NZ540085A - Novel hydroxyindoles, their use as inhibitors of phosphodiesterase 4, and processes for preparing them - Google Patents

Abstract

Disclosed are compounds and processes for comparing compounds of general formula 1 wherein: n is 1 or 2; and R1 is optionally substituted alkyl; R2 and R3 are H or optionally substituted alkyl or NR2R3 together forms a saturated or unsaturated five membered or six membered ring which can contain up to 3 heteroatoms, wherein at least one of R2 and R3 is other than H; and R4 and R5 are H or OH wherein at least one of R4 and R5 is OH. Compounds of the type disclosed are phosphodiesterase-4 inhibitors useful in the treatment of diseases associated with the activity of eosinophils and neutrophils.

Description

New Zealand Paient Spedficaiion for Paient Number 540085 54 0 0 8 5 Novel hydroxyindoles, their use as inhibitors of phosphodiesterase 4, and processes for preparing them Description The invention relates to substituted 4- or/and 7-hydroxyindoles, to processes for preparing them, to pharmaceutical preparations which comprise these compounds and to the pharmaceutical use of these 10 compounds, which are inhibitors of phosphodiesterase 4, as active compounds for treating diseases which can be influenced by using the compounds according to the invention to inhibit phosphodiesterase 4 activity in immunocompetent cells (e.g. macrophages and lympho-15 cytes) .

Activation of cell membrane receptors by transmitters leads to activation of the "second messenger" system. Adenylate cyclase synthesizes the active cyclic AMP 20 [cAMP] or cyclic GMP [cGMP] from AMP and GMP, respectively. The cyclic AMP and cyclic GMP give rise, for example, to relaxation in smooth muscle cells or to inhibition of mediator release or synthesis in inflammatory cells. The "second messengers" cAMP and 25 cGMP are broken down by the phosphodiesterases (PDEs) . To date, 11 families of PDE enzymes (PDE1-11) are known, with these families differing from each other in their substrate specificity (cAMP, cGMP or both) and they are dependent on other substrates (e.g. 30 calmodulin). These isoenzymes possess different functions in the body and are expressed to different extents in the individual cell types (Beavo, JA, Conti, M and Heaslip, RJ, Multiple cyclic nucleotide phosphodiesterases, Mol. Pharmacol. 1994, 46: 399-405; 35 Hall, IP, Isoenzyme selective phosphodiesterase inhibitors: potential clinical uses, Br. J. clin. Pharmacol. 1993, 35: 1-7). Inhibiting the different PDE isoenzyme types results in cAMP and/or cGMP accumulating in cells, a situation which can be used therapeutically (Torphy, TJ, Livi, GP, Christensen, SB, Novel phosphodiesterase Inhibitors for the Therapy of Asthma, Drug News and Perspectives 1993, 6: 203-214).

Type 4 is the predominant PDE isoenzyme in the cells (lymphocytes, mast cells, eosinophilic granulocytes, macrophages) which are of importance for allergic inflammations (Torphy, JT and Undem, BJ, phosphodiesterase inhibitors: new opportunities for the 10 treatment of asthma, Thorax 1991, 46: 512-523). Using suitable inhibitors to inhibit PDE 4 is therefore regarded as being an important approach for treating a large number of allergically induced diseases (Schudt, Ch, Dent, G, Rabe, K, Phosphodiesterase 15 Inhibitors, Academic Press London 1996).

The important property of phosphodiesterase 4 inhibitors is their ability to inhibit the release of tumour necrosis factor a (TNFa) from inflammatory cells. TNFa 20 is an important proinflammatory cytokine which exerts an influence on a large number of biological processes. TNFa is released, for example, from activated macrophages, activated T-lymphocytes, mast cells, basophils, fibroblasts, endothelial cells and astrocytes in the 25 brain. It has a self-activating effect on neutrophils, eosinophils, fibroblasts and endothelial cells, resulting in a variety of tissue-destroying mediators being released. In monocytes, macrophages and T lymphocytes, TNFa brings about an increase in the 30 production of other proinflammatory cytokines, such as GM-CSF (granulocyte-macrophage colony-stimulating factor) or interleukin 8. As a result of its inflammation-promoting and catabolic effect, TNFa plays a central role in a large number of diseases, such as 35 inflammations of the airways, inflammations of the joints, endotoxic shock, tissue rejections, AIDS and many other immunological diseases. Inhibitors of phosphodiesterase 4 are consequently also suitable for treating these TNFa-associated diseases.

Chronic obstructive pulmonary diseases, COPD, are widespread in the population and are also of great economic importance. Thus, COPD diseases are responsible for approx. 10-15% of all disease costs in 5 the developed countries and approx. 25% of all deaths in the USA can be attributed to this cause (Norman, P.: COPD: New developments and therapeutic opportunities, Drug News Perspect. 11(7), 431-437, 1998), although it is true that the patients are usually aged over 55 at 10 the time of death (Nolte, D: Chronische Bronchitis -eine Volkskrankheit multifaktorieller Genese [Chronic bronchitis - a wide-spread disease of multifactorial origin], Atemw.-Lungenkrkh. [Airway-lung diseases] 20(5), 260-267, 1994). The WHO estimates that COPD will 15 be the third most frequent cause of death within the next 20 years.

The clinical picture of chronic obstructive pulmonary diseases (COPDs) encompasses a variety of clinical 20 pictures of chronic bronchitides, involving the symptoms of coughing and expectoration, and also progressive and irreversible deterioration in lung function (expiration is particularly affected). The cause of the disease is episodic and frequently 25 complicated by bacterial 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 declines steadily and the lung 30 becomes increasingly emphysematous and the difficulty patients have in breathing becomes evident. This disease markedly impairs the quality of life of patients (shortness of breath, low exercise tolerance) and significantly reduces their life expectancy. Apart 35 from environmental factors, the main risk factor is smoking (Kummer, F: Asthma und COPD [Asthma and COPD] Atemw.-Lungenkrkh. [Airway-lung diseases] 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 men are therefore much more frequently affected than are women. However, this picture will shift in the future as a result of changes in custom and the increase in the 5 number of female smokers.

Current therapy is only aimed at alleviating the symptoms without attacking the causes for the progression in the disease. The use of long-acting 10 beta2 agonists (e.g. salmeterol), where appropriate in combination with muscarinergic antagonists (e.g. ipratropium), improves lung function as a result of bronchodilatation and is employed routinely (Norman, P: COPD: New developments and therapeutic opportunities, 15 Drug News Perspect. 11(7), 431-437, 1998). Bacterial infections, which have to be treated with antibiotics, play an important role in the COPD episodes (Wilson, R: The role of infection in COPD, Chest, 113(4) Suppl. 242S-248S, 1998; Grossman, RF: The value of antibiotics 20 and the outcomes of antibiotic therapy in exacerbations of COPD, Chest, 113(4) Suppl., 249S-255S, 1998). The therapy of this disease is still unsatisfactory, particularly in view of the steady decline in lung function. Novel therapeutic approaches which are 25 directed against inflammation mediators, proteases or adhesion molecules could be very promising (Barnes, PJ: Chronic obstructive disease: new opportunities for drug development, TiPS 10(19), 415-423, 1998).

Independently of the bacterial infections which complicate the disease, a chronic inflammation, which is dominated by neutrophilic granulocytes, can be found in the bronchi. The mediators and enzymes which are released by neutrophilic granulocytes are thought to be 35 responsible, inter alia, for the structural changes which are observed in the airways (emphysema) . Consequently, inhibiting the activity of the neutrophilic granulocytes is a rational approach for preventing or retarding the progress of the COPD (deterioration in lung function parameters). The proinflammatory cytokine TNFa (tumour necrosis factor) is an important stimulus for activating the granulocytes. Thus, it is known that TNFa stimulates 5 the formation of oxygen radicals by neutrophilic 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). PDE 4 inhibitors are 10 able very effectively to inhibit the release of TNFa from a large number of cells and consequently suppress the activity of the neutrophilic granulocytes. The nonspecific PDE inhibitor pentoxifylline is able to inhibit both the formation of oxygen radicals and the 15 ability of neutrophilic granulocytes to phagocytose (Wenisch, C; Zedwitz-Liebenstein, K; Parschalk, B and Graninger, W: Effect of pentoxifylline in vitro on neutrophil reactive oxygen production and phagocytic ability assessed by flow cytometry, Clin. Drug Invest., 20 13(2): 99-104, 1997).

A variety of PDE 4 inhibitors are already known. These are primarily xanthine derivatives, rolipram analogues or nitraquazone derivatives (review in: Karlsson, J-A, 25 Aldos, D, Phosphodiesterase 4 inhibitors for the treatment of asthma, Exp. Opin. Ther. Patents 1997, 7: 989-1003) . It has not thus far been possible to bring any of these compounds into clinical use. It has come to be realized that the known PDE 4 inhibitors also 30 possess a variety of side-effects, such as nausea and vomiting, which it has not thus far been possible to suppress adequately. It is therefore necessary to discover new PDE 4 inhibitors which have better therapeutic breadth.

Indol-3-ylglyoxylic acid amides, and methods for preparing them, have already been described on a number of occasions. In every case, indoles which are unsubstituted in the 3 position, and which were synthesized by substituting a commercially available indole in the 1 position, were converted, by reaction with oxalyl halides, into indol-3-ylglyoxylyl halides, which then, by reacting with ammonia or with primary or 5 secondary amines, give the corresponding indol-3-ylglyoxylic acid amides (Scheme 1).

Scheme 1 r ' Thus, the patents US 2, 825, 734 and US 3,188,313 15 describe various indol-3-ylglyoxylic acid amides which are prepared in accordance with Scheme 1. These compounds were used as intermediates for preparing indole derivatives which were formed by reductions. The patent US 3,642,803 also describes indol-3-ylglyoxylic 20 acid amides.

Farmaco 22 (1967), 229-244 describes the preparation of 5-methoxyindol-3-ylglyoxylic acid amides. Once again, the indole derivative which is employed is reacted with 25 oxalyl chloride and the resulting indol-3-ylglyoxylyl chloride is reacted with an amine.

In addition, the patent US 6,008,231 also describes indol-3-ylglyoxylic acid amides and methods for 30 preparing them. Once again, use is made of the reaction steps and reaction conditions depicted in Scheme 1. 4-or 7-hydroxyindole derivatives are not described.

Substituted 5-hydroxyindolylglyoxylic acid amides and 35 6-hydroxyindolylglyoxylic acid amides, and methods for X = halogen preparing them, and their first use as PDE 4 inhibitors, were described for the first time in patent application DE 198 18 964 A1. However, 4- or 5 7-hydroxyindole derivatives, and their preparation and use, are not disclosed.

The invention relates to compounds of the general formula 1, R R (C=0)n R R 1 in which n can be = 1 or 2, and R1 (i) is -Ci_io-alkyl, which is straight-chain or branched and optionally substituted, once or more than once, by mono-, bi- or tricyclic saturated or monounsaturated or polyunsaturated carbocycles having 3-14 ring members, where the carbocyclic substituents for their part are substituted once or more than once by -NO2 intellectual property office of n.z. - 2 MAR 200/ RECEIVED and can be optionally substituted, once or more than once, by -Ci-6-alkyl, -OH, NH2, -NHCi-e-alkyl, -N (Cx-g-alkyl) 2, -N02, -CN, -F, -CI, -Br, -I, -0-Ci-6-alkyl, -S-Ci_6-5 alkyl, -SO3H, -S02Ci-6-alkyl, 0S02Ci-6-alkyl, COOH, - (CO) Ci-5-alkyl or -0 (CO) Ci_5-alkyl, and where the alkyl groups on the carbocyclic substituents can, for their part, be optionally substituted, once or 10 more than once, by -OH, -SH, -NH2, -F, - CI, -Br, -I, -SO3H or -COOH, R2 and R3 (i) are, in each case independently of each other, hydrogen or -Ci-5-alkyl, which is optionally substituted, once or more than once, by -OH, -SH, -NH2, -NHCi-6-20 alkyl, -N (Ci_6-alkyl) 2, -N02, -CN, -F, -CI, -Br, -I, -0-Ci_6-alkyl, -S-Ci_6-alkyl, phenyl or -pyridyl, -phenyl which is optionally substituted, once or 25 more than once, by -Ci_3-alkyl, -OH, -SH, - NH2, -NHCi-3-alkyl, -N (Ci_3-alkyl) 2, -N02, -CN, -COOH, -COOCi-3-alkyl, -F, -CI, -Br, -I, -O-Ci-3-alkyl, -S-Ci-3-alkyl or -O-(CO)-Ci-3-alkyl, -pyridyl intellectual property office of n.z. - 2 MAR 2007 RECEIVED which is optionally substituted, once or more than once, by -Ci-3-alkyl, -OH, -SH, -N02, -CN, -COOH, -COOCi-3-alkyl, -F, -CI, -Br, -I, -O-Ci-3-alkyl, -S-Ci-3-alkyl or -0-5 (CO)-Ci-3-alkyl, where only one of R2 and R3 is hydrogen and where the alkyl groups on the carbocyclic and heterocyclic substituents can, for their part, be optionally 10 substituted, once or more than once, by - OH, -SH, -NH2, -F, -CI, -Br, -I, -S03H, -COOH, - (CO)-Ci-5-alkyl, or -0 (CO) Ci-5-alkyl, or (ii) NR2R3 together form a saturated or unsaturated five-membered or six-membered ring which can contain up to 3 heteroatoms, preferably N, S and 0, and which is optionally substituted, once or more than once, by -Ci_3-alkyl, -OH, -SH, 20 N02, -CN, -COOH, -COOCi-3-alkyl, -F, -CI, - Br, -I, -O-Ci-3-alkyl, -S-Ci-3-alkyl or -0(C0) -Ci-3-alkyl, R4 and R5 are -H or -OH, where at least one of the two must be -OH, or salts of the compounds according to formula 1. intellectual property ofpicf of n.z - 2 MAR 2007 RECEIVED The invention furthermore relates to the physiologically tolerated salts of the compounds according to formula 1.

The physiologically tolerated salts are obtained in a customary manner by neutralizing the bases with inorganic or organic acids or by neutralizing the acids with inorganic or organic bases. Examples of suitable inorganic acids are 10 hydrochloric acid, sulphuric acid, phosphoric acid or hydrobromic acid, while examples of suitable organic acids are carboxylic acid, sulpho acid or sulphonic acid, such as acetic acid, tartaric acid, lactic acid, propionic acid, glycolic acid, malonic 15 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, salicylic acid, 3-aminosalicyclic acid, ascorbic acid, embonic acid, 20 nicotinic acid, isonicotinic acid, oxalic acid, amino acids, methanesulphonic acid, ethanesulphonic acid, 2-hydroxyethanesulphonic acid, ethane-1,2-disulphonic acid, benzenesulphonic acid, 4-methylbenzenesulphonic acid or naphthalene-2-25 sulphonic acid. Examples of suitable inorganic bases are sodium hydroxide, potassium hydroxide and ammonia, while examples of suitable organic bases are amines, preferably, however, tertiary amines, such as trimethylamine, triethylamine, pyridine, 30 N,N-dimethylaniline, quinoline, isoquinoline, intellectual property ofrcf of m.z - 2 MAS 2007 RECEIVED a-picoline, p-picoline, y-picoline, quinaldine and pyrimidine.

In addition, physiologically tolerated salts of the compounds according to formula 1 can be obtained by 5 converting derivatives which possess tertiary amino groups into the corresponding quaternary ammonium salts in a manner known per se using quaternizing agents. Examples of suitable quaternizing agents are alkyl halides, such as methyl iodide, ethyl bromide and 10 n-propyl chloride, and also arylalkyl halides, such as benzyl chloride or 2-phenylethyl bromide.

Furthermore, in the case of the compounds of the formula _1 which contain an asymmetric carbon atom, the 15 invention relates to the D form, the L form and D,L mixtures and also, where more than one asymmetric carbon atom is present, to the diastereomeric forms. Those compounds of the formula 1 which contain asymmetric carbon atoms, and which as a rule accrue as 20 racemates, can be separated into the optically active isomers in a known manner, for example using an optically active acid. However, it is also possible to use an optically active starting substance from the outset, with a corresponding optically active or 25 diastereomeric compound then being obtained as the end product.

The compounds according to the invention have been found to have pharmacologically important properties 30 which can be used therapeutically. The compounds according to formula 1 can be used on their own, in combination with each other or in combination with other active compounds. The compounds according to the invention are inhibitors of phosphodiesterase 4. It is 35 therefore a part of the subject-matter of this invention that the compounds according to formula 1., and their salts and also pharmaceutical preparations which comprise these compounds or their salts, can be used for treating diseases in which inhibiting phosphodiesterase 4 is of value.

These diseases include, for example joint inflammations, including arthritis and rheumatoid 5 arthritis and also other arthritic diseases, such as rheumatoid spondylitis and osteoarthritis. Other possible applications are the treatment of patients who are suffering from osteoporosis, sepsis, septic shock, Gram-negative sepsis, toxic shock syndrome, dyspnoea 10 syndrome, asthma or other chronic pulmonary diseases, such as COPD, bone resorption diseases or transplant rejection reactions, or other autoimmune diseases, such as lupus erythematosus, multiple sclerosis, glomerulonephritis and uveitis, insulin-dependent 15 diabetes mellitus and chronic demyelination.

In addition, the compounds according to the invention can also be used for therapy of infections, such as viral infections and parasite infections, for example 20 for therapy of malaria, leishmaniasis, infection-induced fever, infection-induced muscular pains, AIDS and cachexias, and also nonallergic rhinitis.

The compounds according to the invention can also be 25 used as bronchodilators and for asthma prophylaxis.

Furthermore, the compounds according to formula 1 are inhibitors of the accumulation and activity of eosinophils. As a consequence, the compounds according 30 to the invention can also be used in connection with diseases in which eosinophils play a role. These diseases include, for example, inflammatory airway diseases, such as bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, eczemas, 35 allergic angiitis, eosinophil-induced inflammations, such as eosinophilic fasciitis, eosinophilic pneumonia and PIE (pulmonary Infiltration involving eosinophilia) syndrome, urticaria, ulcerative colitis, Crohn's disease and proliferative skin diseases, such as psoriasis or keratosis.

It is also part of the subject-matter of this invention that the compounds according to formula 1 and their 5 salts are also able to inhibit LPS-induced pulmonary neutrophil infiltration in rats in vivo. The pharmacologically important properties which have been found verify that the compounds according to formula 1, and their salts and also pharmaceutical preparations 10 which comprise these compounds or their salts, can be used therapeutically for treating chronic obstructive lung diseases.

The compounds according to the invention furthermore 15 possess neuroprotective properties and can be used for treating diseases in which neuroprotection is of value. Examples of these diseases are senile dementia (Alzheimer's disease), loss of memory, Parkinson's disease, depressions, strokes and intermittent 20 claudication.

Other possible applications of the compounds according to the invention are the prophylaxes and therapy of prostate diseases, such as benign prostate hyperplasia, pollakiuria, nocturia and the treatment of incontinence, of colic caused by urinary calculi, and of male and female sexual dysfunctions.

Finally, the compounds according to the invention can also be used for inhibiting the development of pharmaceutical dependency in connection with the repeated use of analgesics, such as morphine, and for using the development of tolerance in connection with the repeated use of the analgesics.

An effective dose of the compounds according to the invention, or their salts, is used, in addition to the customary auxiliary substances, carrier substances and additives, for producing the pharmaceuticals. The dose of the active compounds can vary depending on the route of administration, the age and weight of the patient, the nature and severity of the diseases to be treated, and similar factors. The daily dose can be given as a 5 single dose, which is to be administered once, or be subdivided into two or more daily doses, and is as a rule 0.001-100 mg. Particular preference is given to administering daily doses of 0.1-50 mg.

Suitable administration forms are oral, parenteral, intravenous, transdermal, topical, inhalative and intranasal preparations. Particular preference is given to using topical, inhalative and intranasal preparations of the compounds according to the 15 invention. The customary galenic preparation forms, such as tablets, sugar-coated tablets, capsules, dispersible powders, granulates, aqueous solutions, aqueous or oily suspensions, syrups, juices or drops, are used.

Solid medicinal forms can comprise inert components and carrier substances, such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatine, guar gum, magnesium stearate, 25 aluminium stearate, methyl cellulose, talc, highly dispersed silicic acids, silicone oil, higher molecular weight fatty acids, (such as stearic acid), gelatine, agar agar or vegetable or animal fats and oils, or solid high molecular weight polymers (such as 30 polyethylene glycol); preparations which are suitable for oral administration can comprise additional flavourings and/or sweetening agents, if desired.

Liquid medicinal forms can be sterilized and/or, where 35 appropriate, comprise auxiliary substances, such as preservatives, stabilizers, wetting agents, penetrating agents, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols for regulating the osmotic pressure or for buffering, and/or viscosity regulators.

Examples of such additives are tartrate and citrate 5 buffers, ethanol and sequestering agents (such as ethylenediaminetetraacetic acid and its non-toxic salts). High molecular weight polymers, such as liquid polyethylene oxides, microcrystalline celluloses, carboxymethyl celluloses, polyvinylpyrrolidones, dex-10 trans or gelatine, are suitable for regulating the viscosity. Examples of solid carrier substances are starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar 15 agar, calcium phosphate, magnesium stearate, animal and vegetable fats, and solid high molecular weight polymers, such as polyethylene glycol.

Oily suspensions for parenteral or topical applications 20 can be vegetable synthetic or semisynthetic oils, such as liquid fatty acid esters having in each case from 8 to 22 C atoms in the fatty acid chains, for example palmitic acid, lauric acid, tridecanoic acid, margaric acid, stearic acid, arachidic acid, myristic acid, 25 behenic acid, pentadecanoic acid, linoleic acid, elaidic acid, brasidic acid, erucic acid or oleic acid, which are esterified with monohydric to trihydric alcohols having from 1 to 6 C atoms, such as methanol, ethanol, propanol, butanol, pentanol or their isomers, 30 glycol or glycerol. Examples of such fatty acid esters are commercially available miglyols, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG 6-capric acid, caprylic/capric acid esters of saturated fatty alcohols, polyoxyethylene glycerol trioleates, 35 ethyl oleate, waxy fatty acid esters, such as artificial ducktail gland fat, coconut fatty acid isopropyl ester, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol fatty acid esters, inter alia. Silicone oils of differing viscosity, or fatty alcohols, such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or oleyl alcohol, or fatty acids, such as oleic acid, are also suitable. It is furthermore possible to 5 use vegetable oils, such as castor oil, almond oil, olive oil, sesame oil, cotton seed oil, groundnut oil or soybean oil.

Suitable solvents, gelatinizing agents and solubilizers 10 are water or water-miscible solvents. Examples of suitable substances are alcohols, such as ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerol, di- or tripropylene glycol, waxes, 15 methyl cellosolve, cellosolve, esters, morpholines, dioxane, dimethyl sulphoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, etc.

Cellulose ethers which can dissolve or swell both in 20 water or in organic solvents, such as hydroxypropyl-methyl cellulose, methyl cellulose or ethyl cellulose, or soluble starches, can be used as film-forming agents.

Mixtures of gelatinizing agents and film-forming agents are also perfectly possible. In this case, use is made, in particular, of ionic macromolecules such as sodium carboxymethyl cellulose, polyacrylic acid, polymeth-acrylic acid and their salts, sodium amylopectin 30 semiglycolate, alginic acid or propylene glycol alginate as the sodium salt, gum arabic, xanthan gum, guar gum or carrageenan. The following can be used as additional formulation aids: glycerol, paraffin of differing viscosity, triethanolamine, collagen, allan-35 toin and novantisolic acid. Use of surfactants, emulsifiers or wetting agents, for example of Na lauryl sulphate, fatty alcohol ether sulphates, di-Na-N-lauryl-p-iminodipropionate, polyethoxylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (e.g. Tween), cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene stearate, alkyl-phenol polyglycol ethers, cetyltrimethylammonium chloride or mono-/dialkylpolyglycol ether orthophos-5 phoric acid monoethanolamine salts can also be required for the formulation. Stabilizers, such as montmorillonites or colloidal silicic acids, for stabilizing emulsions or preventing the breakdown of active substances such as antioxidants, for example 10 tocopherols or butylhydroxyanisole, or preservatives, such as p-hydroxybenzoic acid esters, can likewise be used for preparing the desired formulations.

Preparations for parenteral administration can be 15 present in separate dose unit forms, such as ampoules or vials. Use is preferably made of solutions of the active compound, preferably aqueous solution and, in particular, isotonic solutions and also suspensions. These injection forms can be made available as ready-20 to-use preparations or only be prepared directly before use, by mixing the active compound, for example the lyophilisate, where appropriate containing other solid carrier substances, with the desired solvent or suspending agent.

Intranasal preparations can be present as aqueous or oily solutions or as aqueous or oily suspensions. They can also be present as lyophilisates which are prepared before use using the suitable solvent or suspending 30 agent.

The preparations are produced, aliquoted and sealed under the customary antimicrobial and aseptic conditions.

The invention furthermore relates to processes for preparing the compounds according to the invention.

According to the invention, the compounds of the general formula 1, having the previously described meanings of R1, R2, R3, R4, R5 and n = 1, are prepared by initially converting indole-3- carboxylic acids of the formula 2 having an identical meaning of R1, in which R4 and R5 are -H or -OR6, where at least one of the two must be -OR6 and R6 is a protecting group or 15 leaving group, in particular alkyl, cycloalkyl, aryl-alkyl, aryl, heteroaryl, acyl, alkoxycarbonyl, aryloxy-carbonyl, aminocarbonyl, N-substituted aminocarbonyl, silyl or sulphonyl groups, and also sequestering agents, such as compounds of boric acid or of 20 phosphoric acid, and also covalently or coordinately bound metals, such as zinc, aluminium or copper, in a manner known per se, using acid chlorides, preferably using thionyl chloride or oxalyl chloride, 25 into the analogous indole-3-carbonyl chlorides of the formula 3.

CL 4 R* Compounds of the general formula 1, having the previously described meanings of R1, R2 and R3 and n = 5 1, and also the meanings for R4 and R5 as described for formulae 2 and 3^ are then formed from the isolated indole-3-carbonyl chlorides of the formula _3 by reacting them with a primary or secondary amine. The reaction proceeds advantageously in the presence of an 10 auxiliary base. Auxiliary bases which can be used are an excess of the amine employed as the coreactant, a tertiary amine, preferably pyridine or triethylamine, and inorganic bases, preferably alkali metal hydroxides or alkali metal hydrides.

The compounds of the formula 1 according to the invention are liberated by eliminating the leaving group R6 which is still present in R4 and/or R5.

Both acids and bases, such as hydrobromic acid, hydrochloric acid or hydriodic acid, or sodium hydroxide, potassium hydroxide and sodium carbonate or potassium carbonate, and also activating Lewis acids, such as AICI3, BF3, BBr3 or LiCl, are employed for 25 eliminating the -R6 substituent. The elimination reaction in each case takes place in the absence or presence of additional activators, such as ethane-1,2-dithiol or benzylmercaptan and also ether cleavages, using hydrogen, under elevated pressure or 30 under normal pressure, in the presence of a suitable catalyst, such as palladium or iridium catalysts.

According to the invention, the compounds of the general formula 1, having the previously described meanings of R1, R2 and R3, and n = 2, R2 R— / -N R5 (c=o), 7 R4 R1 are prepared by initially converting indoles of the formula £, having an identical meaning of R1, in which R4 and R5 are -H or -OR6, where at least one of the two must be -OR6 and R6 is a protecting group or leaving group, in particular alkyl, cycloalkyl, aryl-15 alkyl, aryl, heteroaryl, acyl, alkoxycarbonyl, aryloxy-carbonyl, aminocarbonyl, N-substituted aminocarbonyl, silyl or sulphonyl groups, and also sequestering agents, such as compounds of boric acid or of phosphoric acid, and also covalently or coordinatively 20 bound metals, such as zinc, aluminium or copper, in a manner known per se, by acylating them with oxalyl chloride, into the analogous indol-3-ylglyoxyl chlorides of the formula 5.

Compounds of the general formula 1_, having the previously described meanings of R1, R2 and R3, and n = 2, and also the meanings for R4 and R5 as described for 5 formulae _4 and 5, are then formed from the isolated indol-3-ylglyoxyl chlorides of the formula _5 by reacting them with a primary or secondary amine. The reaction proceeds advantageously in the presence of an auxiliary base. Auxiliary bases which can be used are 10 an excess of the amine employed as the coreactant, a tertiary amine, preferably pyridine or triethylamine, and also inorganic bases, preferably alkali metal hydroxides or alkali metal hydrides.

The compounds of the formula 1 according to the invention are liberated by eliminating the leaving group R6 which is still present in R4 and/or R5.

Both acids and bases, such as hydrobromic acid, 20 hydrochloric acid or hydriodic acid, or sodium hydroxide, potassium hydroxide and sodium carbonate or potassium carbonate, and also activating Lewis acids, such as AICI3, BF3, BBr3 or LiCl, are employed for eliminating the -R6 substituent. The elimination 25 reaction in each case takes place in the absence or presence of additional activators, such as ethane-1,2-dithiol or benzylmercaptan and also ether cleavages, using hydrogen, under elevated pressure or under normal pressure, in the presence of a suitable 30 catalyst, such as palladium or iridium catalysts.

Examples Example 1: Preparing N-(3,5-dichloropyrdin-4-yl)-[1-(4-fluorobenzyl)-4-hydroxyindol-3-yl]carboxylic acid amide This is an example of a process for preparing compounds of the formula 1 according to the invention in which n = 1. 3.22 g of 4-benzyloxy-l-(4-fluorobenzyl)indole-3-car-boxylic acid (8.6 mmol) are suspended in 15 ml of dichloromethane. While cooling with water, 1.8 ml of oxalyl chloride (17.4 mmol) are added. The reaction mixture is stirred for 8 hours. During this time, 10 4-benzyloxy-l-(4-fluorobenzyl)indole-3-carbonyl chloride crystallized out. It is isolated and dissolved in 18 ml of tetrahydrofuran (THF). 1.14 g of sodium hydride (60% strength) are suspended 15 in 21 ml of THF. While the suspension is being stirred at approx. 10°C, a solution of 1.5 g of 4-amino-3,5-dichloropyridine (8.6 mmol) in 21 ml of THF is added dropwise. After approx. 15 minutes, the previously prepared solution of the 4-benzyloxy-l-(4-fluoro-20 benzyl)indole-3-carbonyl chloride is added dropwise to the reaction mixture. After that, the whole is boiled at reflux for 3 hours. 36 ml of ethyl acetate and 36 ml of water are then added to the reaction mixture after it has cooled down. The phases are separated and the 25 organic phase is washed with water. The solvent is distilled off and the residue is recrystallized from ethanol and dried.

The N-(3,5-dichloropyridin-4-yl)-[4-benzyloxy-l-(4- fluorobenzyl)indol-3-yl]carboxamide which has been obtained in this way is dissolved in 100 ml of dichloromethane. The solution is heated to reflux and a solution of 1 ml of BBr3 in 10 ml of dichloromethane is then added dropwise. After that, the mixture is heated 35 to reflux, and while stirring, for a further 3 hours. After it has been cooled down to 10°C, 100 ml of a 1 M solution of NaHCC>3 are added, thereby achieving a pH of 8-9. During this procedure, the temperature has to be kept below 20°C. The mixture is subsequently stirred for a further 3 hours. The product, which has crystallized out, is filtered off with suction, washed with water and dried. The crude product is recrystallized from ethanol.

Yield: 1.4 g (37.8% of theory) Melting point: 263-265°C Example 2: Preparing N- (3,5-dichloropyrdin-4-yl)-[1-10 (4-chlorobenzyl)-7-hydroxyindol-3-yl]gly- oxylic acid amide This is an example of a process for preparing compounds of the formula 1 according to the invention in which 15 n = 2: .9 g of 7-benzyloxy-l-(4-chlorobenzyl)indole (17 mmol) are dissolved in 50 ml of tert-butyl methyl ether. A solution of 2.6 ml of oxalyl chloride (30 mmol) in 20 10 ml of tert-butyl methyl ether is added dropwise at 0°C and while stirring. After that, the mixture is boiled at reflux for 2 hours. The solvent is then distilled off in vacuo. The resulting 7-benzyloxy-l-(4-chlorobenzyl)indole-3-ylglyoxyl chloride is obtained as 25 a solid residue, which is suspended in 50 ml of tetrahydrofuran (THF).

A solution of 2.77 g of 4-amino-3,5-dichloropyridine (17 mmol) in 20 ml of THF is added dropwise, at -5°C, 30 to a suspension of 2.7 g of sodium hydride in 80 ml of THF. After that, the mixture, while being stirred, is kept at a constant temperature of 20°C for 1 hour. The previously prepared suspension of the 7-benzyloxy-l-(4-chlorobenzyl)indol-3-ylglyoxyl chloride is then added 35 dropwise at approx. 0°C. Finally, the reaction mixture is boiled at reflux for 4 hours. The solvent is removed in vacuo. The residue is stirred up with 50 ml of ethyl acetate and 50 ml of water. The phases are separated. The organic phase is washed with water. The solvent is distilled in vacuo. The residue is recrystallized from isopropanol.

The N-(3,5-dichloropyridin-4-yl)-[7-benzyloxy-l-(4- chlorobenzyl)indol-3-yl]glyoxylic acid amide which has been obtained in this way is dissolved in 100 ml of dichloromethane. The solution is heated to reflux and a solution of 1 ml of BBr3 in 10 ml of dichloromethane is added dropwise. After that, the mixture is heated to 10 reflux, while being stirred, for a further 3 hours. After the mixture has been cooled down to 10°C, 100 ml of a 1 M solution of NaHC03 are added, thereby achieving a pH of 8-9. During this procedure, the temperature has to be kept below 20°C. The mixture is 15 subsequently stirred for a further 3 hours. The product, which has crystallized out, is filtered off with suction, washed with water and dried. The crude product is recrystallized from ethanol.

Yield: 3.8 g (47.5% of theory) Melting point: 245-247°C Example 3: Preparing other compounds The given preparation process can be used to prepare a large number of other compounds of the formula 1, of which the following are cited by way of example: Compound -r1 -nr2r3 -r" -r5 n 1 4-fluorobenzyl- 3,5-dichloro-4-pyridyl- -H -OH 1 amino- 2 4-chlorobenzyl- 3,5-dichloro-4-pyridyl-amino- -OH -H 2 3 4-chlorobenzyl- 3,5-dichloro-4-pyridyl-amino- -OH -H 1 4 4-fluorobenzyl- 3,5-dichloro-4-pyridyl-amino- -H -OH 2 4-fluorobenzyl- 3,5-dichloro-4-pyridyl-amino- -OH -H 2 6 2-fluorobenzyl- 3,5-dichloro-4-pyridyl-amino- -OH -H 2 7 3-nitrobenzyl- 3,5-dichloro-4-pyridyl-amino- -OH -H 2 8 2,6-difluoro-benzyl- 3,5-dichloro-4-pyridyl-amino- -OH -H 2 9 2,4-difluoro-benzyl- 3,5-dichloro-4-pyridyl-amino- -OH -H 2 2-chlorobenzyl- 3,5-dichloro-4-pyridyl-amino- -OH -H 2 11 2,6-dichloro-benzyl- 3,5-dichloro-4-pyridyl-amino- -OH -H 2 12 2-methylbenzyl- 3,5-dichloro-4-pyridyl-amino- -OH -H 2 13 2,6-dimethyl-benzyl- 3,5-dichloro-4-pyridyl-amino- -OH -H 2 14 n-hexyl- 3,5-dichloro-4-pyridyl-amino- -OH -H 2 isobutyl- 3,5-dichloro-4-pyridyl-amino- -OH -H 2 16 cyclopropyl-methyl- 3,5-dichloro-4-pyridyl-amino- -OH -H 2 17 4-fluorobenzyl- 2,6-dichlorophenylamino- -OH -H 2 18 2-fluorobenzyl- 2,6-dichlorophenylamino- -OH -H 2 19 2-fluorobenzyl- 4-pyridylamino- -OH -H 2 4-pyridyl-methyl- 3,5-dichloro-4-pyridyl-amino- -OH -H 2 21 4-fluorobenzyl- piperidyl- -OH -H 2 22 4-hydroxy- 3,5-dichloro-4-pyridyl- -OH -H 2 benzyl- amino- 23 2-chloro-6-fluorobenzyl- 3,5-dichloro-4-pyridyl-amino- -OH -H 2 24 2-trifluoro-methylbenzyl- 3,5-dichloro-4-pyridyl-amino- -OH -H 2 2-fluorobenzyl- N-methyl-4-pyridylamino- -OH -H 2 26 2-fluorobenzyl- 2,6-dimethyl-4-pyridyl-amino- -OH -H 2 27 2-carboxy-benzyl- 3,5-dichloro-4-pyridyl-amino- -OH -H 2 The compounds according to the invention are powerful inhibitors of phosphodiesterase 4. Their therapeutic potential is verified in vivo by, for example, 5 inhibiting the asthmatic late-phase reaction (eosinophilia), and by inhibiting LPS-induced neutrophilia, in rats.

Example 4: Inhibiting phosphodiesterase 4 The PDE 4 activity is determined using enzyme preparations from human polymorphonuclear lymphocytes (PMNLs). Human blood (buffy coats) was anticoagulated with citrate. The platelet-rich plasma in the supernatant is 15 separated from the erythrocytes and leucocytes by centrifuging at 700 x g for 20 minutes at room temperature (RT). The PMNLs for the PDE 4 determination are isolated by means of a subsequent dextran sedimentation followed by a gradient centrifugation 20 using Ficoll-Paque. After the cells have been washed twice, the erythrocytes which are still present are lysed within 6 minutes by adding 10 ml of hypotonic buffer (155 mM NH4C1, 10 mM NaHC03, 0.1 mM EDTA, pH = 7.4) at 4°C. The PMNLs, which are still intact, are 25 washed a further two times with PBS and lysed by ultrasonication. The supernatant obtained after centrifuging at 48 000 x g at 4°C for one hour contains the cytosolic PDE 4 fraction and is used for the PDE 4 measurements.

The phosphodiesterase activity is measured using a 5 modified Amersham Pharmacia Biotech method, i.e. an SPA (scintillation proximity assay) assay. The reaction mixtures contain buffer (50 mM tris-HCl (pH 7.4), 5 mM MgCl2, 100 jj,M cGMP) , varying concentrations of the inhibitors, and the corresponding enzyme preparation. 10 The reaction is started by adding the substrate, i.e. 0.5 (0.M [3H]-cAMP. The final volume is 100 (j.1. Test substances are prepared as stock solutions in DMSO. The concentration of DMSO in the reaction mixture is 1% v/v. This DMSO concentration has no effect on PDE 15 activity. After the reaction has been started by adding the substrate, the samples are incubated at 37°C for 30 minutes. The reaction is stopped by adding a defined quantity of SPA beads and the samples are measured in a beta counter after one hour. The nonspecific enzyme 20 activity (i.e. the blank) is determined in the presence of 100 (J.M rolipram and subtracted from the test values. The incubation mixtures for the PDE 4 assay contain 100 (J.M cGMP in order to inhibit any contamination of PDE 3 which may be present.

In regard to inhibiting phosphodiesterase 4, the compounds according to the invention were found to have IC50 values in the range from 10-9 to 10"5 M. The selectivity towards PDE types 3, 5 and 7 is a factor of 30 from 100 to 10 000.

The PDE 4 inhibition results obtained with selected application examples are compiled in the following table: Compound Inhibition of PDE 4 IC50 [pmol/1] 2 0.002 4 0. 938 0.015 6 0. 001 7 0.002 8 0.002 0. 020 16 0.030 17 0.141 22 0. 003 Example 5: Inhibiting late-phase eosinophilia 48 h after inhalative ovalbumin challenge formed on actively sensitized Brown Norway rats The inhibition exerted by the substances according to the invention on pulmonary eosinophil infiltration is examined in male Brown Norway rats (200-250 g) which have been actively sensitized against ovalbumin (OVA). 10 The sensitization is effected by subcutaneously injecting a suspension of 10 jxg of OVA, together with 20 mg of aluminium hydroxide as adjuvant, in 0.5 ml of physiological sodium chloride solution per animal on days 1, 14 and 21. In addition to this, each of the 15 animals is injected at the same time with 0.25 ml of Bordetalla pertussis vaccine dilution i.p. On the 28th day of the experiment, the animals are placed individually in open 1 1 Plexiglass boxes which are connected to a head/nose exposure appliance. The 20 animals are exposed to an aerosol consisting of a 1.0% suspension of ovalbumin (Allergen Challenge). The ovalbumin aerosol is generated using a compressed air (0.2 MPa)-driven nebulizer (Bird micro nebulizer, Palm Springs CA, USA) . The exposure time is 1 hour, with 25 normal controls likewise being nebulized for 1 hour with an aerosol consisting of a 0.9% solution of sodium chloride. 48 hours after the allergen challenge, there is a 5 massive immigration of eosinophilic granulocytes into the lungs of the animals. At this time, the animals are anaesthetized with an overdose of ethylurethane (1.5 g/kg of body weight, given i.p.) and a bronchoalveolar lavage (BAL) is carried out using 3 x 10 4 ml of Hank's balance solution. The total cell count, and the number of eosinophilic granulocytes, in the pooled BAL liquid are then determined using an automatic haemocytometer (Bayer Diagnostics Technicon HIE). For each animal, the eosinophils (EOS) in the BAL 15 are calculated in 106/animal: EOS/nl x BAL recovery (ml) = EOS/animal. Two control groups (nebulization with physiological sodium chloride solution and nebulization with OVA solution) are included in each test.

The percentage inhibition of the eosinophilia in the substance-treated experimental group is calculated using the following formula: {((OVAC-SC)-(OVAD-SC))/(OVAC-SC)} x 100% = % inhibition (SC = control group treated with vehicle and challenged with 0.9% sodium chloride solution; OVAC = control group treated with vehicle and challenged with 1% of ovalbumin suspension; OVAD = experimental group treated 30 with substance and challenged with 1% of ovalbumin suspension) The test substances are administered intraperitoneally or orally, 2 hours prior to the allergen challenge, as 35 a suspension in 10% polyethylene glycol 300 and 0.5% 5-hydroxyethyl cellulose. The control groups are treated with the vehicle in accordance with the manner in which the test substance is administered.

Following intraperitoneal administration of 10 mg/kg the compounds according to the invention inhibit late-phase eosinophilia by from 30% to 100%, while they inhibit it by from 30% to 75% following the oral 5 administration of 30 mg/kg.

The compounds according to the invention are consequently particularly suitable for producing pharmaceuticals for treating diseases which are associated with 10 the activity of eosinophils.

Example 6: Inhibiting lipopolysaccharide (LPS)-induced pulmonary neutrophilia in Lewis rats The ability of the substances according to the invention to inhibit pulmonary neutrophil infiltration is examined in male Lewis rats (200-350 g) . On the day of the experiment, the animals are placed individually in open 1 1 Plexiglass boxes which are connected to a 20 head/nose exposure appliance. The animals are exposed to an aerosol consisting of a suspension of lipopolysaccharide (100 (ag of LPS/ml of 0.1% hydroxylamine solution) in PBS (LPS provocation) . The LPS/hydroxylamine aerosol is generated using a 25 compressed air (0.2 MPa)-driven nebulizer (Bird micro nebulizer, Palm Springs CA, USA) . The exposure time is 40 minutes, with normal controls likewise being nebulized for 40 minutes with an aerosol consisting of a 0.1% solution of hydroxylamine in PBS. 6 hours after the LPS provocation, there is a maximal and massive immigration of neutrophilic granulocytes into the lungs of the animals. At this time, the animals are anaesthetized with an overdose of 35 ethylurethane (1.5 g/kg of body weight, given i.p.) and a bronchoalveolar lavage (BAL) is carried out using 3 x 4 ml of Hank's balance solution. The total cell count, and the number of neutrophilic granulocytes, in the pooled BAL liquid are then determined using an

Claims (22)

- 31 - automatic haemocytometer (Bayer Diagnostics Technicon HIE) . In the case of each animal, the neutrophils (NEUTRO) in the BAL are calculated in 106/animal: NEUTRO/^1 x BAL recovery (ml) = NEUTRO/animal. 5 Two control groups (nebulization with a 0.1% hydroxylamine solution in PBS and nebulization with 100 (j.g of LPS/ml of 0.1% hydroxylamine solution in PBS) are included in each test. The percentage inhibition of 10 the neutrophilia in the substance-treated experimental group is calculated using the following formula: {((LPSC-SC)-(LPSD-SC))/(LPSC-SC)} x 100% = % inhibition 15 SC = control group treated with vehicle and challenged with 0.1% hydroxylamine solution; LPSC = control group treated with vehicle and challenged with LPS (100 pg/ml of 0.1% hydroxylamine solution); LPSD = experimental group treated with substance and challenged with LPS 20 (100 |ag/ml of 0.1% hydroxylamine solution) The test substances are administered orally, 2 hours prior to the LPS provocation, as a suspension in 10% polyethylene glycol 300 and 0.5% 5-hydroxyethyl 25 cellulose. The control groups are treated with the vehicle in accordance with the mode of administration used for the test substance. Following oral administration of 1 mg/kg, the compounds 30 according to the invention inhibit the neutrophilia by from 30% to 90% and are consequently particularly suitable for producing pharmaceuticals for treating diseases which are associated with the activity of neutrophils. 35 - 32 - Claims

1. Compounds of the general formula 1, in which n can be =1 or 2, and R1 (i) is -Ci-j.0-alkyl, which is straight-chain or branched and optionally substituted, once or more than once, by mono-, bi- or tricyclic sa-turated or monounsaturated or polyunsaturated carbocycles having 3-14 ring members, where the carbocyclic substituents for their part are substituted once or more than once by -N02 and can be optionally substituted, once or more than once, by -Chalky!,' -OH, -NH2, -NHCi-s-alkyl, -N (Ci_6-alkyl) 2, -N02, -CN, -F, -CI, -Br, -I-, -O-C^-alkyl, S Ci-6 alkyl, SO3-ti, SO2C3.-6 alkyl, OSO^Ci—$ alkyl, -COOH, - (GO) Ci-S-alkyl or -0(C0)Ci_s-alkyl, and where the alkyl groups on the carbocyclic substituents■can, for their part, be optionally substituted, once or more than once, by -OH, -SH, -NH2, -F, -CI, -Br, -I, —SO3H or -COOH, R2 and R3 (i) are, in each case independently of each -33- other, hydrogen or -Ci-s-alkyi, which is optionally substituted, once or more than once, by -OH, -SH, -NH2, -NHCi_6-alkyl, -N (Ci_6-alkyl) 2, -N02, -CN, -F, -CI, -Br, -I, -O-Ci-e-alkyl, -S-CX-6-5 alkyl, -phenyl or -pyridyl, -phenyl which is optionally substituted, once or more than once, by -Ci_3-alkyl, -OH, -SH, -NH2, -NHCi_3-alkyl, -N(C1_3-alkyl)2, -N02, -CN, -COOH, -COOCi_3-alkyl, -F, -10 CI, -Br, -I, -O-Ci-3-alkyl, -S-Ci_3-alkyl or -0-(CO)-Ci_ 3-alkyl, -pyridyl which is optionally substituted, once or more than once, by -C^-alkyl, -OH, -SH, -N02, -CN, -COOH, -15 C00Ci_3-alkyl, -F, -CI, -Br, -I, -0-Ci_3-alkyl, -S-Ci-3- alkyl or -0-(CO)-Ci_3-alkyl, where only one of R2 and R3 is hydrogen and where the alkyl groups on the carbocyclic and heterocyclic substituents can, for their part, be optionally 20 substituted, once or more than once, by -OH, -SH, -NH2, -F, -CI, -Br, -I, -S03H, -COOH, - (CO)-Ci_5-alkyl, or -0 (CO) Ci-5-alkyl, or (ii) NR2R3 together form a saturated or unsaturated five-membered or six-membered ring which can contain up to 25 3 heteroatoms, preferably N, S and O, and which is optionally substituted, once or more than once, by -Ci_ 3-alkyl, -OH, -SH, N02, -CN, -COOH, -C00Ci_3-alkyl, -F, -CI, -Br, -I, -0-C;L_3-alkyl, -S-C^-alkyl or -0(C0)-C!_ 3-alkyl, 30 R4 and R5 are -H or -OH, where at least one of the two must be -OH, or salts of the compounds according to formula 1. 35 2. Compounds according to formula 1_ according to intellectual. property officf of n.z. -

2 MAR 2007 RECEIVED - 34 - Claim 1 having ah asymmetric carbon atom in the D form or L form, or D,L mixtures or, when more than one asymmetrical carbon atom is present, the diastereomeric forms!.

3 . Compounds according' to Claim 1 or 2, wherein n = 2.

4. Compounds according to one of Claims 1 to 3, wherein R* = -OH and Rs = -H. .

5. Compounds according to one of Claims 1 to 4, wherein —NR2R3 is a pheiiylamino or pyridylamino which is substituted by one or inore halogen atoms.

6. Compounds according to one of Claims 1 to 4, wherein R1 is a substituted benzyl radical.

7. Compounds according to Claim 6, wherein the benzyl radical . contains at least one substituent in the ortho position on the phenyl ring.

8. Compound according to formula 1 according to one of Claims 1 to 7: N- (3, t>-dichlorop'yridin-4-yl) - [1- (3-nitrobenzyl) -7-hydroxyindol-3-yl]glyoxylic acid amide, and physiologically tolerated salts thereof.

Process for preparing compounds according to formula 1 according to Claim 1 in. which n = 1, wherein INTELLECTUAL PROPERTY #WCE OF N1 -7 SEP 2005 RECEIVER -35- indole-3-carboxylic acids of the formula 2 are converted, using acid chlorides, into the analogous indole-3-carbonyl chloride of the formula 3, the latter are converted into the corresponding amides by reaction with primary and secondary amines, and the compounds according to formula 1, in which n = 1, are liberated by eliminating a protecting group.

10. Process according to Claim 9, wherein thionyl chloride or oxalyl chloride are used as acid chlorides for synthesizing the indole-3-carbonyl chlorides according to formula 3.

11. Process according to Claim 9 or 10, wherein the indole-3-carbonyl chlorides according to formula 3 are reacted with primary or secondary amines in the presence of an auxiliary base, preferably in the presence of an excess of the amine employed as coreactant, of a tertiary ail[11j^LLEC:TUAL pR0pERp for example of pyridine or triethylamine, and alscpfficf of m.z. of inorganic bases, preferably alkali r.etal- 2 MAR 2007 hydroxides or alkali metal hydrides. 0 _ __ HbuEiV E C 36 HO, O 2 r CI. indole-3-carboxylic acids of the formula are converted, using acid chlorides, into the analogous indole-3-carbonyl chloride of the formula 3, the latter are converted into the corresponding amides by reaction with primary and secondary amines, and the compounds according to formula 1, in which n = 1, are liberated by eliminating a protecting group.

10. Process according to Claim 9, wherein thionyl chloride or oxalyl chloride are used as acid chlorides for synthesizing the indole-3-carbonyl chlorides according to formula 3^.

11. Process according to Claim 9 or 10, wherein the indole-3-carbonyl chlorides according to formula 3 are reacted with primary or secondary INTELLECTUAL PROPERTY offiof of m.z. "2 MAS 2007 RECEI VFn 37 amines in the presence of an auxiliary base, preferably in the presence of an excess of the amine employed as coreactant, of a tertiary amine, for example of pyridine or triethylamine, and also of inorganic bases, preferably alkali metal hydroxides or alkali metal hydrides.

12. Process for preparing compounds according to formula 1 according to Claim 1 in which n = 2, indoles of the formula are converted, using oxalyl chloride, into the analogous indol-3-ylglyoxylyl chlorides of the formula 5, the latter are converted into the corresponding amides by reaction with primary or secondary amines, and the compounds according to formula in which n = 2, are liberated by eliminating a protecting group.

13. Process according to Claim 12, wherein 4 wherein INTEUtCTUAL prqpert ofrof qp i\j 2. - 2 MAR 2007 38 indol-3-ylglyoxylyl chlorides according to formula 5 are reacted with primary or secondary amines in the presence of an auxiliary base, preferably in the presence of an excess of the amine employed as coreactant, of a tertiary amine, for example of pyridine or triethylamine, and also of inorganic bases, preferably alkali metal hydroxides or alkali metal hydrides.

14. Use of the compounds according to formula 1 according to one of Claims 1 to 8 as therapeutic active compounds for producing pharmaceuticals for treating diseases in which inhibiting phosphodiesterase 4 is of therapeutic value.

15. Use of the compounds according to formula 1 according to one of Claims 1 to 8 as therapeutic active compounds for producing pharmaceuticals for treating diseases which are associated with the activity of eosinophils.

16. Use of the compounds according to formula _1 according to one of Claims 1 to 8 as therapeutic active compounds for producing pharmaceuticals for treating diseases which are associated with the activity of neutrophils. intellectual property office of m.z -2 MAR aw -RECEIVED 39

17. Pharmaceuticals which comprise one or more compounds according to any one of Claims 1 to 8 in addition to customary, physiologically tolerated excipients and/or diluents or auxiliary substances.

18. Process for producing a pharmaceutical according to Claim 17, wherein one or more compounds according to one of Claims 1 to 8, together with customary pharmaceutical carrier substances and/or diluents or other auxiliary substances, is/are processed into pharmaceutical preparations or brought into a form which can be used therapeutically.

19. Use of compounds of the general formula 1 according to one of Claims 1 to 8 and/or pharmaceuticals as claimed in Claim 17 in combination with each other or in combination with other pharmaceutical active compounds in the manufacture of a medicament.

20. Compounds of the general formula 1, as claimed in any one of Claims 1 to 8, substantially as herein described with reference to Examples 1 to 3.

21. A process according to any one of Claims 9 to 11, substantially as herein described with reference to Example 1. IN i ELll-C mJAl PROPERTY offiof of n.z - 2 MAS 2007 RECEIVED 40

22. A process according to Claim 12 or Claim 13, substantially as herein described with reference to Example 2. ELBION AG AcUOJlfl f By its Attorneys BALDWINS INiELLECTUAL property ofrof of mz. -2 MAS 2007 RECEIVED