DE10053275A1 - New 7-aza-indole-3-carboxamides or glyoxylamides, useful e.g. for treating rheumatoid arthritis, osteoporosis, sepsis, asthma or multiple sclerosis are phosphodiesterase-4 and tumor necrosis factor-alpha inhibitors - Google Patents

Abstract

7-Aza-indole-3-carboxamides or glyoxylamides (I) are new. 7-Aza-indoles of formula (I), including their acid or base addition salts, quaternary salts, D-, L- or D,L-isomers and diastereomers, are new: n = 1 or 2; R1 = 1-10C alkyl or 2-10C alkenyl (both optionally substituted (os) by one or more of OH, SH, NH2, NHT, NT2, NHAr, NAr2, NTAr, NO2, CN, halo, OT, OAr, ST, SAr, SO3H, SO2T, SO2Ar, OSO2T, OSO2Ar, COOH, 2-6C alkanoyl, Car or Het); Car = mono-, bi- or tricyclic, 3-14 membered saturated or mono- or polyunsaturated carbocycle (os by one or more R4); Het = mono-, bi- or tricyclic, 5-14 membered saturated or mono- or polyunsaturated heterocycle containing 1-6 heteroatoms (preferably N, O or S) (os by one or more R4); R2, R3 = H (but not both H), 1-5C alkyl (os by one or more of OH, SH, NH2, NHT, NT2, NO2, CN, halo, OT, ST, Ph and pyridyl), phenyl (os by one or more of OH, SH, NH2, NHU, NU2, NO2, CN, COOH, COOU, F, Cl, Br, OU and SU), pyridyl (os by one or more of NO2, CN, COOH, COOU, Cl, Br, OU and SU), halo, OT, ST, Ph and pyridyl), 2,4-dioxo-1,2,6-trimethyl-1,2,3,4-tetrahydropyrimidin-5-yl, 2,4-dioxo-4,6-dimethyl-1,2,3,4-tetrahydropyrimidin-5-yl, 2,4-dioxo-6-methyl-1,2,3,4-tetrahydropyrimidin-5-yl or 4H-1,2,4-triazol-3-yl; or NR2R3 = morpholino, thiomorpholino, S,S-dioxo-thiomorpholino or 4-methyl-piperazino; R4 = H, OH, SH, NH2, NHT, NT2, NHAr, NAr2, NTAr, NHCOT, NO2, CN, COOH, COOT, COT, CST, halo, OT, OAr, ST, SAr, SOT or SO2T; T = 1-6C alkyl; Ar = 6-14C aryl; U = 1-3C alkyl. Independent claims are included for the preparation of (I).

Description

Technical field

The invention relates to substituted 7-azaindoles 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) are to be influenced by the compounds according to the invention.

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 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 11 families of PDE enzymes (PDE1-11) known by their substrate specificity (cAMP, cGMP or both) and differentiate the dependence on other substrates (e.g. calmodulin). This Isoenzymes have different functions in the body and are in the different types of cells differ (Beavo JA, Conti M and Heaslip  RJ. Multiple cyclic nucleotide phosphodiesterases. Mol. Pharmacol. 1994, 46: 399- 405; Hall IP. Isoenzyme selective phosphodiesterase inhibitors: potential clinical uses, Br. J. clin. Pharmacol. 1993, 35: 1-7). By inhibiting the different There is a cumulation of cAMP or cGMP in the PDE isoenzyme types Cells, which can be used therapeutically (Torphy TJ, Livi GP, Christensen SB. Novel Phosphodiesterase Inhibitors for the Therapy of Asthma, Drug News and Perspectives 1993, 6: 203-214).

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. phosphodiesterase inhibitors: new opportunities for the treatment of asthma. Thorax 1991, 46: 512-523). The Inhibition of PDE 4 by suitable inhibitors is therefore considered an important approach considered for the therapy of 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 the release of tumor necrosis factor α (TNFα) from inflammatory cells. TNFα is a major pro-inflammatory cytokine that has a wide variety biological processes affected. TNFα is released, for example activated macrophages, activated T-lymphocytes, mast cells, basophils, Fibroblasts, endothelial cells and astrocytes in the brain. It is self-activating on neutrophils, eosinophils, fibroblasts and endothelial cells, whereby various tissue-destroying mediators are released. In monocytes, Macrophages and T lymphocytes cause TNFα to produce more further pro-inflammatory cytokines such as GM-CSF (Granulocy-macrophage colony-stimulating factor) or interleukin-8. Because of his TNFα plays an inflammatory and catabolic effect 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 therapy such diseases associated with TNFα are inhibitors of Phosphodiesterase 4 is therefore also suitable.  

Chronic obstructive pulmonary disease diseases, COPD) are widespread in the population and also have one great economic importance. How COPD diseases cause approx. 10-15% of all medical expenses in developed countries and approximately 25% of all Deaths in the U.S. are attributed to this cause (Norman P .: COPD: New developments and therapeutic opportunities, Drug News Perspect. 11 (7), 431-437, 1998), however, the patients are mostly at the time of death over 55 years old (Nolte D .: Chronic bronchitis - a common disease multifactorial genesis. Atemw.-Lungenkrkh. 20 (5), 260-267, 1994). The WHO estimates that COPD will be the third most common over the next 20 years Cause of death will be.

Under the clinical picture of chronic obstructive pulmonary diseases (COPD) are associated with various clinical pictures of chronic bronchitis the symptoms of coughing and expectoration, as well as progressive and irreversible Worsening of lung function (expiration is particularly affected) summarized. The course of the disease is relapsing and often bacterial Infections complicated (Rennard S. I .: COPD: Overview of definitions, Epidemiology, and factors influencing its development. Chest, 113 (4) Suppl., 235S-241S, 1998). In the course of the disease, the lung function steadily decreases, the lungs become increasingly emphysematous and the patient becomes short of breath obviously. This disease significantly affects the quality of life Patients (shortness of breath, low resilience) and significantly shortened them Life expectancy. The main risk factor alongside environmental factors is smoking (Kummer F .: Asthma and COPD. Atemw.-Lungkrkh. 20 (5), 299-302, 1994; Rennard S. I .: COPD: Overview of definitions, Epidemiology, and factors influencing its development. Chest, 113 (4) Suppl., 235S-241S, 1998) and therefore men are affected much more often than women. By changing the Lifestyle habits and the increase in the number of smokers will change but shift this picture in the future.  

The current therapy only aims to relieve the symptoms without to intervene causally in the progression of the disease. The use of long-acting beta2 agonists (e.g. salmeterol) possibly in combination with muscarinic antagonists (e.g. ipratropium) improve lung function due to bronchodilation and is used routinely (Norman P .: COPD: New developments and therapeutic opportunities, Drug News Perspect. 11 (7), 431-437, 1998). Bacterial play a major role in COPD relapses Infections requiring antibiotic treatment (Wilson R .: The role of infection in COPD, Chest, 113 (4) Suppl., 242S-248S, 1998; Grossman R. F .: The value of antibiotics and the vutcomes of antibiotic therapy in exacerbations of COPD. Chest, 113 (4) Suppl., 249S-255S, 1998). Therapy of this disease has so far been unsatisfactory, especially with regard to the steady decrease the lung function. New therapeutic approaches based on inflammation mediators, Attacking proteases or adhesion molecules could be very promising (Barnes P. J .: Chronic obstructive disease: new opportunities for drug development, TiPS 10 (19), 415-423, 1998).

Regardless of the bacterial infections complicating the disease there is a chronic inflammation in the bronchi, which is caused by neutrophil granulocytes is dominated. For the observed structural Changes in the airways (emphysema) are caused by, among other things neutrophil granulocytes released mediators and enzymes responsible made. The inhibition of the activity of the neutrophil granulocytes is therefore a rational approach to COPD progression (worsening of Prevent or slow down lung function parameters). An important The stimulus for the activation of the granulocytes is the pro-inflammatory Cytokine TNFα (tumor necrosis factor). So it is known that TNFα the formation of Oxygen radicals stimulated by neutrophil granulocytes (Jersmann, H. P. A .; Rathjen, D.A. and Ferrante A .: Enhancement of LPS-induced neutrophil oxygen radical production by TNFα, Infection and Immunity, 4, 1744-1747, 1998). PDE4 inhibitors can be very effective at releasing TNFα from a Inhibit a large number of cells and thus the activity of the neutrophil granulocytes suppress. The non-specific PDE inhibitor pentoxifylline is able to  both the formation of oxygen radicals and the phagocytosis ability inhibit neutrophil granulocytes (Wenisch, C .; Zedtwitz-Liebenstein, K .; Parschalk, B. and Graninger W .: Effect of pentoxifylline in vitro on neutrophil reactive oxygen production and phagocytic ability assessed by flow cytometry, Clin. Drug Invest., 13 (2): 99-104, 1997).

Various PDE 4 inhibitors are already known. It acts primarily are xanthine derivatives, rolipram analogues or nitraquazone Descendants (overview in: Karlsson J-A, Aldos D Phosphodiesterase 4 inhibitors for the treatment of asthma, Exp. Opin. Ther. 1997, 7: 989-1003). No These compounds have so far been brought to clinical use become. It had to be found that the known PDE 4 inhibitors too have various side effects such as nausea and emesis that have not so far could be pushed back sufficiently. That is why the discovery is new PDE 4 inhibitors with better therapeutic range required.

The use of 7-azaindoles in the development of new active ingredients for Various indications have so far only been described in relatively few cases.

In Japanese patent JP 10120681 (Fujisawa Pharmaceutical Co., Ltd.) 5- and 7-azaindoles of the general formula

claimed, wherein R ^{1 is} hydrogen or short alkyl groups, R ^{2 can be} hydrogen, halogen, short alkyl groups, cycloalkyl groups, alkylcarbonyl groups or alkanoyl groups, R ³ for alkanoyl groups, protected carboxylic acid groups , the cyano group or substituted carbamoyl groups. L means a short alkylene bridge. Q stands for substituted aromatics and heterocycles. Of A ¹ and A ² , one stands for N and the other for CH. These compounds differ from the compounds according to the invention in particular with regard to the substituents R ² and R ³ , in some cases in R ¹ and A ² . The compounds described are claimed as inhibitors of a cGMP-specific phosphodiesterase (PDE 5). Areas of application are various cardiovascular diseases, bronchitis, asthma, rhinitis, impotence, diabetic complications and glaucoma.

By LN Yakhontov, SS Liberman, DM Krasnokutskaya et al. are in Khim.- Farm. Zh. 8 (11), 1974, 5-9 describe the syntheses of various 3-aminoalkyl-4-azaindoles and 3-aminoalkyl-7-azaindoles. For 3- (2-aminoethyl) -7-azaindoles, depressive or antidepressant effects are described. An antihypertensive effect has been found for 3-aminomethyl-7-azaindoie. AJ Verbiscar describes in J. Med. Chem. 15 (2), 1972, 149-52 the compound of the formula

for which an antimalaria effect has been determined.

The synthesis is described in GB 1141949 (Sterling Drug Inc.) various 2- (imidazolin-2-yl) alkyl-7-azaindoles or 3- (imidazolin-2-yl) alkyl 7-azaindoles from the corresponding 2- or 3-cyanoalkyl-7-azaindoles described and for these compounds use as vasoconstrictors claimed.

So far, 7-azaindoles are completely unknown as inhibitors of PDE 4.  

Description of the invention

The invention relates to substituted 7-azaindoles of the general formula 1 ,

wherein
n can be 1 or 2, and
R ¹ for
-C _{1 ... 10} -alkyl, 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), -NO ₂ , -CN, -F, -Cl, -Br , -I, -OC _{1 ... 6} -alkyl, -OC _{6 ... 14} -aryl, -SC _{1 ... 6} -alkyl, -SC _{6 ... 14} aryl, -SO ₃ H, -SO ₂ C _{1 ... 6} alkyl, -SO ₂ C _{6 ... 14} aryl, -OSO ₂ C _{1 ... 6} alkyl, -OSO ₂ C _{6 ... 14} aryl, -COOH, - (CO) C _{1 ... 5} alkyl, with mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3 ... 14 ring members, with mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5. ..15 ring members and 1 ... 6 heteroatoms, which are preferably N, O and S,
where the C _{6 ... 14} aryl groups and the carbocyclic and heterocyclic substituents in turn may be substituted one or more times with R ⁴ ,
-C _{2 ... 10} 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), -NO ₂ , -CN, -F, -Cl, -Br , -I, -OC _{1 ... 6} alkyl, -OC _{6 ... 14} aryl, SC _{1 ... 6} alkyl, -SC _{6 ... 14} aryl, -SO ₃ H, -SO ₂ C _{1 ... 6} alkyl, -SO ₂ C _{6 ... 14} aryl, -OSO ₂ C _{1 ... 6} alkyl, -O ₂ C _{6 ... 14} aryl, -COOH, - (CO) C _{1 ... 5} alkyl, with mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3 ... 14 ring members, with mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5 .. .15 ring members and 1 ... 6 heteroatoms, which are preferably N, O and S,
where the C _{6 ... 14} aryl groups and the carbocyclic and heterocyclic substituents in turn may be substituted one or more times with R ⁴ ,
stands.

R ² and R ³ can be the same or different, with only one of them being hydrogen. R ² and R ³ can continue
-C _{1 ... 5} alkyl,
optionally substituted one or more times with -OH, -SH, -NH ₂ , -NHC _{1 ... 6} -alkyl, -N (C _{1 ... 6} -alkyl) ₂ , -NO ₂ , -CN, - F, -Cl, -Br, -I, -OC _{1 ... 6} alkyl, -SC _{1 ... 6} alkyl, -phenyl, -pyridyl
phenyl,
optionally substituted one or more times with -OH, -SH, -NH ₂ , -NHC _{1 ... 3} -alkyl, -N (C _{1 ... 3} -alkyl) ₂ , -NO ₂ , -CN, - COOH, -COOC _{1 ... 3} alkyl, -F, -Cl, -Br, -OC _{1 ... 3} alkyl, -SC _{1 ... 3} alkyl,
pyridyl,
optionally substituted one or more times with -NO ₂ , -CN, -COOH, -COOC _{1 ... 3} alkyl, -Cl, -Br, -OC _{1 ... 3} alkyl, -SC _{1 ... 3} alkyl,
such as

mean.  

Together the group -NR ² R ³ for

stand.
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), -NHCOC _{1 ... 6} alkyl, -NO ₂ , -CN, -COOH, - COOC _{1 ... 6} alkyl, - (CO) C _{1 ... 6} alkyl, - (CS) C _{1 ... 6} alkyl, -F, -Cl, -Br, -I, -OC _{1 ... 6} -alkyl, -OC _{6 ... 14} -aryl, -SC _{1 ... 6} -alkyl, -SC _{6 ... 14} aryl, -SOC _{1 ... 6} alkyl, -SO ₂ C _{1 ... 6} alkyl.

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

The physiologically acceptable salts are in the usual way Neutralization of the bases with inorganic or organic acids or by Obtain neutralization of the acids with inorganic or organic bases. Examples of inorganic acids are hydrochloric acid, sulfuric acid, Phosphoric acid or hydrobromic acid, as organic acids for example Carbonic, sulfonic 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. As  Inorganic bases come, for example, sodium hydroxide solution, potassium hydroxide solution, ammonia and as organic bases amines, but preferably tertiary amines, such as Trimethylamine, triethylamine, pyridine, N, N-dimethylaniline, quinoline, isoquinoline, 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.

The invention further relates to the compounds of the formula 1 which contain an asymmetric carbon atom, the D form, the L form and D, L mixtures and, in the case of several asymmetric carbon atoms, the diastereomeric forms. Those compounds of formula 1 which contain asymmetric carbon atoms and which are generally obtained as racemates can be separated into the optically active isomers in a manner known per se, for example using an optically active acid. 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.

For the compounds according to the invention, pharmacologically important ones Properties found that 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 TNFα is useful.

These diseases include, for example, joint inflammation including arthritis and rheumatoid arthritis as well as other arthritic Diseases such as rheumatoid spondylitis and osteoarthritis. Further Applications include the treatment of patients who are under  Osteoporosis, sepsis, septic shock, gram-negative sepsis, toxic Shock syndrome, respiratory distress syndrome, asthma or other chronic pulmonary Diseases, bone resorption diseases or graft Rejection or other autoimmune diseases such as lupus erythematosus, multiple sclerosis, glomerulonephritis and uveitis, insulin dependent diabetes mellitus and chronic demyelination.

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, leishmaniasis, infection-related fever, infection muscle pain, AIDS and cachexia.

The compounds according to the invention are inhibitors of phosphodiesterase 4. It is therefore the subject of this invention that the compounds according to 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 , Crohn's disease and proliferative skin diseases such as psoriasis or keratosis.

The object of this invention is that the compounds according to formula 1 and their salts can inhibit both the release of TNFα in vitro and the LPS-induced pulmonary neutrophil infiltration in rats in vivo. The entirety of these pharmacologically important properties found proves that the compounds according to formula 1 and their salts and pharmaceutical preparations which contain these compounds or their salts can be used therapeutically for the treatment of chronic obstructive pulmonary diseases.

The compounds of the invention also have neuroprotective properties Properties and can be used to treat diseases where neuroprotection is useful. Such diseases are, for example senile dementia (Alzheimer's disease), memory loss, Parkinson's Illness, depression, strokes and intermittent claudication.

Further possible uses of the compounds according to the invention are the prophylaxis and therapy of prostate diseases, such as benign prostate hyperplasia, pollakiuria, nocturia and the treatment of incontinence, colic caused by urinary stones and male and female sexual dysfunction.

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 divided into single doses or divided once to be given in 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 regulating 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). High-molecular polymers can be used to regulate the viscosity such as liquid polyethylene oxide, microcrystalline celluloses Carboxymethyl celluloses, polyvinyl pyrrolidones, dextrans or gelatin. firm 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 fats, solid high-molecular polymers such as polyethylene glycol.

Oily suspensions for parenteral or topical applications can vegetable synthetic or semi-synthetic oils such as liquid fatty acid esters with 8 to 22 carbon atoms in the fatty acid chains, for example palmitin,
Lauric, tridecyl, margaric, stearic, arachine, myristic, behenic, pentadecyl, linoleic, elaidic, brasidic, erucic or oleic acid, which are combined with mono- to trihydric alcohols with 1 to 6 C -Atoms such as methanol, ethanol, propanol, butanol, pentanol or their isomers, glycol or glycerol are esterified. Such fatty acid ester, for example, commercially available Miglyols, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG 6-capric acid, caprylic / Caprinsäureester of saturated fatty alcohols, Polyoxyethylenglyceroltrioleate, ethyl oleate, waxy fatty acid ester such as artificial duck preen gland fat, coconut fatty acid isopropyl ester, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol Fatty acid esters, etc. Also suitable are silicone oils of different viscosities or fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or oleyl alcohol, fatty acids such as oleic acid. Vegetable oils such as castor oil, almond oil, olive oil, sesame oil, cottonseed oil, peanut oil or soybean oil can also be used.

Water can be used as solvent, gelling agent and solubilizer or water-miscible solvents. For example, alcohols are suitable such as 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, tetrahydrofuran, Cyclohexanone etc.

Cellulose ethers can be used as film formers, which are both in Can dissolve or swell water as well as in organic solvents, such as hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose or soluble starches.  

Mixed forms between gel and film formers are also quite possible. Ionic macromolecules in particular are used here, 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- / Dialkyl 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 solutions of the active ingredient are used, preferably aqueous solutions and especially isotonic solutions but also suspensions. These injection forms can be provided as a ready-to-use product or only directly before the Application by mixing the active compound, for example the Lyophilisates, optionally with other solid carriers, with the desired solvents or suspending agents can be 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 aspetic conditions.

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

According to the invention the compounds of general formula 1 with the above shown definitions of R ^1, R ² are R ³ and n = 1 is prepared,

by 7-azaindole-3-carboxylic acids of formula 2 with identical meaning of R ¹

in a manner known per se using acid chlorides, preferably with thionyl chloride or oxalyl chloride, are first converted into the analog 7-azaindole-3-carboxylic acid chlorides of the formula 3 .

From the isolated 7-azaindole-3-carboxylic acid chlorides of the formula 3, the compounds of the general formula 1, with the meanings of R ¹ , R ² , R ³ and n = 1 described above, are subsequently formed by reaction with a primary or secondary amine. The reaction advantageously takes place in the presence of an auxiliary base. An excess of the amine used as the reactant, a tertiary amine, preferably pyridine or triethylamine, and inorganic bases, preferably alkali metal hydroxides or alkali metal hydrides, can be used as auxiliary bases.

According to the invention, the compounds of general formula 1 are prepared with the meanings of R ¹ , R ² , R ³ and n = 2 shown above,

by 7-azaindoles of formula 4 with identical meaning of R ¹

are first converted into the analog 7-azaindol-3-yl-glyoxylic acid chlorides of the formula 5 in a manner known per se by acylation with oxalyl chloride.

From the isolated 7-azaindol-3-yl-glyoxylic acid chlorides of the formula 5 , the compounds of the general formula 1 according to the invention with the meanings of R ¹ , R ² , R ³ and n = 2 described above are subsequently obtained by reaction with a primary or secondary amine The reaction proceeds advantageously in the presence of an auxiliary base: an excess of the amine used as the reactant, a tertiary amine, preferably pyridine or triethylamine, and inorganic bases, preferably alkali metal hydroxides or alkali metal hydrides, can be used as auxiliary bases.

embodiments

Exemplary production process for compounds of formula 1 according to the invention with n = 1:

example 1 N- (4-pyridylmethyl) -1-cyclopropylmethyl-7-azaindol-3- carboxamide

1.87 g of 1-cyclopropylmethyl-7-azaindole-3-carboxylic acid (8.6 mmol) are in 15 ml Dichloromethane suspended. While cooling with water, 1.8 ml Oxalyl chloride (17.4 mmol) added. The reaction mixture is 8 hours touched. The 1-cyclopropylmethyl-7-azaindole-3- crystallizes carboxylic acid chloride. It is isolated and in 18 ml of tetrahydrofuran (THF) solved.

1.14 g sodium hydride (60%) are suspended in 21 ml THF. A solution of 0.93 g of 4-aminomethylpyridine (8.6 mmol) in 21 ml of THF is added dropwise with stirring at about 10 ° C. After about 15 minutes, the previously prepared solution of 1-cyclopropylmethyl-7-azaindole-3-carboxylic acid chloride is added dropwise to the reaction mixture. The whole is then boiled under reflux for 3 hours. After cooling, the reaction mixture is mixed with 36 ml of ethyl acetate and 36 ml of water. The phases are separated and the organic phase washed with water. The solvent is distilled off and the residue is recrystallized from ethanol.
Yield: 1.3 g (50% of theory)
Melting point: 187-189 ° C

Numerous other compounds of formula 1 with n = 1 can be prepared using the preparation process indicated, of which the following are given by way of example:

Exemplary production process for compounds of formula 1 according to the invention with n = 2:

Example 12 N- (3,5-Dichloro-pyridin-4-yl) - [1- (3-methoxybenzyl) -7-azaindol-3-yl] - glyoxylic acid amide

3.57 g of 1- (3-methoxybenzyl) -7-azaindole (15 mmol) are tert in 50 ml. Butyl methyl ether dissolved. At 0 ° C, a solution of 1.54 ml Oxalyl chloride (18 mmol) tert in 10 ml. Butyl methyl ether added dropwise. After that the mixture was refluxed for 2 hours. Then that will Distilled off solvent in vacuo. The resulting 1- (3-methoxybenzyl) -7- azaindol-3-yl-glyoxylic acid chloride is obtained as a solid residue, which in 50 ml Tetrahydrofuran (THF) is suspended.

A solution of 2.4 g of 4-amino-3,5-dichloropyridine (15 mmol) in 30 ml of THF is added dropwise to a suspension of 2 g of sodium hydride in 20 ml of THF at -5 ° C. The mixture is then heated to 20 ° C. for 1 hour with stirring. Then the previously prepared suspension of 1- (3-methoxybenzyl) -7-azaindol-3-yl-glyoxylic acid chloride is added dropwise at about 0 ° C. Finally, the reaction mixture is refluxed for 4 hours. The solvent is removed in vacuo. The residue is mixed with 50 ml of ethyl acetate and 50 ml of water. stirred. The phases are separated. The organic phase is washed with water. The solvent is distilled off in vacuo. The residue is recrystallized from isopropanol.
Yield: 3.5 g (51.5% of theory)
Melting point: 165-167 ° C

Numerous further compounds of the formula 1 with n = 2 can be prepared using the preparation process indicated, of which the following are given by way of example:

The compounds according to the invention are strong inhibitors of phospho diesterase 4 and the TNFα release. Their therapeutic potential is in vivo for example by inhibiting the late phase asthmatic reaction (Eosinophilia) and by influencing the allergen-induced vascular Permeability demonstrated in actively sensitized Brown Norway rats.

Inhibition of phosphodiesterase

The PDE 4 activity is in enzyme preparations from human polymorphonuclear Lymphocytes (PMNL) determined the PDE 2, 3 and 5 activity with PDE human platelets. Human blood was anticoagulated with citrate. By centrifugation at 700 × g for 20 minutes at RT will platelet-rich plasma in the supernatant from the erythrocytes and leukocytes Cut. The platelets are lysed by ultrasound and in PDE 3 and PDE 5 assay used. To determine the PDE 2 activity, the cytosolic platelet fraction using an anion exchange column NaCl gradient is cleaned and the PDE 2 peak is obtained for the assay. The PMNLs for PDE 4 determination are given by the following Dextran sedimentation and subsequent gradient centrifugation with Ficoll Paque isolated. After washing the cells twice, they will still be containing erythrocytes by adding 10 ml of hypotonic buffer (155 mM NH4Cl, 10 mM NaHCO3, 0.1 mM EDTA, pH = 7.4) within 6 Minutes lysed at 4 ° C. The PMNLs that are still intact are checked twice with PBS washed and lysed using ultrasound. The supernatant of an hour Centrifugation at 4 ° C at 48000 × g contains the cytosolic fraction of 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 vessels are centrifuged at 3000 × g 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.

The results for the inhibition of PDE 4 are summarized in the following table for selected application examples:

Inhibition of TNFα 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 TNFα 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. TNFα 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 not stimulated with anti-IgE hardly produce TNFα, stimulated cells, on the other hand, secrete large amounts of TNFα. 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 (TNFα release of the cells stimulated with anti-IgE = 100%) of the tested substances at different concentrations.

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

The results for the inhibition of TNFα release were compiled in the following table for selected application examples:

Inhibition of late-phase eosinophilia 48 hours after inhalation Oval albumin challenge on actively sensitized Brown Norway rats

The inhibition of pulmonary eosinophil infiltration by the substances according to the invention become active against ovalbumin (OVA) Sensitized male Brown Norway rats (200-250 g) tested. The Sensitization takes place by subcutaneous injections of a suspension of 10 µg OVA together with 20 mg aluminum hydroxide as adjuvant in 0.5 ml physiological saline solution per animal on day 1, 14 and 21. In addition to this the animals receive Bordetella pertussis vaccine at the same times Dilution per animal 0.25 ml i. p. injected. On the 28th day of the experiment, the animals individually placed in open 1 liter plexiglass boxes attached to a head nose Exposure device are connected. The animals are made of an aerosol 1.0% ovalbumin suspension suspended (allergen challenge). The ovalbumin Aerosol is delivered through a nebulizer (Bird micro nebulizer, Palm Springs CA, USA). The exposure time is 1 Hour, taking normal controls with an aerosol of 0.9% saline also be nebulized for 1 hour.

There is a massive 48 hours after the allergen challenge Immigration of eosinophilic granulocytes into the lungs of the animals. To this The animals are overdosed with ethyl urethane (1.5 g / kg Body weight i. p.) anesthetized and bronchoalveolar lavage (BAL) with 3 × 4 ml of Hank's balance solution performed. The total number of cells and the number of Eosinophilic granulocytes of the pooled BAL fluid are then removed  with an automatic cell differentiation device (Bayer Diagnostics Technicon H1E) determined. For each animal, the eosinophils (EOS) are in the BAL in Mio / animal calculated: EOS / µl × BAL recovery (ml) = EOS / animal.

In each test, 2 control groups (nebulization with physiological Saline solution and nebulization with OVA solution).

The percentage inhibition of eosinophilia in the test group treated with the substance is calculated using the following formula:

{((OVAC - SC) - (OVAD - SC)) / (OVAC - SC)} × 100% =% inhibition

(SC = Vehicel treated and challenged with 0.9% saline Control group; OVAC = Vehicel treated and with 1% Ovalbumin suspension controlled group; OVAD = substance treated test group and challenged with 1% ovalbumin suspension)

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 after intraperitoneal application of 10 mg / kg by 30% to 100% and after oral application of 30 mg / kg by 30% to 75%.

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.

The results for the inhibition of eosinophilia have been compiled in the following table as an example for selected application examples:

Inhibition of lipopolysaccharide (LPS) -induced lung neutrophilia in Lewis rats

The inhibition of pulmonary neutrophil infiltration by the substances according to the invention are administered to male Lewis rats (250-350 g) checked. On the day of the experiment, the animals are placed individually in open 1 liter plexiglass boxes set, which are connected to a head-nose exposure device. The animals become an aerosol from a lipopolysaccharide suspension (100 µg LPS / ml 0.1% hydroxylamine solution) in PBS (LPS provocation). The LPS / hydroxylamine aerosol is powered by a compressed air (0.2 MPa) Nebulizer (Bird micro nebulizer, Palm Springs CA, USA). The Exposure time is 40 minutes, with normal controls using an aerosol Nebulized from 0.1% hydroxylamine solution in PBS also for 40 minutes become.

6 hours after the LPS provocation there is a maximum, massive Immigration of neutrophil granulocytes into the lungs of the animals. To this The animals are overdosed with ethyl urethane (1.5 g / kg Body weight i. p.) anesthetized and bronchoalveolar lavage (BAL) with 3 × 4 ml of Hank's balance solution performed. The total number of cells and the number of neutrophils of the pooled BAL fluid are then removed with an automatic cell differentiation device (Bayer Diagnostics Technicon H1E) determined. For each animal, the neutrophils (NEUTRO) are in the BAL in Mio / animal calculated: NEUTRQ / µl × BAL-Recovery (ml) = NEUTRO / animal.  

In each test, 2 control groups (nebulization with 0.1% Hydroxylamine solution in PBS and nebulization with 100 µg LPS / ml 0.1% Hydroxylamine solution in PBS) carried.

The percentage inhibition of neutrophilia in the test group treated with the substance is calculated according to the following farm egg:

{((LPSC - SC) - (LPSD - SC)) / (LPSC - SC)} × 100% =% inhibition

SC = Vehicel treated and challenged with 0.1% hydroxylamine solution Control group; LPSC = Vehicel treated and with LPS (100 µg / ml 0.1% Hydroxylamine solution) controlled control group; LPSD = substance treated and with LPS (100 pg / ml 0.1% hydroxylamine solution) gallallen test group.

The test substances are taken orally as a suspension in 10% polyethylene glycol 300 and 0.5% 5-hydroxyethyl cellulose 2 hours before the LPS challenge applied. The control groups are selected according to the application form Test substance treated with the Vehicel.

The compounds of the invention inhibit oral neutrophilia Application of 1 mg / kg by 40% to 90% and are therefore particularly suitable for the manufacture of medicines for the treatment of diseases associated with the Acts of neutrophils are linked.

For selected application examples, the results for neutrophil inhibition are summarized in the following table:

Claims (17)

1. 7-azaindoles of formula 1
wherein
n can be 1 or 2, and
R ¹ for
-C _{1 ... 10} -alkyl, 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 _{5 ... 14} aryl) ₂ , -N (C _{1 ... 6} alkyl) (C _{6 ... 14} aryl), -NO ₂ , -CN, -F, -Cl, -Br , -I, -OC _{1 ... 6} -alkyl, -OC _{6 ... 14} -aryl, -SC _{1 ... 6} -alkyl, -SC _{6 ... 14} aryl, -SO ₃ H, -SO ₂ C _{1 ... 6} alkyl, -SO ₂ C _{6 ... 14} aryl, -OSO ₂ C _{1 ... 6} alkyl, -OSO ₂ C _{6 ... 14} aryl, -COOH, - (CO) C _{1 ... 5} alkyl, with mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3 ... 14 ring members, with mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5. ..15 ring members and 1 ... 6 heteroatoms, which are preferably N, O and S,
where the C _{6 ... 14} aryl groups and the carbocyclic and heterocyclic substituents in turn may be substituted one or more times with R ⁴ ,
-C _{2 ... 10} 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), -NO ₂ , -CN, -F, -Cl, -Br , -I, -OC _{1 ... 6} -alkyl, -OC _{6 ... 14} -aryl, -SC _{1 ... 6} -alkyl, -SC _{6 ... 14} aryl, -SO ₃ H, -SO ₂ C _{1 ... 6} alkyl, -SO ₂ C _{6 ... 14} aryl, -OSO ₂ C _{1 ... 6} alkyl, -OSO ₂ C _{6 ... 14} aryl, -COOH, - (CO) C _{1 ... 5} alkyl, with mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3 ... 14 ring members, with mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5. ..15 ring members and 1 ... 6 heteroatoms, which are preferably N, O and S,
where the C _{6 ... 14} aryl groups and the carbocyclic and heterocyclic substituents in turn may be substituted one or more times with R ⁴ ,
stands,
R ² and R ^{3 may be the} same or different, with only one of the two being hydrogen, R ² and R ³ still
-C _{1 ... 5} alkyl,
optionally substituted one or more times with -OH, -SH, -NH ₂ , -NHC _{1 ... 6} -alkyl, -N (C _{1 ... 6} -alkyl) ₂ , -NO ₂ , -CN, - F, -Cl, -Br, -I, -OC _{1 ... 6} alkyl, -SC _{1 ... 6} alkyl, -phenyl, -pyridyl
phenyl,
optionally substituted one or more times with -OH, -SH, -NH ₂ , -NHC _{1 ... 3} -alkyl, -N (C _{1 ... 3} -alkyl) ₂ , -NO ₂ , -CN, - COOH, -COOC _{1 ... 3} alkyl, -F, -Cl, -Br, -OC _{1 ... 3} - alkyl, -SC _{1 ... 3} alkyl,
pyridyl,
optionally substituted one or more times with -NO ₂ , -CN, -COOH, -COOC _{1 ... 3} alkyl, -Cl, -Br, -OC _{1 ... 3} alkyl, -SC _{1 ... 3} alkyl,
such as
can mean
continue the group -NR ² R ³ together for
can stand
R ⁴ 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), -NHCOC _{1 ... 6} alkyl, -NO ₂ , -CN, -COOH, - COOC _{1 ... 6} alkyl, - (CO) C _{1 ... 6} alkyl, - (CS) C _{1 ... 6} alkyl, -F, -Cl, -Br, -I, -OC _{1 ... 6} -alkyl, -OC _{6 ... 14} -aryl, -SC _{1 ... 6} -alkyl, -SC _{6 ... 14} aryl, -SOC _{1 ... 6} alkyl, -SO ₂ C _{1 ... 6} alkyl
stands. 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 neutralization of 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 asymmetric carbon atom in the D-form, the L-form and D, L-mixtures and in the case of several asymmetric carbon atoms, the diastereomeric forms. 4. Of the compounds of formula 1 according to claims 1 to 3 with n = 1, especially one of the following compounds:
N- (4-pyridylmethyl) -1-cyclopropylmethyl-7-azaindol-3-carboxamide
N- (3,5-Dichloro-pyridin-4-yl) -1-isobutyl-7-azaindol-3-carboxamide
N- (3,5-Dichloro-pyridin-4-yl) -1-hexyl-7-azaindol-3-carboxamide
N- (3,5-Dichloro-pyridin-4-yl) -1-cyclopropylmethyl-7-azaindol-3-carboxamide
N- (4-pyridylmethyl) -1- (4-fluorobenzyl) -7-azaindol-3-carboxamide
N- (3,5-Dichloro-pyridin-4-yl) -1- (4-fluorobenzyl) -7-azaindol-3-carboxamide
N- (3,5-Dichloro-pyridin-4-yl) -1- (4-methoxybenzyl) -7-azaindol-3-carboxamide
N- (4-pyridylmethyl) -1- (4-chlorobenzyl) -7-azaindol-3-carboxamide
1- (4-fluorobenzyl) -7-azaindol-3-carboxylic acid morpholide
N- (2,6-dichlorophenyl) -1- (2-methylpropen-3-yl) -7-azaindol-3-carboxamide
N- (3,5-Dichloro-pyridin-4-yl) -1- (4-pyridylmethyl) -7-azaindol-3-carboxamide 5. Of the compounds of formula 1 according to claim 1 to 3 with n = 2 especially one of the following compounds:
N- (3,5-dichloropyridin-4-yl) - [1- (3-methoxybenzyl) -7-azaindol-3-yl] glyoxylic acid amide
N- (4-pyridyl) - [1- (4-fluorobenzyl) -7-azaindol-3-yl] -glyoxylsäureamid hydrochloride
N- (3,5-Dichloro-pyridin-4-yl) - [1- (4-fluorobenzyl) -7-azaindol-3-yl] -glyoxylsäureamid
N- (4-pyridyl) - [1- (4-chlorobenzyl) -7-azaindol-3-yl] -glyoxylsäureamid hydrochloride
N- (3,5-Dichloro-pyridin-4-yl) - [1- (4-chlorobenzyl) -7-azaindol-3-yl] -glyoxylsäureamid
N- (3,5-dichloropyridin-4-yl) - [1- (4-methoxybenzyl) -7-azaindol-3-yl] glyoxylic acid amide
N- (2,6-dichlorophenyl) - [1- (4-chlorobenzyl) -7-azaindol-3-yl] -glyoxylsäureamid
N- (4-carboxyphenyl) - [1- (4-fluorobenzyl) -7-azaindol-3-yl] -glyoxylsäureamid
N- (4-ethoxycarbonylphenyl) - [1- (4-fluorobenzyl) -7-azaindol-3-yl] -glyoxylsäureamid
N- (3,4-dimethoxyphenyl) - [1- (4-fluorobenzyl) -7-azaindol-3-yl] -glyoxylsäureamid
N- (3,5-Dichloro-pyridin-4-yl) - [1- (4-methylbenzyl) -7-azaindol-3-yl] -glyoxylsäureamid
N- (3,5-dichloropyridin-4-yl) - [1- (4-hydroxybenzyl) -7-azaindol-3-yl] glyoxylic acid amide
N- (3,5-Dichloro-pyridin-4-yl) - [1- (3-hydroxybenzyl) -7-azaindol-3-yl] -glyoxylsäureamid
N- (3,5-dichloropyridin-4-yl) - (1-cyclopropylmethyl-7-azaindol-3-yl) glyoxylic acid amide
N- (3,5-Dichloro-pyridin-4-yl) - (1-hexyl-7-azaindol-3-yl) -glyoxylsäureamid
N- (3,5-Dichloro-pyridin-4-yl) - (1-isobutyl-7-azaindol-3-yl) -glyoxylsäureamid
N- (3,5-dichloropyridin-4-yl) - [1- (2-methylpropen-3-yl) -7-azaindol-3-yl] glyoxylic acid amide
N- (3,5-Dichloro-pyridin-4-yl) - [1- (2-methoxyethyl) -7-azaindol-3-yl] -glyoxylsäureamid
N- (3,5-dichloropyridin-4-yl) - [1- (1-naphthylmethyl) -7-azaindol-3-yl] glyoxylic acid amide
N- (3,5-Dichloro-pyridin-4-yl) - [1- (4-pyridylmethyl) -7-azaindol-3-yl] -glyoxylsäureamid
N- (3,5-dichloropyridin-4-yl) - [1- (3,5-dimethylisoxazol-4-ylmethyl) -7-azaindol-3-yl] glyoxylic acid amide
N, N-bis (2-methoxyethyl) - [1- (4-fluorobenzyl) -7-azaindol-3-yl] -glyoxylsäureamid
[1- (4-fluorobenzyl) -7-azaindol-3-yl] -glyoxylsäuremorpholid
[1- (4-fluorobenzyl) -7-azaindol-3-yl] -glyoxylsäure- (S, S-dioxo-thiomorpholide)
[1- (4-fluorobenzyl) -7-azaindol-3-yl] -glyoxylsäure- (4-methylpiperazide)
N- (6-methyluracil-5-yl) - [1- (4-fluorobenzyl) -7-azaindol-3-yl] -glyoxylsäureamid
N- (3,6-dimethyluracil-5-yl) - [1- (4-fluorobenzyl) -7-azaindol-3-yl] -glyoxylsäureamid
N- (1,3,6-Trimethyluracil-5-yl) - [1- (4-fluorobenzyl) -7-azaindol-3-yl] -glyoxylsäureamid
N- (1,2,4-4H-triazol-3-yl) - [1- (4-fluorobenzyl) -7-azaindol-3-yl] -glyoxylsäureamid 6. A process for the preparation of compounds according to formula 1 according to claims 1 to 4 with n = 1, characterized in that 7-azaindole-3-carboxylic acids of the formula 2 are converted into the analog 7-azaindole-3-carboxylic acid chlorides of the formula 3 by means of acid chlorides and then reacted by reaction with primary or secondary amines to give the compounds of formula 1 according to the invention with n = 1. 7. Preparation of compounds according to formula 1 by the process according to claim 6, characterized by the particularly preferred use of thionyl chloride or oxalyl chloride as acid chlorides for the synthesis of 7-azaindole-3-carboxylic acid chlorides according to formula 2 . 8. Preparation of compounds according to formula 1 by the process according to claim 6, characterized by the reaction of the 7-azaindole-3-carboxylic acid chlorides according to formula 2 with primary or secondary amines in the presence of an auxiliary base, preferably in the presence of an excess of the amine used as reactant , a tertiary amine, for example pyridine or triethylamine, and inorganic bases, preferably alkali metal hydroxides or alkali metal hydrides. 9. A process for the preparation of compounds of formula 1 according to claims 1 to 3 and 5 with n = 2, characterized in that 7-azaindoles of formula 4 with oxalyl chloride are converted into the analog 7-azaindot-3-yl-glyoxylic acid chlorides of formula 5 and then by reaction with primary or secondary amines to give the compounds of formula 1 according to the invention with n = 2. 10. Preparation of compounds according to formula 1 by the process according to claim 9, characterized by the reaction of the 7-azaindol-3-yl-glyoxylic acid chlorides according to formula 5 with primary or secondary amines in the presence of an auxiliary base, preferably in the presence of an excess of the reaction partner used amine, a tertiary amine, for example pyridine or triethylamine, and inorganic bases, preferably alkali metal hydroxides or alkali metal hydrides. 11. Use of the compounds of formula 1 according to claims 1 to 5 as therapeutic agents for the manufacture of medicaments for the treatment of diseases in which the inhibition of TNFα is therapeutically useful. 12. Use of the compounds of formula 1 according to claims 1 to 5 as therapeutic agents for the manufacture of medicaments for the treatment of diseases in which the inhibition of phosphodiesterase 4 is therapeutically useful. 13. Particularly preferred use of the compounds of formula 1 according to claims 1 to 5 as therapeutic agents for the manufacture of medicaments for the treatment of diseases which are associated with the action of eosinophils. 14. Particularly preferred use of the compounds of formula 1 according to claims 1 to 5 as therapeutic agents for the manufacture of medicaments for the treatment of diseases which are associated with the action of neutrophils. 15. Medicament containing one or more compounds according to Claims 1 to 5 in addition to conventional physiologically compatible carriers and / or Diluents or auxiliaries. 16. A method for producing a medicament according to claim 12, characterized in that one or more compounds according to the Claims 1 to 5 with common pharmaceutical carriers and / or diluents or other auxiliaries pharmaceutical preparations processed or in a be brought into a therapeutically applicable form. 17. Use of compounds of general formula 1 according to claims 1 to 5 and / or of pharmaceutical preparations according to claims 15 and 16 alone or in combination with one another or in combination with carriers and / or diluents or other auxiliaries.