain 50 mM Tris-HCl (pH 7.4), 5 mM MgCl2, the inhibitors in variable concentration, the corresponding enzyme preparation as well as the other components necessary for the detection of the individual isoenzymes (see below) ). The reaction is initiated by the addition of 0.5 μM substrate of [3 H] -cAMP or [3 H] -cGMP (approximately 6000 CPM / assay). The final volume is 100 ml. The test substances are prepared as stock solutions in DMSO. The concentration of DMSO in the reaction mixture is 1% v / v. With this concentration of DMSO, PDE activity is not influenced. After the reaction is initiated by the addition of substrate, the tests are incubated for 30 minutes at 37 ° C. The reaction is cut by heating the test tubes at 110 ° C for 2 minutes. The tests remain for another 10 minutes on ice. After adding 30 μl of 5 '-nucleotidase (1 mg / ml of a snake venom suspension of Crotalus adamanteus) an incubation is carried out at 37 aC for 10 minutes. The tests are cut on ice, each case is added 400 μl of a mixture of Dowex-water-ethanol (1 + 1 + 1), mixed well and incubated again 15 minutes on ice. The reaction vessels are centrifuged for 20 minutes at 3000 x g. Aliquots of 200 μl of the supernatant are transferred directly to scintillation vessels. After adding 3 ml of scintillating compound, the tests are measured in the beta counter. For the determination of PDE activity 4, 3 and 2 is used as a substrate [3 H] -cAMP, for the determination of PDE 5 [3 H] -cGMP activity. The enzymatic activities in each case are not specific in the presence of 100 μM of rolipram in the determination of PD4 and in the presence of 100 μM of IBMX in the determination of PDE 3 and 5, and subtract from the test values. The incubation preparations of the PDE 3 assay contain 10 μM of rolipram in order to inhibit possible impurities due to PDE 4. The PDE 2 is tested by a SPA test from the company Amersham. The assay is carried out in the presence of the PDE 2 activator (5 μM cGMP). For the compounds according to the invention, IC 50 values were determined in the range of 10"9 to 10 ~ 5 M with respect to the inhibition of phosphodiesterase 4.

The selectivity with respect to the types of PDE 2, 3 and 5 is from a factor of 100 to 10000. Inhibition of the release of TNFa from nasal polyps cells The test arrangement corresponds substantially to the method described by Campbell, A.M. and Bousquet J (Anti-allergic activity of Hi-blockers, Int. Arch. Allergy Im unol. 1993, 101, 308-310). The starting material is formed by nasal polyps (OP material) of patients who have undergone surgical treatment. The tissue is washed with RPMI 1640 and then opened with protease (2.0 mg / ml), collagenase (1.5 mg / ml), hyaluronidase (0.75 mg / ml) and DNAse (0.05 mg / ml) for 2 hours at 37 ° C. (1 g of tissue per 4 ml of RPMI 1640 with enzymes). The cells obtained, a mixture of epithelial cells, monocytes, macrophages, lymphocytes, fibroblasts and granulocytes are filtered and washed by repeated centrifugation in a culture solution, passively sensitized by the addition of human IgE and the cell suspension is adjusted to a concentration of 2 Mio cells / ml in RPMI 1640 (supplemented with antibiotics, 10% fetal calf serum, 2 mM glutamine and 25 mM hepes). This suspension is distributed over 6-well cell culture plates (1 ml / well). The cells are preincubated for 30 minutes with the test substances at various final concentrations and then stimulated to release TNFa by the addition of anti-IgE (7.2 μg / ml). The maximum release to the culture medium occurs after approximately 18 hours. In this time interval the cells are incubated at 37 ° C and 5% C02. The culture medium (supernatant) is obtained by centrifugation (5 min 4000 rpm) and stored at -70 ° C until the determination of the cytosine. The determination of TNFa in the supernatant is carried out with what is known as ELISA sandwiches (basic material of the Pharmingen company) with which cytosine concentrations in the range of 30-1000 pg / ml can be checked. Cells not stimulated with anti-IgE barely produce TNFa, the stimulated cells secrete large amounts of TNFα, which can be reduced, for example, by PDE 4 inhibitors as a function of dose. Percent inhibition (release of TNFα from cells stimulated with anti-IgE = 100%) of the tested substances at various concentrations, the IC 50 (concentration at 50% inhibition) is calculated. For the compounds according to the invention, IC50 values were determined in the range of 10 ~ 7 to 10 ~ 5 M. Inhibition of late phase eosinophilia 24 h after inhalation challenge with ovalbumin in actively sensitized guinea pigs Inhibition of the Pulmonary infiltration of the eosinophils by the substances is checked in an in vivo assay in Dunkin-Hartley male guinea-pigs (200-250 g) actively sensitized against ovalbumin (OVA). Sensitization is carried out by two intraperitoneal injections of a suspension of 20 μg of OVA in addition to 20 mg of aluminum hydroxide as an adjuvant in 0.5 ml of physiological saline solution per animal in two successive days. 14 days after the second injection, the animals undergo pre-treatment with mepyramine maleate (10 mg / kg i.p.) to protect against anaphylactic death. 30 minutes later the animals are exposed for 30 seconds in a plastic box to an OVA spray (0.5 mg / ml). , which is produced by an atomizer operated by compressed air (19.6 kPa) (allergenic provocation). The control animals were atomized with a physiological saline solution. 24 hours after the challenge the animals are anesthetized with an overdose of ethyl urethane (1.5 g / kg body weight i.p.) and a bronchoalveolar lavage (BAL) is carried out with 2 x 5 ml of physiological saline. BAL fluid meets, it is centrifuged at 300 rpm for 10 minutes and then the cell pellet is resuspended in 1 ml of physiological saline. Eosinophils in the BAL are equipped with an automatic cell differentiation device (Bayer Diagnostics Technicon Hl). Each test is accompanied by 2 control groups (atomization with physiological saline and atomization with OVA solution). Percent inhibition of the eosinophils of the test group treated with substance is calculated according to the following formula: 100 • (B-C)% inhibition = 100 - (A-C) A = essinophils in the control group with provocation by OVA and vehicle B = eosinophils in the group elicited with OVA treated with substance C = eosinophils in the control group elicited with 0.9% OVA and vehicle The test substances are applied intraperitoneally or orally as suspension in 10% polyethylene glycol 300 and 5 -hydroxyethylcellulose 0.5% two hours before the allergenic provocation. The control groups are treated with the vehicle in a manner analogous to the manner of application of the test substance. The compounds according to the invention inhibit late phase eosinophilia after intraperitoneal application of 10 mg / kg in 30% to 80%, and after oral application of 30 mg / kg in 40% to 70%. Accordingly, the compounds according to the invention are particularly suitable for the preparation of medicaments for the treatment of diseases related to the activity of eosinophils. Influence of allergenically induced vascular permeability in actively sensitized Brown-Norway rats Brown-Norway male rats weighing 280-300 g are actively sensitized 2 consecutive days by intraperitoneal injection of a suspension of 1 mg of ovalbumin in addition to 100 mg of hydroxide of aluminum of 1 ml / animal. Three weeks after sensitization rats are anesthetized with sodium thiopental and fixed in the supine position. For the perfusion of the nostril a polyethylene catheter is inserted retrogradely into the trachea into the interior opening of the choanae, so that the solution could drip through the nostrils. A short tracheal catheter was ligated orthogonally to the trachea to allow breathing. For perfusion, a phosphate-regulated saline solution (PBS) was pumped continuously through the nostril with a roller pump (0.5 ml / min) and collected by a fraction collector. Evans blue was used as the plasma marker and injected intravenously (respectively 1 ml / animal of a 1% solution in PBS) by means of a jugular vein catheter. The application of the substance was topical. In this application the test substance was added to the perfusion agent (PBS). The nasal mucosa was sprayed for 30 minutes with a solution containing the PDE 4 inhibitor. Then Evans blue was injected immediately before the start of perfusion with the solution containing ovalbumin (challenge). After initiation of challenge with ovalbumin (10 mg / ml ovalbumin dissolved in PBS) fractions were collected every 15 minutes in the fraction collector over a 60 minute time interval. The concentration of Evans blue in the perfusions was measured with the Digiscan photometer at a wavelength of 620 nm. In this the blank values were automatically subtracted. The course of the activity over 60 minutes was calculated with an AUC program. The activity of the group substance of the preparations was calculated in percent against vehicle controls. For the compounds according to the invention, IC 50 values were determined in the range of 10 ~ 8 to 10 ~ 5. The ability of the compounds of formula 1 according to the invention to be used in the therapy of chronically obstructive lung diseases is confirmed by the inhibition of the release of TNFα induced by LPS in human blood as well as by the inhibition of infiltration neutrophil lung function induced by LPS in mustelas and guinea pigs. The stimulation of isolated leukocytes for the release of cytosine can be carried out in various ways. Adequate stimulus for the investigation of TNFa release are lipopolysaccharides (LPS). LPS is a component of the walls of microbial cells and is released by destroying bacteria (antibiotics or immune system). LPS particularly stimulates the activity of phagocytosis leukocytes (tissue macrophages, granulocytes, monocytes) and causes the migration of leukocytes from the bloodstream to affected tissues. An important cytosine for these mechanisms is TNFa, which is secreted in large quantities by the affected cells (the main source is monocytes and macrophages) and together with other mediators initiates and maintains inflammation. Release of TNFα induced by LPS in human blood diluted 1: 5 For the investigation on the influence on the release of TNFα, blood was collected from various donors (inhibition of coagulation by citrate) and diluted 1: 5 with cell culture medium RPMI 1640. The test substances were added to the tests in various concentrations before the provocation by LPS. The stimulation of the leukocytes was carried out 30 minutes later with lipopolysaccharide (LPS) of Salmonella abo rtus equi in a final concentration of 10 μg / ml. After incubation of the test preparations for 24 hours at 37 ° C and 5% C02 in the incubator, the diluted blood was centrifuged, and in the cell-free supernatant the concentration of TNFa was measured by ELISA. For the compounds according to the invention, IC 50 values were determined in the range of 10 ~ 7 to 10 ~ 5 M. For the compound according to the embodiment 1, for example, an IC 5 value of 0.8 μmol / 1 was determined. . In comparison, for the reference substance SB 207499 an IC 50 value of 7.0 μmol / 1 was determined. Inhibition of neutrophils induced by lipopolysaccharide (LPS) in mustelas The inhibition of pulmonary infiltration of neutrophils by substances is investigated in an in vivo test in male mustelas (0.6-2 kg). The animals are anesthetized with pentobarbital-sodium (40 mg / kg body weight ip), individually placed in an atomizer box with a volume of 5 1 and exposed for 10 minutes to an aerosol sprayed by ultrasound of an LPS solution (lipopolysaccharide). at 0.01% (added with 0.1% hydroxylamine in PBS) the aerosol is produced by an atomizer operated with compressed air (0.2 Mpa). The control animals are treated with an aerosol of physiological saline solution. The animals are kept under observation throughout the process, and are removed from the atomization box after having fed fresh air. When aspirated, atomized LPS immediately triggers inflammation of the airways, which is characterized by a massive immigration of neutrophil granulocytes to the lungs of the test animals. Neutrophilia reaches its maximum 4 to 6 hours after exposure to LPS. In order to measure the amount of the immigrated neutrophil granulocytes, 6 hours after the LPS challenge the animals are anesthetized with an excess of ethyl urethane (1.5 g / kg of body weight ip) and a bronchoalveolar lavage (lung lavage) is carried out. , BAL) with 2 x 10 ml of physiological saline. The quantity of the cells in the liquid of the assembled original BAL (100 μl) is determined with the automatic Technicon H1E cell counter device (Bayer Diagnostics Company), and the various leukocytes are differentiated per μl. Each trial is accompanied by 2 control groups (atomization with physiological saline solution or with LPS solution). Substances with anti-inflammatory activity, in particular those that influence the release of TNFα or the function of neutrophil granulocytes, inhibit the migration of leukocytes. The inhibition of immigration is determined by comparing the number of neutrophils immigrated in animals without treatment (with and without provocation by LPS). For the compounds according to the invention, DI5o values were determined in the range from 1 to 20 mg / kg ip The compound according to embodiment 1, for example, was applied in doses 1, 3 and 10 mg / kg ip 2 hours before the LPS challenge in up to 3 test animals per dose. Neutrophilia in BAL was inhibited as a function of dose (18%, 64% and 78%). The DI = 0 is 2.4 mg / kg i.p. The application of the selective inhibitor RPR-73401 (reference substance) of PDE 4 caused an inhibition of neutrophilia of 49% at the dose of 1 mg / kg i.p. For intrapulmonary application to drugged animals (40 mg / kg i.p. of pentobarbital-sodis, at 3%, 1.3 ml / kg) the trachea is opened, a 7 cm long PVC catheter is ligated, and the test substances are applied by intrpulmonary injection 2 hours before the challenge with LPS in powder form (mixed with lactose up to 20 mg / kg). The intrapulmonary administration of the compound according to embodiment 1 in the doses of 1, 3 and 10 mg / kg inhibits the neutrophilia induced by LPS as a function of dose [43%, 65% and 100%). The DI50 is 1.65 mg / kg i.pulm. v LPS-induced neutrophilia in the domestic pig A pulmonary neutrophilia can be triggered in the domestic piglet in a similar way as in the mustela. The animals are anesthetized (pentobarbital 10 mg / kg i.v.) and intubated. With a bronchoscope a partial bronchoalveolar lavage is performed to detect the proportion of neutrophil granulocytes under physiological conditions. The test substance is then applied, and through the tracheal tube the animals breathe ultrasound-atomized aerosol of 0.03% LPS (lipopolysaccharide) solution (with the addition of 0.1% hydroxylamine in PBS) for 20 minutes. Inhaled LPS triggers reactive inflammation of the airways, and neutrophil granulocytes migrate in bulk. Neutrophilia reaches its maximum 4 to 6 hours after exposure to LPS. After 6 hours the bronchoalveolar lavage is repeated, and the increase in the number of neutrophils is determined arithmetically. The pig as a type of animal is particularly suitable for these investigations, since there are great anatomical and physiological similarities with the human being. For the compounds according to the invention, inhibitions of LPS-induced neutrophilia were determined from 20% to 65% with intrapulmonary administration of 10 mg / animal. The intrapulmonary administration of the compound according to embodiment 1 in the dosage of 10 mg / animal (approximately 0.75 mg / kg) inhibited LPS-induced pulmonary neutrophilia in 51%.

Claims (14)

2. Hydroxyindoles of the formula 1 wherein R1, R5 represents Ci.sub.2 Ci.sub.2 alkyl, straight chain or branched chain, optionally mono- or polysubstituted with -OH, -SH, NH.sub.2, -NH- Ccy.C.sub.6 alkyl, -N- (Ccy.C.sub.6 alkyl) 2 , -NH- arylCβ .. C14, -N- (arylCg - .C? 4) 2, -N- (alkylC .. Cg) - (arylCg..C? 4), -NHCOR6, -N02, -CN, -F, -Cl, -Br, -I, O- alkylCi. -C6, -O-arylCg .. Ci4, 0 (CO) R6, -S- alkylCi. -C6, -S-arylCg .. Ci4, -SOR6, -S03H, -S02R6, -OS02-alkylC? .. C6, -OS02-arylC6 .. Ci4, - (CS) R6, -COOH, - (CO) R6, mono, bi or tricyclic carbocycles saturated or mono or polyunsaturated, with 3 ... 14 ring members, mono, bi or tricyclic saturated mono or polyunsaturated heterocycles, with 5 ... 15 ring members and 1 ... 6 heteroatoms, which are preferably N, O and S, whereby the C6..C.sub.4 aryl groups and the carbocyclic and heterocyclic substituents enclosed can in turn be optionally mono or polysubstituted with R4, C2 alkenyl. -C? 2, mono or polyunsaturated, straight chain or branched chain, optionally mono or polysubstituted with -OH, -SH, -NH2, -NH-alkylC? .. C6, -N- (Ccy..C6 alkyl) 2, -NH-arylCg .. C? 4, -N- (arylCg .. Ci4) 2, -N- (alkylCi ..Cg) (arylCg..Ci4 ), -NHCOR6, -N02, -CN, -F, -Cl, -Br, -I, O-alkylCi..C6, -O-arylCg .. Ci4, 0 (CO) R6, -S-cycloC .. C6, -S-arylC6 .. Ci4 / -SOR6, -S03H, -S02R6, -OS02-alkylC? .. Cg, -OS02-arylC6 .. u, - (CS) R6, -COOH, - (CO) R6 , mono, bi or tricyclic carbocycles, saturated or mono or polyunsaturated, with 3 ... 14 ring members, mono, bi or tricyclic saturated, or mono or polyunsaturated heterocycles, with 5 ... 15 ring members and 1 .. .6 heteroatoms, which are preferably N, O and S, where the C6..C14 aryl groups and the carbocyclic and heterocyclic substituents enclosed may in turn be optionally mono or polysubstituted with R4, mono, bi or tricyclic carbocycles, saturated or mono- or polyunsaturated, with 3 ... 14 ring members, optionally mono- or polysubstituted with -OH, -SH, NH2, -NH-Ccy..C6 alkyl, -N- (Ccy- • C6 alkyl) z, -NH-arylCg .. CX4, -N- (arylCg .. Ci4 ) 2, -N- (alkylC .. Cg) - (arylCg..Ci4), -NHCOR6, -N02, -CN, -F, -Cl, -Br, -I, 0-alkylCi..Cg, -O -arylCg .. Ci, 0 (CO) R6, -S-Ci.C6 alkyl, -S-arylC6 .. Ci4, -SOR6, -S03H, -S02R6, -OS02-alkylC? .. Cg, -OS02-arylC6 .. Ci4, - (CS) R6, -COOH, - (CO) R6, mono, bi or tricyclic saturated or mono- or poly-unsaturated carbocycles, with 3 ... 14 ring members, mono, bi or tricyclic saturated or mono monocyclics or polyunsaturated, with 5 ... 15 ring members and 1 ... 6 heteroatoms, which preferably are N, 0 and S, being that the Cg..C? 4 aryl groups and the carbocyclic and heterocyclic substituents enclosed can possibly mono or polysubstituted with R 4, mono, bi or tricyclic, saturated or mono- or poly-unsaturated heterocycles, with 5 ... 15 ring members and 1 ... 6 heteroatoms, preferably N, O and S, optionally mono or polysubstituted with -OH, -SH, NH2, -NH-Ci.C6 alkyl / -N- (Ci.C6 alkyl) 2, -NH-arylC6. -C? 4, -N- (arylC6 .. Ci4) 2, -N- (alkylC .. Cg) - (arylCg..C14), -NHCOR6, -N02, -CN, -F, -Cl, -Br , -I, 0-alkylCi..C6, -O-arylCg .. Ci4, 0 (C0) R6, -S-alkylCi..C6, -S-arylC6..C14, -SOR6, -S03H, -S02R6, -0S02-C1alkyl? .. Cg, -OS02-arylC6 .. Ci4, - (CS) R6, -COOH, - (CO) R, mono, bi or tricyclic carbocycles saturated or mono- or polyunsaturated, with 3 ... 14 ring members, mono, bi or tricyclic saturated or mono- or polyunsaturated heterocycles, with 5 ... 15 ring members and 1 ... 6 heteroatoms, which preferably are N, O and S, being the C .. aryl groups C? 4 and the carbocyclic and heterocyclic substituents enclosed may themselves be optionally mono- or polysubstituted with R4, carbo or heterocyclic saturated or mono- or poly-unsaturated spirocycles, with 3 ... 10 ring members, the heterocyclic systems containing 1. ..6 heteroatoms, which preferably are N, O and S, optionally mono or polysubstituted with -OH, -SH, -NH2, -NH-C1-6alkyl, -N- (C1-C6alkyl) 2, -NH-arylC6..C14, -N- (arylCg.Ci4) 2, -N- (C1-6alkyl) .. Cg) - (arylCg..C? 4), -NHCOR6, -N02, -CN, -F, -Cl, -Br, -I, 0-alkylCi..C6, -O-arylCg .. Ci4, 0 (CO) R6, -S-Ci-Ci-alkyl, -S-arylC6 .. Ci, -SOR6, -S03H, -S02R6, -OS02-alkylC? .. C6, -OS02-arylC6 .. Ci4, - ( CS) R6, -COOH, - (CO) R6, mono, bi or tricyclic carbocycles saturated or mono or polyunsaturated, with 3 ... 14 ring members, mono, bi or tricyclic saturated or mono- or polyunsaturated heterocycles, with 5. .. 15 ring members and 1 ... 6 heteroatoms, which preferably are N, O and S, whereby the C6..C.sub.4 aryl groups and the carbocyclic and heterocyclic substituents enclosed may in turn be optionally mono- or polysubstituted with R4, where R1 and R5 can be the same or different; R2, R3 can be hydrogen or -OH, where at least one of the two substituents must be OH, R4 represents -H, -OH, -SH, ~ NH2, -NH-alkylC? .. C6, -N- (C1-Cg alkyl) 2, -NH-arylCg .. Ci4, -N- (arylCg .. Ci4) 2, - N- (alkylCi ..Cg) - (arylCg..Ci4) , -NHCOR6, -N02, -CN, -COOH, - (CO) R6, - (CS) R6, -F, -Cl, -Br, -I, 0- Ccy..C6 alkyl, -O-arylC .. Ci, 0 (CO) R6, -S- Ccy..Cg alkyl, -S-arylCg .. Ci4, -SOR6, -S02R6. R6 can mean -H, -NH2, -NH-C1-6alkyl, -N- (C1-Cg-alkyl) 2, -NH-arylCg..C? 4, -N- (arylCg.Ci4) 2, - N- (C1-C6alkyl) - (arylC6 .. Ci4), 0 -alkylC? .. C6, -0-arylC6 .. C? 4, -S- alkylCi..Cg, -S-arylCg .. C? 4, -Ci .. C 2 alkyl, straight chain or branched chain, C 2 alkenyl C 2, mono or polyunsaturated, straight chain or branched chain, mono, bi or tricyclic carbocycles, saturated or mono or polyunsaturated, with 3 ... 14 ring members, mono, bi or tricyclic saturated or mono- or polyunsaturated heterocycles, with 5 ... 15 ring members and 1 ... 6 heteroatoms, which preferably are N, O and S. A represents or either a bond or, - (CH2) m-, - (CH2) m- (CH = CH) n- (CH2) p-, - (CH0Z) m-, - (C = 0) -, - (C = S) -, - (C = NZ) -, -0-, -S-, -NZ-, being that they are m, p = 0 ... 3 and n = 0..2, and Z represents -H, or straight or branched chain alkyl, Ci.C.sub.2, C2.sub.2.C.sub.2 alkenyl, mono- or polyunsaturated, straight-chain or branched chain, carbocycles mono, bi or tricyclic, saturated or mono or polyunsaturated, with 3 ... 14 ring members, mono, bi or tricyclic, saturated or mono or polyunsaturated heterocycles, with 5 ... 15 ring members and 1 ... 6 heteroatoms, which preferably they are N, 0 and S.
3. B can be either carbon or sulfur, or signify - (S = 0) -, D can be oxygen, sulfur, CH2, or N-Z, where D can only be S or CH2 if B means carbon. E can represent a bond, or represent - (CH2) m-, -O-, -S-, - (N-Z) -, where m and Z have the meaning already described above. 2. Physiologically acceptable salts of the compounds according to formula 1 according to claim 1, characterized by the neutralization of the bases with inorganic or organic acids, either by neutralization of the acids with inorganic or organic bases, or by quaternization of the tertiary amines to obtain quaternary ammonium salts. 3. Compounds according to formula 1 according to claim 1 and 2, with an asymmetric carbon atom in the D form, the L-form and D, L mixtures, as well as the diastereomeric forms in the case of several asymmetric carbon atoms.
4. 4. Of the compounds according to formula 1. according to claim 1 to 3, in particular one of the following compounds: N- (3,5-dichloropyridin-4-yl) -2- [1- (4-fluorobenzyl) - 5-hydroxy-indol-3-yl] -2-oxo-acetamide; Sodium salt of N- (3,5-dichloropyridin-4-yl) -2- [l- (4-fluorobenzyl) -5-hydroxy-indol-3-yl] -2-oxo-acetamide; N- (3,5-dichloropyridin-4-yl) -2- [l- (4-fluorobenzyl) -5-hydroxy? -indol-3-yl] -2-hydroxy-acetamide; N- (pyridin-4-yl) -2- [1- (2,6-difluorbenzyl) -5-hydroxy-indol-3-yl] -2-oxo-acetamide; N- (3,5-dichloropyridin-4-yl) -2- [1- (2,6-difluorbenzyl) -5-hydroxy-indol-3-yl] -2-oxo-acetamide; Sodium salt of N- (3,5-dichloropyridin-4-yl) -2- [l- (3-nitro-benzyl) -5-hydroxy-indol-3-yl] -2-oxo-acetamide; N- (3,5-dichloropyridin-4-yl) -2- (1-propyl-5-hydroxy-indol-3-yl) -2-oxo-acetamide; N- (3,5-dichloropyridin-4-yl) -2- (l-isopropyl-5-hydroxy-indol-3-yl) -2-oxo-acetamide; N- (3,5-dichloropyridin-4-yl) -2- (1-cyclopentylmethyl-5-hydroxy-indol-3-yl) -2-oxo-acetamide; N- (2,6-dichlorophenyl) -2- [l- (4-fluorobenzyl) -5-hydroxy-indol-3-yl] -2-oxo-acetamide; N- (2,6-dichloro-4-trifluoromethyl-phenyl) -2- [1- (4-fluorobenzyl) -5-hydroxy-indol-3-yl] -2-oxo-acetamide; N- (2,6-dichloro-4-trifluoromethoxy-phenyl) -2- [1- (4-fluoro-benzyl) -5-hydroxy-indol-3-yl] -2-oxo-ace-amide; N- (3,5-dichloropyridin-4-yl) -2- [1- (4-fluorobenzyl) -6-hydroxy-indol-3-yl] -2-oxo-acetamide; N- (3,5-dichloropyridin-4-yl) -5-hydroxy-1- (4-methoxybenzyl) -indol-3-carboxylic acid amide.
5. 5. Process for the preparation of compounds according to formula 1 according to claim 1 to 4, characterized in that the compounds according to formula 1 ^ for which R2 or R3 or R2 and R3 mean = -0-R7, are transformed in the compounds according to the invention by cleavage of R7, whereby R7 represents suitable substituents as a missing group.
6. 6. Preparation of compounds according to formula 1 according to the process according to claim 5, most preferably starting from compounds of formula 1 for which R7 signifies alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl, acyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, N-substituted aminocarbonyl, silyl, sulfonyl, as well as complexing agents, such as, for example, boric acid compounds, phosphoric acid as well as covalently bound or coordinated metals such as zinc, aluminum or copper. 7. Method for the preparation of compounds according to formula 1 according to claims 1 to 4, characterized in that compounds of the formula 1 are transformed into other compounds of the formula 1 by means of partial structure transformations
7. ^ R 'r /
8. 8. Use of the compounds according to formula 1 according to claims 1 to 4, as therapeutic active ingredients for the preparation of medicaments for the treatment of diseases in which the inhibition of TNFa is of therapeutic utility.
9. 9. Use of the compounds according to formula 1 according to claims 1 to 4, as therapeutic active ingredients for the preparation of medicaments for the treatment of diseases in which the inhibition of phosphodiesterase 4 is of therapeutic utility.
10. 10. Particularly preferred use of the compounds according to formula 1 according to claims 1 to 4, as therapeutic active ingredients for the preparation of medicaments for the treatment of diseases related to the activity of eosinophils.
11. 11. - Particularly preferred use of the compounds according to formula 1 according to claims 1 to 4, as therapeutic active ingredients for the preparation of medicaments for the treatment of chronically obstructive pulmonary diseases.
12. 12. Medicament containing one or more of the compounds according to claims 1 to 4 in addition to the usual, physiologically acceptable vehicles and / or diluents or adjuvants.
13. 13. Method for the preparation of a medicament according to claim 12, characterized in that one or more compounds according to claims 1 to 4 are made to obtain pharmaceutical preparations or are carried to a therapeutically applicable form with the carriers and / or diluents and other pharmaceutically customary adjuvants.
14. 14. Use of the compounds according to formula 1 according to claims 1 to 4 and / or of the pharmaceutical preparations according to claims 11 and 13, alone or in combination with each other or in combination with vehicles and / or diluents and other adjuvants .