DE19818964A1 - New hydroxy-indole derivatives useful in treatment of degenerative joint disease, viral and parasitic infections, bronchial, dermatological, neurodegenerative and prostate disorders, etc. - Google Patents

Abstract

Hydroxyindole derivatives (I) are new. 5- or 6-Hydroxyindole derivatives (I), including optical isomers, racemates and diastereomers, and their addition and base salts are new: A = bond; -(CH2)m-; -(CH2)m-(CH=CH)n-(CH2)p-; -(CHOZ)m-; -C(O)-; -C(S)-; -C(=N-Z)-; -O-; -S-; or -N(Z)-; m and p = 0-3; n = 0-2; Z = H; alkyl; alkenyl; or a heterocycle or carbocycle (each mono-, bi- or tricyclic and saturated or mono- or poly-unsaturated); B = C; S; or S(O); D = O or N-Z or, when B = C, also S or CH2; E = bond; -(CH2)m-; -O-; -S-; or -N(Z)-; R<1> and R<5> = alkyl, alkenyl, a heterocycle, carbocycle or carbocyclic or heterocyclic spirocycle (each optionally mono- or poly-substituted with Q); Q = OH; SH; NH2; NH(alkyl); N(alkyl)2; NH(aryl); N(aryl)2; N(alkyl)(aryl); NHCOR<6>; NO2; CN; F; Cl; Br; I; alkoxy; aryloxy; OC(O)R<6>; alkylthio; arylthio; SOR<6>; SO3H; SO2R<6>; alkyl-SO2O; aryl-SO2O; C(S)R<6>; COOH; C(O)R<6>; or a heterocycle or carbocycle (aryl, heterocycle and carbocycle are optionally mono- or poly-substituted with R<4>); R<2> and R<3> = H or OH, but at least one is OH; R<4> = H; OH; SH; NH2; NH(alkyl) N(alkyl)2; NH(aryl); N(aryl)2; N(alkyl)(aryl); NHCOR<6>; NO2; CN; COOH; C(O)R<6>; C(S)R<6>; F: Cl; Br; I; alkoxy; aryloxy; OC(O)R<6>; alkylthio; arylthio; SOR<6>; or SO2R<6>; R<6> = H; NH2; NH(alkyl); N(alkyl)2; NH(aryl); N(aryl)2; N(alkyl)(aryl); alkoxy; aryloxy; alkylthio; arylthio; arylthio-alkyl; alkenyl; or a heterocycle or carbocycle. The full definitions are given in the DEFINITIONS (Full Definitions) Field. Independent claims are also included for the preparation of compounds (I).

Description

Technical field

The invention relates to substituted hydroxyindoles of the general formula 1 ,

Process for their preparation, pharmaceutical preparations containing them Contain compounds as well as the pharmaceutical use of these Compounds that are inhibitors of phosphodiesterase 4 as active ingredients for Treatment of diseases with an inhibition of phosphodiesterase 4 activity in immunocompetent cells (e.g. macrophages and lymphocytes) the compounds of the invention are to be influenced.

State of the art

The activation of receptors of the cell membrane by transmitters leads to Activation of the "second messenger" system. The adenylate cyclase is synthesized from AMP and GMP the effective cyclic AMP (cAMP) or cyclic GMP (cGMP). These lead z. B. in smooth muscle cells to relax or in Inflammatory cells to inhibit mediator release or synthesis. The The "second messenger" cAMP and cGMP are dismantled by the Phosphodiesterases (PDE). So far 7 families of PDE enzymes (PDE1-7) known by their substrate specificity (cAMP, cGMP or both) and the Differentiate depending on other substrates (e.g. Calmodulin). This Isoenzymes have different functions in the body and are in the different types of cells (Beavo J.A., Conti M. and Heaslip R.J.  Multiple cyclic nucleotide phosphodiesterases. Mol. Pharmacol. 1994, 46: 399-405; Hall I. P. Isoenzyme selective phosphodiesterase inhibitors: potential clinical uses, Br. J. clin. Pharmacol. 1993, 35: 1-7). By inhibiting the different PDE Isoenzyme types there is a cumulation of cAMP or cGMP in the cells, what can be used therapeutically (Torphy T. J., Livi G. P., Christensen S. B., Novel Phosphodiesterase Inhibitors for the Therapy of Asthma, Drug News and Perspectives 1993, 6: 203-214).

In the cells important for allergic inflammation (lymphocytes, mast cells, eosinophilic granulocytes, macrophages) is the predominant PDE isoenzyme Type 4 (Torphy, J.T. and Undem, B.J. Phosphorodiesterase inhibitors: new opportunities for the treatment of asthma. Thorax 1991, 46: 512-523). The inhibition The PDE 4 by suitable inhibitors is therefore an important approach to therapy a variety of allergy-induced diseases (Schudt Ch., Dent G. Rabe K., Phosphodiesterase Inhibitors, Academic Press London 1996). An important property of phosphodiesterase 4 inhibitors is the inhibition of Release of tumor necrosis factor a (TNFa) from inflammatory cells. TNFa is a important pro-inflammatory cytokine that contains a variety of biological Processes affected. TNFa is released, for example, from activated ones Macrophages, activated T-lymphocytes, mast cells, basophils, fibroblasts, Endothelial cells and astrocytes in the brain. It has a self-activating effect Neutrophils, eosinophils, fibroblasts and endothelial cells, causing different tissue-destroying mediators are released. In monocytes, macrophages and T lymphocytes causes TNFa to produce more pro-inflammatory cytokines such as GM-CSF (Granulocy-macrophage colony-sti mulating factor) or Interleukin-8. Because of its inflammatory and TNFa plays a catabolic effect 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 play a central role. For the therapy of those associated with TNFa Diseases are also suitable inhibitors of phosphodiesterase 4.

Various PDE 4 inhibitors are already known. It is primarily thereby xanthine derivatives, rolipram analogues or nitraquazone derivatives  (Overview in: Karlsson J.-A., Aldos D., Phosphodiesterase 4 inhibitors for the treatment of asthma, Exp. Opin. Ther. 1997, 7: 989-1003). None of these connections has so far been brought to clinical use. It had to be determined be that the known PDE 4 inhibitors also have various side effects like Nausea and Emesis, who have not been pushed back enough could become. Therefore, the discovery of new PDE 4 inhibitors is better therapeutic breadth required.

Although indoles are developing new active ingredients for various indications Hydroxyindoles have been important inhibitors for many years So far completely unknown PDE 4.

Description of the invention

The invention relates to substituted hydroxyindoles of the general formula 1

wherein
R ¹ , R ⁵ for -C ₁ .. _.12 -Alkyl, straight-chain or branched-chain, optionally mono- or polysubstituted with -OH, -SH, -NH ₂ , -NHC ₁ .. _.6- alkyl, -N (C _{1. .6-} alkyl) ₂ , -NHC ₆ .. _.14 aryl, -N ( _{C6. .14} aryl) ₂ , -N ( _{C1 . .6} alkyl) ( _{C6. .14} aryl), -NHCOR ⁶ , -NO ₂ , -CN, - F, -Cl, -Br, -I, -OC ₁ .. _.6 -alkyl, -OC ₆ .. _.14 -Aryl, -O (CO) R ⁶ , -SC ₁ .. _.6- alkyl, -SC ₆ .. _.14 aryl, -SOR ⁶ , -SO ₃ H, -SO ₂ R ⁶ , -OSO ₂ C ₁ .. _.6 alkyl, -OSO ₂ C ₆ .. _.14 aryl, - (CS) R ⁶ , -COOH, - (CO) R ⁶ , mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3.. .14 ring members, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5th. .15 ring links and 1.. .6 heteroatoms, which are preferably N, O and S, the C _{6.. .14} aryl groups and the included carbocyclic and heterocyclic substituents may in turn optionally be substituted one or more times with R ⁴ ,
-C ₁ .. _.12 -Alkenyl, one or more unsaturated, straight-chain or branched-chain, optionally substituted one or more times with -OH, -SH, -NH ₂ , -NHC ₁ .. _.6 alkyl, -N (C _{1. .6} -alkyl) ₂ , -NHC ₆ .. _.14 aryl, -N ( _{C6. .14} aryl) ₂ , -N ( _{C1 . .6} alkyl) ( _{C6. .14} aryl), -NHCOR ⁶ , -NO ₂ , -CN, - F, -Cl, -Br, -I, -CC ₁ .. _.6 -alkyl, -CC ₆ .. _.14 -Aryl, -C (CO) R ⁶ , -SC ₁ .. _.6- alkyl, -SC ₆ .. _.14 aryl, -SOR ⁶ , -SO ₃ H, -SO ₂ R ⁶ , -OSO ₂ C ₁ .. _.6 alkyl, -OSO ₂ C ₆ .. _.14 aryl, - (CS) R ⁶ , -COOH, - (CO) R ⁶ , mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3.. .14 ring members, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5th. .15 ring links and 1.. .6 heteroatoms, which are preferably N, O and S, the C _{6.. .14} aryl groups and the included carbocyclic and heterocyclic substituents may in turn optionally be substituted one or more times with R ⁴ ,
-mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3.. .14 ring members, optionally mono- or polysubstituted with -OH, -SH, -NH ₂ , -NHC ₁ .. _.6- alkyl, -N (C _{1. .6-} alkyl) ₂ , -NHC ₆ .. _.14 aryl, -N ( _{C6. .14} aryl) ₂ , -N ( _{C1 . .6} alkyl) ( _{C6. .14} aryl), -NHCOR ⁶ , -NO ₂ , -CN, - F, -Cl, -Br, -I, -OC ₁ .. _.6 -alkyl, -OC ₆ .. _.14 -Aryl, -O (CO) R ⁶ , -SC ₁ .. _.6- alkyl, -SC ₆ .. _.14 aryl, -SOR ⁶ , -SO ₃ H, -SO ₂ R ⁶ , -OSO ₂ C ₁ .. _.6 alkyl, -OSO ₂ C ₆ .. _.14 aryl, - (CS) R ⁶ , -COOH, - (CO) R ⁶ , mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3.. .14 ring members, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5th. .15 ring links and 1.. .6 heteroatoms, which are preferably N, O and S, the C _{6.. .14} aryl groups and the included carbocyclic and heterocyclic substituents may in turn optionally be substituted one or more times with R ⁴ ,
mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5.. .15 ring links and 1.. .6 heteroatoms, which are preferably N, O and S, optionally substituted one or more times with -OH, -SH, -NH ₂ , -NHC ₁ .. _.6- alkyl, -N (C _{1. .6-} alkyl) ₂ , -NHC ₆ .. _.14 aryl, -N ( _{C6. .14} aryl) ₂ , -N ( _{C1 . .6} alkyl) ( _{C6. .14} aryl), -NHCOR ⁶ , -NO ₂ , -CN, - F, -Cl, -Br, -I, -OC ₁ .. _.6 -alkyl, -OC ₆ .. _.14 -Aryl, -O (CO) R ⁶ , -SC ₁ .. _.6 -alkyl, -SC ₁ .. _.14 aryl, -SOR ⁶ , -SO ₃ H, -SO ₂ R ⁶ , -OSO ₂ C ₁ .. _.6 alkyl, -OSO ₂ C ₆ .. _.14 aryl, - (CS) R ⁶ , -COOH, - (CO) R ⁶ , mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3.. .14 ring members, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5th. .15 ring links and 1.. .6 heteroatoms, which are preferably N, O and S, the C _{6.. .14} aryl groups and the included carbocyclic and heterocyclic substituents may in turn optionally be substituted one or more times with R ⁴ ,
carbo- or heterocyclic saturated or mono- or polyunsaturated spirocycles with 3.. .10 ring members, with heterocyclic systems 1.. .6 contain heteroatoms which are preferably N, O and S, optionally mono- or polysubstituted with -OH, -SH, -NH ₂ , -NHC ₁ .. _.6- alkyl, -N (C _{1. .6-} alkyl) ₂ , -NHC ₆ .. _.14 aryl, -N (C _{6.. .14} aryl) ₂ , -N (C _{1 ... 6} alkyl) (C _{6.. .14} aryl), -NHCOR ⁶ , -NO ₂ , -CN, - F, -Cl, -Br, -I, -OC ₁ .. _.6 alkyl, -OC ₆ .. _.14 -Aryl, -O (CO) R ⁶ , -SC ₁ .. _.6- alkyl, -SC ₆ .. _.14 aryl, -SOR ⁶ , -SO ₃ H, -SO ₂ R ⁶ , -OSO ₂ C ₁ .. _.6 alkyl, -OSO ₂ C ₆ .. _.14 aryl, - (CS) R ⁶ , -COOH, - (CO) R ⁶ , mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3.. .14 ring members, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5th. .15 ring links and 1.. .6 heteroatoms, which are preferably N, O and S, the C _{6.. .14} aryl groups and the included carbocyclic and heterocyclic substituents on their part may optionally be substituted one or more times with R ⁴ ,
stands, wherein R ¹ and R ^{5 may be the} same or different
R ² , R ³ can be hydrogen or -OH, at least one of the two substituents must be -OH;
R ⁴ stands for -H, -OH, -SH, -NH ₂ , -NHC ₁ .. _.6- alkyl, -N (C _{1. .6-} alkyl) ₂ , -NHC ₆ . . . ₁₄ aryl, -N (C _{6 ... 14} aryl) ₂ , -N (C ₁ ... ⁶ alkyl) (C _{6 ... 14} aryl), -NHCOR ⁶ , -NO ₂ , -CN, -COOH , - (CO) R ⁶ , - (CS) R ⁶ , -F, -Cl, -Br, -I, -OC ₁ .. _.6 -alkyl, -OC ₆ .. _.14 -Aryl, -O (CO) R ⁶ , -SC ₁ .. _.6- alkyl, -SC ₆ .. _.14 aryl, -SOR ⁶ , -SO ₂ R ⁶ .

R ⁶ can be -H, -NH ₂ , -NHC ₁ .. _.6- alkyl, -N (C _{1. .6-} alkyl) ₂ , -NHC ₆ .. _.14 aryl, -N ( _{C6. .14} aryl) ₂ , -N ( _{C1 . .6} alkyl) ( _{C6. .14} aryl), -OC1 _{. .6} -alkyl, -CC ₆ .. _.14 -Aryl, -SC ₁ .. _.6- alkyl, -SC ₆ .. _.14 Aryl -C _{1 .. .12} -Alkyl, straight-chain or branched-chain, -C ₁ .. _.12 -Alkenyl, mono- or polyunsaturated, straight-chain or branched-chain, -mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3.. .14 ring members, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5th. .15 ring links and 1.. .6 heteroatoms, which are preferably N, O and S,
mean.

A either represents a bond or (CH ₂ ) _m -, (CH ₂ ) _m - (CH = CH) _n - (CH ₂ ) _p -, - (CHOZ) _m -, - (C = O) - , - (C = S) -, - (C = NZ) -, -O-, -S-, -NZ-, where m, p = 0 ,. . ., 3 and n = 0 ,. . ., 2 are and
Z for -H, or -C ₁ .. _.12 -Alkyl, straight-chain or branched-chain, -C ₁ .. _.12 -Alkenyl, mono- or polyunsaturated, straight-chain or branched-chain, -mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3.. .14 ring members, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5th. .15 ring links and 1.. .6 heteroatoms, which are preferably N, O and S,
stands.

B can be either carbon or sulfur, or - (S = O) -, D can be oxygen, sulfur, CH ₂ or NZ, where D can only be S or CH ₂ if B is carbon.

E can stand for a bond, or for (CH ₂ ) _m -, -O-, -S-, - (NZ) -, where m and Z have the meaning already described above.

The invention further relates to the physiologically tolerable salts of the compounds of the formula 1 .

The physiologically acceptable salts are neutralized in the usual way the bases with inorganic or organic acids or by neutralization the acids obtained with inorganic or organic bases. As inorganic Acids come for example hydrochloric acid, sulfuric acid, phosphoric acid or Hydrobromic acid, as organic acids for example carbon, sulfo or Sulfonic acid such as acetic acid, tartaric acid, lactic acid, propionic acid, glycolic acid, Malonic acid, maleic acid, fumaric acid, tannic acid, succinic acid, alginic acid, Benzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, cinnamic acid, Mandelic acid, 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 in question. For example, come as inorganic bases Sodium hydroxide solution, potassium hydroxide solution, ammonia and, as organic bases, amines are preferred however tertiary amines such as trimethylamine, triethylamine, pyridine, N, N-dimethylaniline, Quinoline, isoquinoline, α-picoline, β-picoline, γ-picoline, quinaldine or pyrimidine in Question.

Furthermore, physiologically tolerable salts of the compounds of the formula 1 can be obtained by converting derivatives which have tertiary amino groups in a manner known per se using quaternizing agents into the corresponding quaternary ammonium salts. Suitable quaternizing agents are, for example, 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.

Furthermore, the invention 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. However, it is also possible to use an optically active starting substance from the outset, in which case a corresponding optically active or diastereomeric compound is then obtained as the end product. Pharmacologically important properties have been found for the compounds according to the invention which can be used therapeutically. The compounds according to the invention are inhibitors of the release of TNFa.

It is therefore an object of this invention that the compounds of formula 1 and their salts and pharmaceutical preparations containing these compounds or their salts can be used for the treatment of diseases in which an inhibition of TNFa is useful. These diseases include, for example, joint inflammation including arthritis and rheumatoid arthritis as well as other arthritic diseases such as rheumatoid spondylitis and osteoarthritis. Other possible uses are the treatment of patients suffering from sepsis, septic shock, gram-negative sepsis, toxic shock syndrome, respiratory distress syndrome, asthma or other chronic pulmonary diseases, bone resorption diseases or transplant rejection reactions or other autoimmune diseases, such as lupus erythematosus and glulomeric diseases, multiple sclerosis Uveitis, insulin-dependent diabetes mellitus and chronic demyelination suffer.

In addition, 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 Therapy of malaria, infection-related fever, infection-related Muscle pain, AIDS and cachexia are used.  

The compounds according to the invention are inhibitors of phosphodiesterase 4.

It is therefore the subject of this invention that the compounds of formula 1 and their salts and pharmaceutical preparations containing these compounds or their salts can be used for the treatment of diseases in which an inhibition of phosphodiesterase 4 is useful.

Thus, the compounds of the invention can be used as bronchodilators and 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 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 urosinophilia, ulcerative colitis , the Crohn's disease and proliferative skin diseases such as psoriasis or keratosis. The compounds of the invention also have neuroprotective properties and can be used to treat diseases in which neuroprotection is useful. Such diseases include senile dementia (Alzheimer's disease), memory loss, Parkinson's disease, depression, strokes and intermittent claudication.

Further possible uses of the compounds according to the invention are Prophylaxis and therapy of prostate diseases, such as benign Prostate hyperplasia, pollakiuria, nocturia and for the treatment of Bladder weakness and colic caused by urinary stones.

Finally, the compounds according to the invention can also be used for inhibition the emergence of a drug addiction with repeated use of Analgesics such as morphine and to reduce the Tolerance development used with repeated use of these analgesics become.  

In addition to the usual auxiliaries, carriers and Additives an effective dose of the compounds of the invention or their salts used. The dosage of the active ingredients can vary depending on the route of administration, age, weight of the Patients, type and severity of the diseases to be treated and the like Factors vary. The daily dose can be administered as a single dose or divided into 2 or more daily doses and is usually 0.001-100 mg.

Oral, parenteral, intravenous, transdermal, topical, inhalative and intranasal preparations in question.

The usual galenical preparation forms such as Tablets, dragees, capsules, dispersible powders, granules, aqueous solutions, aqueous or oily suspensions, syrups, juices or drops.

Solid dosage forms can contain inert ingredients and carriers, such as. B. 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 weight Fatty acids (such as stearic acid), gelatin, agar or vegetable or animal Fats and oils, solid high molecular weight polymers (such as polyethylene glycol); for oral Preparations suitable for application can, if desired, be additional Contain flavor and / or sweeteners.

Liquid dosage forms can be sterilized and / or auxiliary substances if necessary such as preservatives, stabilizers, wetting agents, penetrants, Emulsifiers, spreading agents, solubilizers, salts, sugar or sugar alcohols for Regulation of the osmotic pressure or for buffering and / or Viscosity regulators included. Such additives are, for example, tartrate and citrate buffers, ethanol, Complexing agents (such as ethylenediamine tetraacetic acid and its non-toxic salts). To regulate the viscosity, high molecular weight polymers can be used, such as  for example liquid polyethylene oxide, microcrystalline celluloses Carboxymethyl celluloses, polyvinyl pyrrolidones, dextrans or gelatin. Celebrations Carriers are, for example, starch, lactose, mannitol, methyl cellulose, talc, finely divided silicas, higher molecular fatty acids (such as stearic acid), Gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable Fat, solid, high molecular weight polymers such as polyethylene glycol.

Oily suspensions for parenteral or topical applications can be vegetable synthetic or semi-synthetic oils such as liquid fatty acid esters each with 8 to 22 carbon atoms in the fatty acid chains, for example palmitin, Laurin, tridecyl, margarine, stearin, arachine, myristic, behen, pentadecyl, Linoleic, elaidic, brasidic, erucic or oleic acid, with mono- to trivalent Alcohols with 1 to 6 carbon atoms such as methanol, ethanol, propanol, Butanol, pentanol or their isomers, glycol or glycerol are esterified. 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 duckling glandular fat, isopropyl coconut fatty acid, oleic acid oleyl ester, Oleic acid decyl ester, lactic acid ethyl ester, dibutyl phthalate, Diisopropyl adipate, polyol fatty acid esters and the like. a. Are also suitable Silicone oils of various viscosities or fatty alcohols such as isotridexyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or oleyl alcohol, fatty acids such as for example oleic acid. Vegetable oils such as castor oil, almond oil, Use olive oil, sesame oil, cottonseed oil, peanut oil or soybean oil Find.

Suitable solvents, gelling agents and solubilizers are water or water-miscible solvents. For example, alcohols such as for example ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, Polyethylene glycols, phthalates, adipates, propylene glycol, glycerin, di- or Tripropylene glycol, waxes, methyl cellosolve, cellosolve, esters, morpholines, dioxane, Dimethyl sulfoxide, dimethylformamide, tetrahydrofuren, cyclohexanone etc.  

Cellulose ethers can be used as film formers, which are both in water can also dissolve or swell in organic solvents, such as for example hydroxypropylmethyl cellulose, methyl cellulose, ethyl cellulose or soluble starches.

Mixed forms between gel and film formers are also quite possible. Here mainly ionic macromolecules are used, e.g. B. Sodium carboxymethyl cellulose, polyacrylic acid, polymethacrylic acid and their Salts, sodium amylopectin semiglycolate, alginic acid or propylene glycol alginate as Sodium salt, gum arabic, xanthan gum, guar gum or carrageenan. Other formulation aids that can be used are: glycerol, paraffin different viscosities, triethanolamine, collagen, allantoin, novantisol acid. The use of surfactants, emulsifiers or wetting agents can also be used Wording may be necessary, such as B. Na lauryl sulfate, Fatty alcohol ether sulfates, di-Na-N-lauryl-β-iminodipropionate, polyoxyethylated 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- / di alkyl polyglycol ether orthophosphoric acid monoethanolamine salts. Stabilizers such as montmorillonites or colloidal silicas for stabilization of emulsions or to prevent the breakdown of active substances such as Antioxidants, for example tocopherols or butylated hydroxyanisole, or Preservatives such as p-hydroxybenzoic acid esters can also be used Preparation of the desired formulations may be necessary.

Preparations for parenteral administration can be found in separate Dosage unit forms such as B. ampoules or vials. Preferably be Solutions of the active ingredient used, preferably aqueous solutions and above all isotonic solutions but also suspensions. These injection forms can be used as Finished product can be made available or only immediately before use by mixing the active compound, for example the lyophilizate,  optionally with other solid carriers, with the desired solution or Suspensions are prepared.

Intranasal preparations can be in the form of aqueous or oily solutions or aqueous or oily suspensions are present. They can also be used as lyophilisates are present before use with the appropriate solution or Suspensions are prepared.

The preparation, filling and sealing of the preparations takes place under the usual antimicrobial and aseptic conditions.

The invention further relates to methods for producing the invention Links.

According to the invention, the compounds of general formula 1 are prepared with the meanings of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , A, B, D and E shown above,

in that compounds of the formula 1 for R ² or R ³ or R ² and R ³ = -OR ⁷ , are converted into the compounds according to the invention by splitting off R ⁷ .

R ⁷ stands for substituents suitable as leaving groups, such as, for example, alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl, 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. A particularly preferred reaction for the elimination of R ⁷ in the sense of the production process according to the invention is saponification with suitable bases, such as, for example, sodium hydroxide solution, potassium hydroxide solution or sodium carbonate or potassium carbonate.

These saponifications are for R ⁷ = acyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, N-substituted aminocarbonyl, silyl, sulfonyl groups and complexing agents, such as, for example, compounds of boric acid, phosphoric acid and coordinatively bound metals such as zinc , Aluminum or copper is preferably used.

A particularly preferred reaction for the elimination of R ⁷ from the compounds in which R ^{7 is} an alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl group is ether cleavage, for example by means of hydrobromic acid, hydrochloric acid, hydroiodic acid and with activating Lewis acids, such as AlCl ₃ , BF ₃ , BBr ₃ or LiCl, in each case in the absence or in the presence of additional activators, such as ethane-1,2-dithiol or benzyl mercaptan, and ether cleavage using hydrogen, under elevated pressure or under Normal pressure, in the presence of a suitable catalyst, such as palladium or iridium catalysts.

According to the invention, the compounds of general formula 1 with the meanings of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , A, B, D and E shown above are also prepared by converting the partial structure:

compounds of the invention by reactions known per se are converted to the Formula 1 into other compounds of the invention F1. Particularly preferred conversion reactions with compounds of formula 1 according to the invention are, for example, for A = - (C = O) reductions to A = - (CH-OH) - or A = -CH ₂ - by means of reducing agents known per se, such as sodium borohydride or by hydrogenations, which can optionally also be carried out stereoselectively.

Further preferred conversion reactions are the conversion of Compounds for which D and E means oxygen in substances where only D still means oxygen, but E stands for - (N-Z) -, where Z is the one already explained Has meaning.

Embodiments

Exemplary production processes for compounds of formula 1 according to the invention from starting materials of the type described, in which R ^{7 is} an alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl group:

example 1 N- (3,5-dichloropyridin-4-yl) -2- [1- (4-fluorobenzyl) -5-hydroxy-indol-3-yl] -2-oxo-acet amide (1)

1.4 g of N- (3,5-dichloropyridin-4-yl) -2- [1- (4-fluorobenzyl) -5-methoxy-indol-3-yl] -2-oxo-acet amide (3 mmol) are dissolved in 100 ml dichloromethane. The solution is heated to reflux and a solution of 14 mmol BBr ₃ in 15 ml dichloromethane is added with stirring. The reaction mixture is refluxed for 3 hours. After cooling, the solution is stirred vigorously with 200 ml of an aqueous sodium hydrogen carbonate solution at 20 ° C. for 3 hours. The product crystallizes out. It is isolated, dried at 60 ° C. and recrystallized from 80 ml of ethanol.
Yield: 1.1 g (80% of theory),
Melting point: 213-214 ° C.

Example 2 N- (3,5-dichloropyridin-4-yl) -2- [1- (4-fluorobenzyl) -5-hydroxy-indol-3-yl) -2-oxo-acet amide (1)

5 g (38 mmol) of anhydrous aluminum chloride are placed 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 -oxo-acetamide (10 mmol) in 50 ml dichloromethane added. The mixture is stirred at 0 ° C for 4 hours. 50 ml of 10% hydrochloric acid are added dropwise at 0-10 ° C. with stirring. The crystallizing product is isolated, washed with water and dried at 20 ° C. A pure product is obtained by recrystallization from ethanol (180 ml).
Yield: 3.1 g (67% of theory),
Melting point: 212-214 ° C.

Exemplary production process for compounds of formula 1 according to the invention from starting materials of the type described, in which R ^{7 is} an acyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, N-substituted aminocarbonyl, silyl, sulfonyl group:

Example 3 N- (3,5-dichloropyridin-4-yl) -2- [1- (4-fluorobenzyl) -5-hydroxy-indol-3-yl] -2-oxo-acet amide Na salt (2)

5 g of N- (3,5-dichloropyridin-4-yl) -2- [5-acetoxy-1- (4-fluorobenzyl) indol-3-yl] -2-oxo-acet amide (10 mmol) are in 50 ml of dilute sodium hydroxide solution stirred at 40-50 ° C for 1 hour. The solution is neutralized while cooling with ice using hydrochloric acid (10%) and concentrated to dryness. The residue is dissolved in 80 ml of acetone. Insoluble components are separated. A solution of 0.4 g NaOH in 3 ml water is added to the clear solution and the mixture is stirred at 20 ° C. for 2 hours. The crystallized product is isolated, washed with acetone and dried at 60 ° C.
Yield: 2.44 g (51% of theory),
Melting point: 265 ° C.

Exemplary Production Process for Compounds of Formula 1 According to the Invention from Other Compounds of Formula 1 According to the Invention:

Example 4 N- (3,5-dichloropyridin-4-yl) -2- [1- (4-fluorobenzyl) -5-hydroxyindol-3-yl] -2-hy droxyacetamide (3)

1 g of N- (3,5-dichloropyridin-4-yl) -2- [1- (4-fluorobenzyl) -5-hydroxy-indol-3-yl] -2-oxo-acet amide (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 solution, the reaction mixture is stirred at 20 ° C. for 6 hours. After the solvent has been distilled off, the residue is recrystallized from 40 ml of ethanol.
Yield: 0.5 g (50% of theory),
Melting point: 205-207 ° C.

Numerous further compounds of the formula 1 can be prepared using the exemplary variants indicated, of which the following are exemplified:

The compounds according to the invention are strong inhibitors of phospho diesterase 4 and the TNFa release. Their therapeutic potential is in vivo for example by inhibiting the late phase asthmatic reaction (Eosinophilia) on guinea pigs and by influencing the allergen-in reduced vascular permeability in actively sensitized Brown Norway rats busy.

Inhibition of phosphodiesterase

The PDE 4 activity is determined in enzyme preparations from human polymorphonuclear lymphocytes (PMNL), the PDE 2, 3 and 5 activity with PDE from human thrombocytes. Human blood 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 RT. The platelets are lysed by ultrasound and used in the PDE 3 and PDE 5 assay. To determine the PDE 2 activity, the cytosolic platelet fraction is purified over an anion exchange column using a NaCl gradient and the PDE 2 peak is obtained for the assay. The PMNLs for the PDE 4 determination are isolated by a subsequent dextran sedimentation and subsequent gradient centrifugation with Ficoll-Paque. After washing the cells twice, the erythrocytes which are still present are added by adding 10 ml of hypotonic buffer (155 mM NH ₄ Cl, 10 mM NaHCO ₃ , 0.1 mM EDTA, pH = 7.4) at 4 ° within 6 minutes C lysed. The still intact PMNLs are washed two more times 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 PDE 4 and is used for the PDE 4 measurements.

The phosphodiesterase activity is modified with some modifications according to that of Thompson et al. described method determined. (Thompson, WJ; Appleman, MM, Assay of cyclic nucleotide phosphodiesterase and resolution of multiple molecular forms of the enzyme. Adv. Cycl. Nucl. Res. 1979, 10, 69-92). The reaction mixtures contain 50 mM Tris-HCl (pH 7.4), 5 mM MgCl ₂ , the inhibitors in variable concentrations, the corresponding enzyme preparation and the other components necessary for the detection of the individual isoenzymes (see below). The reaction is started by adding the substrate 0.5 µM [ ³ H] -cAMP or [ ³ H] -cGMP (approx. 6000 CPM / test). The final volume is 100 ml. 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. After starting the reaction by adding substrate, the samples are incubated at 37 ° C for 30 minutes. The reaction is stopped by heating the test tubes to 110 ° C. for 2 minutes. The samples remain in the ice for another 10 minutes. After the addition of 30 μl of 5'-nucleotidase (1 mg / ml, from a snake venom suspension from Crotalus adamanteus), incubation is carried out at 37 ° C. for 10 minutes. The samples are stopped on ice, 400 .mu.l of a mixture of Dowex water ethanol (1 + 1 + 1) are added, mixed well and incubated again on ice for 15 minutes. The reaction tubes are centrifuged at 3000 xg for 20 minutes. 200 µl aliquots of the supernatant are transferred directly to scintillation vials. After adding 3 ml of scintillator, the samples are measured in the beta counter.

For the determination of the PDE 4, 3 and 2 activity, [ ³ H] -cAMP is used as the substrate, and for the determination of the PDE 5 activity [ ³ H] -cGMP. The nonspecific enzyme activities in each case are determined in the presence of 100 μM rolipram in PDE 4 and in the presence of 100 μM IBMX in determining PDE 3 and 5 and subtracted from the test values. The incubation batches of the PDE 3 assay contain 10 µM rolipram in order to inhibit any contamination by the PDE 4. The PDE 2 is tested with a SPA assay from Amersham. The assay is carried out in the presence of the activator of PDE 2 (5 μM cGMP).

For the compounds according to the invention, 4 IC ₅₀ values in the range from 10 ^-9 to 10 ^-5 M were determined with regard to the inhibition of the phosphodiesterase. The selectivity for PDE types 2, 3 and 5 is a factor of 100 to 10,000.

Inhibition of TNFa release from nasal polyp cells

The experimental setup essentially corresponds to the method described by Campbell, AM and Bousquet J. (Anti-allergic activity of H ₁ -blockers. Int. Arch. Allergy Immunol., 1993, 101, 308-310). The starting material is nasal polyps (surgical material) from patients who have undergone surgical treatment.

The tissue is washed with RPMI 1640 and then digested with protease (2.0 mg / ml), collagenase (1.5 mg / ml), hyaluronidase (0.75 mg / ml) and DNAse (0.05 mg / ml) for 2 h at 37 ° C ( 1 g tissue on 4 ml 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 nutrient solution, passively sensitized by adding human IgE and the cell suspension to a concentration of 2 million cells / ml in RPMI 1640 (supplemented with antibiotics, 10% fetal calf serum, 2 mM glutamine and 25 mM Hepes). This suspension is distributed on 6-well cell culture plates (1 ml / well). The cells are preincubated with the test substances in various final concentrations for 30 min and then stimulated to release TNFa by adding anti-IgE (7.2 µg / ml). The maximum release into the nutrient medium takes place after approx. 18 hours. During this period, the cells are incubated at 37 ° C and 5% CO ₂ . The nutrient medium (supernatant) is obtained by centrifugation (5 min 4000 rpm) and stored at -70 ° C. until the cytokine is determined. TNFa in the supernatant is determined using so-called sandwich ELISAs (basic material Pharmingen), with which concentrations of the cytokine in the range of 30-1000 pg / ml can be detected.

Cells that are not stimulated with anti-IgE hardly produce TNFa, whereas stimulated cells secrete large amounts of TNFa. B. can be reduced by PDE 4 inhibitors depending on the dose. The IC ₅₀ (concentration at 50% inhibition) is calculated from the percentage inhibition (TNFa release of the cells stimulated with anti-IgE = 100%) of the tested substances at various concentrations.

IC ₅₀ values in the range from 10 ^-7 to 10 ^-5 M were determined for the compounds according to the invention.

Inhibition of late-phase eosinophilia 24 hours after inhaling ovalbumin challenge on actively sensitized guinea pigs

The inhibition of pulmonary eosinophil infiltration by the substances is tested in an in vivo test on male Dunkin-Hartley guinea pigs (200-260 g) actively sensitized to ovalbumin (OVA). The sensitization is carried out by two intraperitoneal injections of a suspension of 20 µg OVA together with 20 mg aluminum hydroxide as adjuvant in 0.5 ml physiological saline per animal on two consecutive days. 14 days after the second injection, the animals are pretreated with mepyramine maleate (10 mg / kg ip) to protect them from anaphylactic death. 30 minutes later, the animals are exposed in a plastic box to an OVA aerosol (0.5 mg / ml) for 30 seconds, which is generated by a nebulizer driven with compressed air (19.6 kPa) (allergen challenge). Control animals are nebulized with physiological saline. 24 hours after the challenge, the animals are anesthetized with an overdose of ethyl urethane (1.5 g / kg body weight ip) and bronchoalveolar lavage (BAL) is carried out with 2 × 5 ml of physiological saline. The BAL liquid is collected, centrifuged at 300 rpm for 10 min and then the cell pellet is resuspended in 1 ml of physiological saline. The eosinophils in the BAL are counted using an automatic cell differentiation device (Bayer Diagnostics Technicon H1). Two control groups (nebulization with physiological saline and nebulization with OVA solution) are included in each test. The percentage inhibition of eosinophilia in the test group treated with the substance is calculated using the following formula:

A = Eosinophils in the control group with OVA Challenge and Vehicel
B = eosinophils in the substance-treated group with OVA challenge
C = eosinophils in the control group with 0.9% NaCl challenge and Vehicel.

The test substances are administered intraperitoneally or orally as a suspension in 10% Polyethylene glycol 300 and 0.5% 5-hydroxyethyl cellulose 2 hours before Allergen Challenge applied. The control groups are designed according to the Application form of the test substance treated with the Vehicel.

The compounds according to the invention inhibit late-phase eosinophilia intraperitoneal application of 10 mg / kg by 30% to 80% and after oral Application of 30 mg / kg by 40% to 70%.

The compounds of the invention are therefore particularly suitable for Manufacture of medicinal products for the treatment of diseases associated with the Acts of eosinophils are linked.

Influencing allergen-induced vascular permeability on active sensitized Brown-Norway rats

Male Brown-Norway rats weighing 280-300 g are fed to 2 consecutive days by intraperitoneal injection of a suspension of 1 mg ovalbumin together with 100 mg aluminum hydroxide active in 1 ml / animal sensitized. The rats become pregnant three weeks after sensitization Sodium thiopental anesthetized and fixed in supine position. To perfuse the In the nasal cavity, a polyethylene catheter was retrograded to the inner trachea Opening the choana advanced so that the solution passed through the nostrils could drip out. A short tracheal catheter was orthograded into the trachea involved to allow breathing. Phosphate became a perfusion buffered saline (PBS) continuously with a roller pump through the Nasal cavity pumped (0.5 ml / min) and collected by a fraction collector. Evans Blue was used as a plasma marker and intravenously (1 ml / animal one each 1% solution in PBS) through a catheter located in the jugular vein injected.

The substance application was topical. In this application, the Test substance added to the perfusion medium (PBS). The nasal mucosa  was perfused with a solution containing PDE4 inhibitor for 30 min. Subsequently Evans blue became ovalbumin-containing immediately before perfusion started Solution (challenge) injected. After the ovalbumin challenge (10 mg / ml Ovalbumin dissolved in PBS) were fractions every 15 min in the fraction collector collected over a period of 60 min. The Evans Blue concentration in the Perfusion was performed with the Digiscan photometer at a wavelength of 620 nm measured. The blank values were automatically subtracted. The The course of effects over 60 min was calculated using an AUC program. The Substance effect of the preparation group was compared to vehicle controls in% calculated.

IC ₅₀ values in the range from 10 ^-8 to 10 ^-5 M were determined for the compounds according to the invention.

Claims (13)

1. Hydroxyindoles of the formula 1
wherein
R ¹ , R ⁵ for -C ₁ .. _.12 -Alkyl, straight-chain or branched-chain, optionally mono- or polysubstituted with -OH, -SH, -NH ₂ , -NHC ₁ .. _.6- alkyl, -N (C _{1. .6-} alkyl) ₂ , -NHC ₆ .. _.14 aryl, -N ( _{C6. .14} aryl) ₂ , -N ( _{C1 . .6} alkyl) ( _{C6. .14} aryl), -NHCOR ⁶ , -NO ₂ , -CN, - F, -Cl, -Br, -I, -OC ₁ .. _.6 -alkyl, -OC ₆ .. _.14 -Aryl, -O (CO) R ⁶ , -SC ₁ .. _.6- alkyl, -SC ₆ .. _.14 aryl, -SOR ⁶ , -SO ₃ H, -SO ₂ R ⁶ , -OSO ₂ C ₁ .. _.6 alkyl, -OSO ₂ C ₆ .. _.14 aryl, - (CS) R ⁶ , -COOH, - (CO) R ⁶ , mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3.. .14 ring members, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5th. .15 ring links and 1.. .6 heteroatoms, which are preferably N, O and S, the C _{6.. .14} aryl groups and the included carbocyclic and heterocyclic substituents may in turn optionally be substituted one or more times with R ⁴ ,
-C ₁ .. _.12 -Alkenyl, one or more unsaturated, straight-chain or branched-chain, optionally substituted one or more times with -OH, -SH, -NH ₂ , -NHC ₁ .. _.6- alkyl, -N (C _{1. .6-} alkyl) ₂ , -NHC ₆ .. _.14 aryl, -N (C _{6.. .14} aryl) ₂ , -N (C _{1 ... 6} alkyl) (C _{6.. .14} aryl), -NHCOR ⁶ , -NO ₂ , -CN, - F, -Cl, -Br, -I, -OC ₁ .. _.6 -alkyl, -OC ₆ .. _.14 -Aryl, -O (CO) R ⁶ , -SC ₁ .. _.6- alkyl, -SC ₆ .. _.14 aryl, -SOR ⁶ , -SO ₃ H, -SO ₂ R ⁶ , -OSO ₂ C ₁ .. _.6 alkyl, -OSO ₂ C ₆ .. _.14 aryl, - (CS) R ⁶ , -COOH, (CO) R ⁶ , mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3.. .14 ring members, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5th. .15 ring links and 1.. .6 heteroatoms, which are preferably N, O and S, the C _{6.. .14} aryl groups and the included carbocyclic and heterocyclic substituents may in turn optionally be substituted one or more times with R ⁴ ,
-mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3.. .14 ring members, optionally mono- or polysubstituted with -OH, -SH, -NH ₂ , -NHC ₁ .. _.6- alkyl, -N (C _{1. .6-} alkyl) ₂ , -NHC ₆ .. _.14 aryl, -N ( _{C6. .14} aryl) ₂ , -N ( _{C1 . .6} alkyl) ( _{C6. .14} aryl), -NHCOR ⁶ , -NO ₂ , -CN, - F, -Cl, -Br, -I, -OC ₁ .. _.6 -alkyl, -OC ₆ .. _.14 -Aryl, -O (CO) R ⁶ , -SC ₁ .. _.6- alkyl, -SC ₆ .. _.14 aryl, -SOR ⁶ , -SO ₃ H, -SO ₂ R ⁶ , -OSO ₂ C ₁ .. _.6 alkyl, -OSO ₂ C ₆ .. _.14 aryl, - (CS) R ⁶ , -COOH, - (CO) R ⁶ , mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3.. .14 ring members, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5th. .15 ring links and 1.. .6 heteroatoms, which are preferably N, O and S, the C _{6.. .14} aryl groups and the included carbocyclic and heterocyclic substituents may in turn optionally be substituted one or more times with R ⁴ ,
mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5.. .15 ring links and 1.. .6 heteroatoms, which are preferably N, O and S, optionally substituted one or more times with -OH, -SH, -NH ₂ , -NHC ₁ .. _.6- alkyl, -N (C _{1. .6-} alkyl) ₂ , -NHC ₆ .. _.14 aryl, -N ( _{C6. .14} aryl) ₂ , -N ( _{C1 . .6} alkyl) ( _{C6. .14} aryl), -NHCOR ⁶ , -NO ₂ , -CN, - F, -Cl, -Br, -I, -OC ₁ .. _.6 -alkyl, -OC ₆ .. _.14 -Aryl, -O (CO) R ⁶ , -SC ₁ .. _.6- alkyl, -SC ₆ .. _.14 aryl, -SOR ⁶ , -SO ₃ H, -SO ₂ R ⁶ , -OSO ₂ C ₁ .. _.6 alkyl, -OSO ₂ C ₆ .. _.14 aryl, - (CS) R ⁶ , -COOH, - (CO) R ⁶ , mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3.. .14 ring members, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5th. .15 ring links and 1.. .6 heteroatoms, which are preferably N, O and S, the C _{6.. .14} aryl groups and the included carbocyclic and heterocyclic substituents may in turn optionally be substituted one or more times with R ⁴ ,
carbo- or heterocyclic saturated or mono- or polyunsaturated spirocycles with 3.. .10 ring members, with heterocyclic systems 1.. .6 contain heteroatoms which are preferably N, O and S, optionally mono- or polysubstituted with -OH, -SH, -NH ₂ , -NHC ₁ .. _.6- alkyl, -N (C _{1. .6-} alkyl) ₂ , -NHC ₆ .. _.14 aryl, -N (C _{6.. .14} aryl) ₂ , -N (C _{1 ... 6} alkyl) (C _{6.. .14} aryl), -NHCOR ⁶ , -NO ₂ , -CN, - F, -Cl, -Br, -I, -OC ₁ .. _.6 -alkyl, -OC ₆ .. _.14 -Aryl, -O (CO) R ⁶ , -SC ₁ .. _.6- alkyl, -SC ₆ .. _.14 aryl, -SOR ⁶ , -SO ₃ H, -SO ₂ R ⁶ , -OSO ₂ C ₁ .. _.6 alkyl, -OSO ₂ C ₆ .. _.14 aryl, - (CS) R ⁶ , -COOH, - (CO) R ⁶ , mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3.. .14 ring members, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5th. .15 ring links and 1.. .6 heteroatoms, which are preferably N, O and S, the C _{6.. .14} aryl groups and the included carbocyclic and heterocyclic substituents may in turn optionally be substituted one or more times with R ⁴ ,
stands, wherein R ¹ and R ^{5 may be the} same or different
R ² , R ³ can be hydrogen or -OH, at least one of the two substituents must be -OH;
R ⁴ stands for -H, -OH, -SH, -NH ₂ , -NHC ₁ .. _.6- alkyl, -N (C _{1. .6-} alkyl) ₂ , -NHC ₆ .. _.14 aryl, -N ( _{C6. .14} aryl, -N ( _{C1 . .6} alkyl) ( _{C6. .14} aryl), -NHCOR ⁶ , -NO ₂ , -CN, -COOH, - (CO) R ⁶ , - (CS) R ⁶ , -F, -Cl, -Br, -I, -OC _{1. .6} -alkyl, -OC _{6. .14} -aryl, -O (CO ) R ⁶ , -SC _{1. .6} -alkyl, -SC _{6. .14} aryl, -SOR ⁶ , -SO ₂ R ⁶ ;
R ⁶ can be -H, -NH ₂ , -NHC ₁ .. _.6- alkyl, -N (C _{1. .6-} alkyl) ₂ , -NHC ₆ .. _.14 aryl, -N ( _{C6. .14} aryl) ₂ , -N ( _{C1 . .6} alkyl) ( _{C6. .14} aryl), -OC1 _{. .6} -alkyl, -OC ₆ .. _.14 -Aryl, -SC ₁ .. _.6- alkyl, -SC ₆ .. _.14 Aryl -C ₁ . . . ₁₂ -alkyl, straight-chain or branched-chain, -C ₁ .. _.12 -Alkenyl, mono- or polyunsaturated, straight-chain or branched-chain, -mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3.. .14 ring links,
mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5.. .15 ring links and 1.. .6 heteroatoms, which are preferably N, O and S,
mean.
A either stands for a bond, or for
- (CH ₂ ) _m -, (CH ₂ ) _m - (CH = CH) _n - (CH ₂ ) _p -, - (CHOZ) _m -, - (C = O) -, - (C = S) - , - (C = NZ) -, -O-, -S-, -NZ-,
where m, p = 0,. . ., 3 and n = 0,. . ., 2 are and
Z for -H, or
-C ₁ .. _.12 -alkyl, straight-chain or branched-chain,
-C ₁ .. _.12 -Alkenyl, mono- or polyunsaturated, straight-chain or branched-chain, -mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3.. .14 ring members, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5th. .15 ring links and 1.. .6 heteroatoms, which are preferably N, O and S,
stands;
B can either be carbon or sulfur, or - (S = O) - mean
D can be oxygen, sulfur, CH ₂ or NZ, where D can only be S or CH ₂ if B is carbon,
E can stand for a bond, or for - (CH ₂ ) _m -, -O-, -S-, - (NZ) -, where m and Z have the meaning already described above. 2. Physiologically acceptable salts of the compounds of formula 1 according to Claim 1, characterized by neutralization of the bases with inorganic or organic acids or by neutralizing the acids with inorganic or  organic bases or by quaternization of tertiary amines to quaternary Ammonium salts. 3. Compounds according to formula 1 according to claim 1 and 2 with an asymmetrical Carbon atom in the D form, the L form and D, L mixtures as well as in the case of several asymmetric carbon atoms the diastereomeric forms. 4. Of the compounds of formula 1 according to claims 1 to 3, especially one of the following compounds:
N- (3,5-dichloropyridin-4-yl) -2- [1- (4-fluorobenzyl) -5-hydroxy-indol-3-yl] -2-oxo-acetamide;
N- (3,5-dichloropyridin-4-yl) -2- [1- (4-fluorobenzyl) -5-hydroxyindol-3-yl] -2-oxo-acetamide Na salt;
N- (3,5-dichloropyridin-4-yl) -2- [1- (4-fluorobenzyl) -5-hydroxyindol-3-yl] -2-hydroxyacetamide;
N- (pyridin-4-yl) -2- [1- (2,6-difluorobenzyl) -5-hydroxy-indol-3-yl] -2-oxo-acetamide;
N- (3,5-dichloropyridin-4-yl) -2- [1- (2,6-difluorobenzyl) -5-hydroxy-indol-3-yl] -2-oxo-acetamide;
N- (3,5-dichloropyridin-4-yl) -2- [1- (3-nitrobenzyl) -5-hydroxy-indol-3-yl] -2-oxo-acetamide Na salt;
N- (3,5-dichloropyridin-4-yl) -2- (1-propyl-5-hydroxyindol-3-yl) -2-oxo-acetamide;
N- (3,5-dichloropyridin-4-yl) -2- (1-isopropyl-5-hydroxyindol-3-yl) -2-oxo-acetamide;
N- (3,5-dichloropyridin-4-yl) -2- (1-cyclopentylmethyl-5-hydroxyindol-3-yl) -2-oxo-acetamide;
N- (2,6-dichlorophenyl) -2- [1- (4-fluorobenzyl) -5-hydroxyindol-3-yl] -2-oxo-acetamide;
N- (2,6-dichloro-4-trifluoromethylphenyl) -2- [1- (4-fluorobenzyl) -5-hydroxyindol-3-yl] -2-oxoacetamide;
N- (2,6-dichloro-4-trifluoromethoxyphenyl) -2- [1- (4-fluorobenzyl) -5-hydroxyindol-3-yl] -2-oxoacetamide;
N- (3,5-dichloropyridin-4-yl) -2- [1- (4-fluorobenzyl) -6-hydroxyindol-3-yl] -2-oxo-acetamide;
N- (3,5-dichloropyridin-4-yl) -5-hydroxy-1- (4-methoxybenzyl) indole-3-carboxamide. 5. A process for the preparation of compounds according to formula 1 according to claim 1 to 4, characterized in that compounds according to formula 1 , for which R ² or R ³ or R ² and R ³ = -OR ⁷ , by elimination of R ⁷ are converted into the compounds according to the invention, where R ⁷ stands for substituents suitable as leaving groups. 6. Preparation of compounds of formula 1 by the process according to claim 5, particularly preferably from compounds of formula 1 for the R ⁷ alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl, 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. 7. A process for the preparation of compounds of formula 1 according to claim 1 to 4, characterized in that compounds of general formula 1 , by conversions of the partial structure:
be converted into other compounds of formula 1 according to the invention. 8. Use of the compounds of formula 1 according to claims 1 to 4 as therapeutic agents for the manufacture of medicaments for the treatment of diseases in which the inhibition of TNFa is therapeutically useful. 9. Use of the compounds of formula 1 according to claims 1 to 4 as therapeutic agents for the manufacture of medicaments for the treatment of diseases in which the inhibition of phosphodiesterase 4 is therapeutically useful. 10. Particularly preferred use of the compounds of formula 1 according to claims 1 to 4 as therapeutic agents for the manufacture of medicaments for the treatment of diseases which are associated with the action of eosinophils. 11. Medicaments containing one or more compounds according to the Claims 1 to 4 in addition to conventional physiologically compatible carriers and / or Diluents or auxiliaries. 12. A method for producing a medicament according to claim 11 characterized in that one or more compounds according to the Claims 1 to 4 with common pharmaceutical carriers and / or Diluents or other auxiliaries for pharmaceutical Prepared preparations or in a therapeutically applicable form to be brought 13. Use of compounds of general formula 1 according to claims 1 to 4 and / or of pharmaceutical preparations according to claims 11 and 12 alone or in combination with one another or in combination with carriers and / or diluents or other auxiliaries.