HK1053839B - Novel 7-azaindoles, use thereof as phosphodiesterase 4 inhibitors and method for producing the same - Google Patents

Description

Technical field

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

Methods for their manufacture, pharmaceutical preparations containing these compounds and the pharmaceutical use of these compounds, which are inhibitors of phosphodiesterase 4, as active substances for the treatment of diseases to be controlled by the compounds of the invention by inhibition of phosphodiesterase 4 activity in immune incompetent cells (e.g. macrophages and lymphocytes).

State of the art

Err1:Expecting ',' delimiter: line 1 column 134 (char 133)

In the cells important for allergic inflammation (lymphocytes, mast cells, eosinophil granulocytes, macrophages), the predominant PDE isoenzyme is type 4 (Torphy, J. T. and Undem, B. J. Phosphordiesterase inhibitors: new opportunities for the treatment of asthma, Thorax 1991, 46:512-523). Inhibition of PDE 4 by appropriate inhibitors is therefore considered an important approach to the treatment of a wide range of allergy-induced diseases (Schudt Ch, Dent G, Rabe K Phosphodiesterase Inhibitors, Academic Press London 1996).

An important property of phosphodiesterase 4 inhibitors is that they inhibit the release of tumor necrosis factor α (TNFα) from inflammatory cells. TNFα is a major pro-inflammatory cytokine that influences a variety of biological processes. TNFα is released from activated macrophages, activated T-lymphocytes, mast cells, basophils, fibroblasts, endothelial cells and astrocytes in the brain, for example. It acts autonomously on neutrophils, eosinophils, fibroblasts and endothelial cells, which release various pro-inflammatory cytokines.

Chronic obstructive pulmonary disease (COPD) is widespread in the general population and is also of great economic importance. COPD accounts for about 10-15% of all disease costs in developed countries and about 25% of all deaths in the United States (Norman P.: COPD: New developments and therapeutic opportunities, Drug News Perspect. 11 (7), 431-437, 1998), but patients are usually over 55 years old at the time of death (Nolte D.: Chronic bronchitis - a multifactorial genetic disease.

The disease is relapsing and often complicated by bacterial infections (Rennard S. I.: COPD: Overview of definitions, Epidemiology, and factors influencing its development. Chest, 113 (4) Supplement, 235S-241S, 1998). In the course of the disease, lung function decreases steadily, the lung becomes increasingly emphysema-related, and the asthma rate increases. This number of patients is therefore significantly affected by the quality of life (Symptoms: short-term asthma, short-term lung disease, respiratory distress, and respiratory distress) of patients with COPD.

The use of long-acting beta-2 agonists (e.g. salmeterol) possibly in combination with muscarinic antagonists (e.g. ipratropium) improves lung function through bronchodilation and is routinely used (Norman P.: COPD: New developments and therapeutic opportunities, Drug News Perspect. 11 (7), 431-437, 1998). A major role in the development of COPD is played by bacterial infections that need to be treated with antibiotics (Wilson R.: The role of antibiotics in chest disease, 1 (4) Supplants 13-24S2S48 (1998, G.J.: The value of antibiotics for the development of antibodies against infection, 10-15S2S4), or by the development of new antibiotics, particularly in the context of the development of new drugs, such as antibacterial therapy (Wilson R.: The role of antibiotics in chest disease, 1 (4) Supplants 24-2S2S48 (1998, G.J.: The value of antibiotics for the development of antibodies against infection, 10-15S2S4 (1998, G.J.: The value of antibiotics for the development of antibodies against infection, 10-15S2S4 (1998, P.J.: The value of antibiotics for the development of antibodies against infection, 11-15S2S2S9 or 11-15S2S4S9), or new antibiotics, or new drugs, especially in the development of COPD, may be an important factor in the development of antibodies against infection, especially in the development of antibodies against antibodies against infection, particularly antibodies against antibodies against COPD, or antibodies against infection, or antibodies against infection, or antibodies against antibodies against infection, or antibodies against antibodies against infection, or antibodies against antibodies against infection, or antibodies against COPD).

Inhibiting the activity of neutrophil granulocytes is therefore a rational approach to preventing or slowing the progression of COPD (degradation of lung function parameters). An important stimulant for activating granulocytes is the pro-inflammatory cytokine TNFNF (Tumor necrosis factor). It is known that the formation of granulocytes by the formation of granulocyte-induced oxygen is stimulated by the production of granulocyte-induced oxygen. The active substance in the blood is known as P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P

Several PDE4 inhibitors are already known, primarily xanthine derivatives, rolipram analogues or nitraquazone derivatives (see Karlsson J-A, Aldos D Phosphodiesterase 4 inhibitors for the treatment of asthma, Exp. Op. Ther. Patents 1997, 7: 989-1003). None of these compounds have been able to be brought to clinical use. It was found that the known PDE4 inhibitors also have various side effects such as nausea and emesis, which have not been adequately reversed so far.

The use of 7-azaindoles in the development of new active substances for various indications has so far been described in relatively few cases.

In Japanese patent JP 10120681 (Fujisawa Pharmaceutical Co., Ltd.) 5- and 7-azaindols are the general formula claimed, where R1 stands for hydrogen or short alkyl groups, R2 can mean hydrogen, halogen, short alkyl groups, cycloalkyl groups, alkylcarbonyl groups or alkanoyl groups, R3 stands for alkanoyl groups, protected carbonic acid groups, cyano group or substituted carbamoyl groups. L stands for a short alkyl bridge. Q stands for substituted aromatics and heterocycles. A1 and A2 each stand for N and the other for CH. These compounds differ from the conventional compounds in particular in regard to the substituents R2 and R3, as described in R1 and A2. The compounds are called specific inhibitors of glycosaminoglycans (GMPG, RDE, CMPG, RDE, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, CMPG, C

The synthesis of various 3-aminoalkyl-4-azaindols and 3-aminoalkyl-7-azaindols is described by L.N. Yakhontov, S.S. Liberman, D.M. Krasnokutskaya et al. in Khim.-Farm. Zh. 8 (11), 1974, 5-9; a depressive or antidepressant effect is described for 3-aminoalkyl-2-azaindols; a blood pressure lowering effect has been found for 3-aminomethyl-7-azaindols.

A.J. Verbiscar describes in J. Med. Chem. 15 (2), 1972, 149-52 the compound of the formula which has been determined to have an antimalarial effect.

WO 96/11929 describes 5 HT 2C/2B antagonists which can be used to treat CNS disorders.

Patent US 650223 (Sterling Drug Inc.) describes the synthesis of various 2-imidazolin-2-yl) alkyl-7-azaindols and 3-imidazolin-2-yl) alkyl-7-azaindols from the corresponding 2- or 3-cyanoalkyl-7-azaindols and claims an application as vasoconstrictors for these compounds.

As inhibitors of PDE 4, 7-azinodol is completely unknown.

Description of the invention

The invention relates to substituted 7-azaindoles of the general:formula 1 , In which n = 1 or 2 and R1 for C1...10-alkyl, straight-chain or branched-chain, unsubstituted or with one or more substitutions of -OH, -SH, -NH2, -NHC1...6-alkyl, -N(C1...6-alkyl), -N(C1...6-alkyl), -NHC6...14-alkyl, -N(C6...14-alkyl), -N(C1...6-alkyl, -C6...14-alkyl, -NO2, -CN, -F, -Cl, -Br, -I, -O-C1...6-alkyl, -O-C6...14-alkyl, -S-C1...6-alkyl, -S-C6...14-alkyl, -S3H, -SO2C1...6-alkyl, -SO2C6...14-alkyl, -SO2C6...14-alkyl, -OS2C6...6-alkyl, -O-C6...14-alkyl, -O-C6A14-alkyl, -O-C614-alkyl, -O-C6--C6--C14-C14-alkyl, -O-C14-C14-C14-C14-C14-C14-C14-C14-C14-C14-C14-C14-C14-C14-C14-C14-C14-C14-C14-C14-C14-C14-C14-C14-C14-C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14C14Other C2...10-alkenyl, unsaturated, single or branched chain, unsubstituted, or single or multiple substitutions with -OH, -SH, -NH2, -NHC1...6-alkyl, -N(C1...6-alkyl) 2, -NHC6...14Aryl, -N(C6...14Aryl), -N(C1...6alkyl, -C6...14Aryl), -NO2, -CN, -F, -Cl, -I, -O-C1...6-alkyl, -O-C6...14-alkyl, -S-C1...6-alkyl, -S-C6...14A, -SO3 or more, -SO2C1...6alkyl, -SO2C6alkyl, -SO2C14-alkyl, -SO2C14-alkyl, -SO2C14-alkyl, -SO2C14-alkyl, -SO2C14-alkyl, -SO2C14-alkyl, -SO2C14-alkyl, -SO2C14-alkyl, -SO2C14-alkyl, -O6C14-alkyl, -O6C14-alkyl, -O6C14-alkyl, -O6 -C14-C14-alkyl, -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -O6 -is R2 and R3 may be the same or different, whereby only one of them may be hydrogen and R2 and R3 may continue to be -C1...5-alkyl, unsubstituted or one or more substitutions of -OH, -SH, -NH2, -NHC1...6-alkyl, -N(C1...6-alkyl) 2, -NO2, -CN, -F, -Cl, -Br, -I, -O-C1...6-alkyl, -S-C1...6-alkyl, -phenyl, -pyridyl, - Phenyl, unsubstituted or with one or more substitutions of -OH, -SH, -NH2, -NHC1...3-alkyl, -N(C1...3-alkyl) 2, -NO2, -CN, -COOH, -COOC1...3alkyl, -F, -Cl, -Br, -O-C1...3-alkyl, -S-C1...3-alkyl, -Pyridyl, unsubstituted or with one or more substitutions of -NO2, -CN, -COOH, -COOC1...3Alkyl, -Cl, -Br, -O-C1...3Alkyl, -S-C1...3Alkyl, and may mean: continue the group -NR2R3 together for can stand, and R4 for The following substances are to be classified in the same category as the active substance:Err1:Expecting ',' delimiter: line 1 column 856 (char 855)

In the 7-azinol formulae of the invention 1, the residue R1 is preferably a C1-C10 alkyl residue. Such an alkyl residue can be linear, branched or cyclic and is preferably linear. Especially preferred are alkyl residues with 1 to 6, even more preferably with 1 to 4 carbon atoms. In another preferred embodiment, R1 stands for a C2-C10, specifically a C2-C6, and most preferably a C2-C4 alkyl. The alkyl can be one- or multiple-fold, for example, two- or three-fold unsaturated.For example, a substituent is substituted two, three, four or five times. The residue R1 is preferably a substitute C1-alkyl (i.e. methyl) residue. Of the substituents specified above for the alkyl or alkyl group of the residue R1, the substitutes -OH, -F, -Cl, -Br, -I, -C1-C4-alkoxy are particularly preferable. Substitutes in which an alkyl, if any, has 1 to 4 carbon atoms and a heterocyclic residue, if any, 6 to 10 carbon atoms are also preferable. Of the carbocyls, the phenyl is preferable, in particular the substitute phenyl, which is substituted with a -Cl, -F, -Cl, -I, -C1, -C1, or hydroxy residue, such as N6, which is preferably the one that is substituted with the heterocyclic residue.The most common of the heterocycles is the pyridyl residue and the isoxazol residue, especially the 3,5-dimethylisooxazole residue.

In particular, R1 is preferred for a grouping containing a cyclic hydrocarbon residue, such as cyclopropylmethyl, for a linear hydrocarbon such as n-hexyl, for a linear hydrocarbon substituted with an alcohol residue, such as 2-methoxyethyl, for a branched hydrocarbon residue such as isobutyl, for an unsaturated hydrocarbon residue, such as 2-methylpropene-3- or for a hydrocarbon residue containing an aromatic group, which may be substituted, if necessary, for a carbon residue such as 4-hydroxyethyl, 3-methoxybenzyl, 4-methoxybenzyl, 4-hydroxybenzyl, 4-methylbenzyl, 3-methylbenzyl, or 4-methylbenzyl, such as a 4-hydroxyethyl, 4-methylbenzyl, or 4-methylbenzyl, or for a hydrocarbon residue such as a 4-hydroxyethyl, 4-methylbenzyl, 4-methylbenzyl, or 4-methylbenzyl, such as a 4-hydroxyethyl, 4-methylbenzyl, or 4-methylbenzyl, or 4-methylbenzyl, such as a 4-hydroxyethylbenzyl, or 4-methylbenzyl, such as a 4-methylbenzyl, or 4-methylbenzyl, or 4-methylbenzyl, such as a 4-methylbenzyl, or 4-methylbenzyl, or 4-methylbenzyl, such as a 4-methylbenzyl, or 4-methylbenzyl, or 4-methylbenzyl, such as a 4-methylbenzyl, or 4-methylbenzyl, or 4-methylbenzyl, such as a hydroxy, or 4-methylbenzyl, such as a hydroxy, or 4-methylbenzyl, as a hydroxy, or 4-methylbenzyl, as a 4-methylbenzyl, or 4-methylbenzyl, as a 4-methylbenzyl, or 4-methylbenzyl, or 4-methylbenzyl, as a 4-methyl, or 4-methylbenzyl, as a 4-methyl

The substituents at the nitrogen atom, R2 and R3, may be in a preferred embodiment a C1-C5 substitute, where appropriate, in particular C1-C3 and in particular C1 (corresponding to methyl) alkyl residue.

Preferably, one of the residues R2 or/and R3 is a residue containing a heteroaromatic hydrocarbon, such as 4-pyridylmethyl, whereby the heteroaromatic hydrocarbon may be further substituted, preferably with a halogen, such as 3,5-dichloro-4-pyridyl. In another preferred embodiment, R2 or/and R3 is the morpholine residue. Furthermore, preferred are residues R2 and R3, which contain an aromatic hydrocarbon, which is further substituted, in particular with a halogen or carboxy, such as 2,6-dichloroethyl, 4-dioxyphenyl, 4-dioxycarbonylphenyl, 3,4-dimethoxyphenyl. R2 or R3 is a preferred embodiment of R2 or M3 and represents a further preferred embodiment. or the group -NR2R3 together for Other

The preferred compounds of formula I, where n = 1, are N- ((4-Pyridylmethyl)-1-Cyclopropylmethyl-7-Azaindol-3-Carboxylic Acid Amide, whether or not containing by weight: N- ((3,5-Dichloropyridine-4-yl) --1-Isobutyl-7-Azaindol-3-Carboxylic Acid Amide, whether or not containing by weight: a width of not more than 15 mm, N- ((3,5-Dichloropyridine-4-yl)-1-cyclopropylmethyl-7-azaindol-3-carbonic acid amide, whether or not chemically defined, a width of not more than 30 mm, a width of not more than 30 mm, N- ((3,5-Dichloropyridine-4-yl)-1- ((4-Methoxybenzyl) -7-Azaindol-3-Carboxylic Acid Amide), whether or not containing by weight: a width of not more than 30 mm, a width of not more than 30 mm, N- ((2,6-Dichlorophenyl)-1- ((2-methylpropene-3-yl) -7-azaindol-3-carbonic acid amide and The following substances are to be classified in the same heading as the active substance:

The preferred compounds of formula (I) where n = 2 are N- ((3,5-Dichlorpyridine-4-yl) -[1- ((3-Methoxybenzyl) -7-Azaindol-3-yl]-Glyoxyl acid amide, N- ((4-pyridyl) -[1- ((4-fluorobenzyl) -7-azaindol-3-yl]-glyoxyl acid amide hydrochloride, containing by weight: a width of not more than 30 mm, N- ((4-pyridyl) -[1- ((4-chlorobenzyl) -7-azaindol-3-yl]-glyoxyl acid amide hydrochloride, containing by weight: N- ((3,5-Dichlorpyridine-4-yl) -[1- ((4-Chlorbenzyl) -7-Azaindol-3-yl]-Glyoxyl acid amide, whether or not chemically defined N- ((3,5-Dichlorpyridine-4-yl) -[1- ((4-Methoxybenzyl) -7-Azaindol-3-yl]-Glyoxyl acid amide, N- ((2,6-Dichlorphenyl) -[1- ((4-Chlorbenzyl) -7-Azaindol-3-yl]-Glyoxyl acid amide, a width of not more than 30 mm, a width of not more than 30 mm, N- ((3,4-dimethoxyphenyl) -[1- ((4-fluorobenzyl) -7-azaindol-3-yl]-glyoxyl acid amide, N- ((3,5-Dichlorpyridine-4-yl) -[1- ((4-methylbenzyl) -7-azaindol-3-yl]-glyoxyl acid amide, N- ((3,5-Dichlorpyridine-4-yl) -[1- ((4-Hydroxybenzyl) -7-Azaindol-3-yl]-Glyoxyl acid amide, N- ((3,5-Dichlorpyridine-4-yl) -[1- ((3-Hydroxybenzyl) -7-Azaindol-3-yl]-Glyoxyl acid amide, N- ((3,5-Dichlorpyridine-4-yl) - ((1-Cyclopropylmethyl-7-Azaindol-3-yl) -Glyoxyl acid amide, N- ((3,5-Dichlorpyridine-4-yl) - ((1-hexyl-7-azaindol-3-yl) -glyoxyl acid amide, a width of not more than 30 mm, N- ((3,5-Dichlorpyridine-4-yl) -[1- ((2-methylpropene-3-yl) -7-azaindol-3-yl]-glyoxyl acid amide, N- ((3,5-Dichlorpyridine-4-yl) -[1- ((2-Methoxyethyl) -7-Azaindol-3-yl]-Glyoxyl acid amide, N- ((3,5-Dichlorpyridine-4-yl) -[1- ((1-naphthylmethyl) -7-azaindol-3-yl]-glyoxyl acid amide, N- ((3,5-Dichlorpyridine-4-yl) -[1- ((4-Pyridylmethyl) -7-Azaindol-3-yl]-Glyoxyl acid amide, N- ((3,5-Dichlorpyridine-4-yl) -[1- ((3,5-Dimethylisoxazole-4-ylmethyl) -7-Azaindol-3-yl]-Glyoxyl acid amide, whether or not chemically defined N,N-Bis ((2-methoxyethyl) -[1- ((4-fluorobenzyl) -7-azaindol-3-yl]-glyoxyl acid amide, [1- (4-fluorbenzyl) -7-azaindol-3-yl]-glyoxyl acid emorpholide, which is a substance of the active substance, The following substances are to be classified in the same category as the active substance: The substance is classified in the additive category 'Fluorocarbons' as defined in point 1 of Annex I to Regulation (EC) No 1907/2006 of the European Parliament and of the Council. N- ((6-Methyluracil-5-yl) -[1- ((4-Fluorbenzyl) -7-Azaindol-3-yl]-Glyoxyl Acid Amide, whether or not containing by weight: N- ((3,6-dimethyluracil-5-yl) -[1- ((4-fluorobenzyl) -7-azaindol-3-yl]-glyoxyl acid amide, N- ((1,3,6-trimethyluracil-5-yl) -[1- ((4-fluorobenzyl) -7-azaindol-3-yl]-glyoxyl acid amide and The following substances are to be classified in the same category as the active substance:

A particularly preferred compound of formula I is The following substances are to be classified in the same heading as the active substance:

The invention also relates to the physiologically compatible salts of the compounds of formula 1.

Physiologically compatible salts are usually obtained by neutralizing the bases with inorganic or organic acids or by neutralizing the acids with inorganic or organic bases. Inorganic acids are, for example, hydrochloric acid, sulphuric acid, phosphoric acid or hydrobromic acid, while organic acids are, for example, carbon, sulphuric or sulphonic acids such as acetic acid, tartaric acid, lactic acid, propionic acid, glycolic acid, ascorbic acid, maleic acid, fumaric acid, sulfuric acid, alginic acid, benzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 2-pyrroxybenzoic acid, cyclin, calcitacins, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methion

Furthermore, physiologically compatible salts of the compounds of formula 1 can be obtained by the conversion of derivatives containing tertiary amino groups into the corresponding quaternary ammonium salts by means of a quaternizer in a known way.

Furthermore, the invention concerns the D-form, L-form and D,L mixtures of the compounds of formula 1 containing an asymmetric carbon atom and the diastereomeric forms in the case of several asymmetric carbon atoms. Those compounds of formula 1 containing asymmetric carbon atoms and usually occurring as racemates can be separated into the optically active isomers in a way that is known in itself, for example by an optically active acid. However, it is also possible to use an optically active starting substance beforehand, which then produces an optically active or diastereomers corresponding to the final product.

The compounds of the invention have been found to have pharmacologically significant properties that can be used therapeutically.

The compounds of the invention are inhibitors of TNFα release.

The compounds can therefore be used to inhibit the release of TNFα.

Therefore, the purpose of this invention is to enable the compounds of formula 1 and their salts, and pharmaceutical preparations containing these compounds or their salts, to be used to treat diseases in which inhibition of TNFα is useful.

These include joint inflammation including arthritis and rheumatoid arthritis, as well as other arthritic conditions such as rheumatoid spondylitis and osteoarthritis, and may also be used to treat patients with osteoporosis, sepsis, septic shock, gram-negative sepsis, toxic shock syndrome, respiratory syndrome, asthma or other chronic lung diseases, bone resorption diseases or transplant rejection reactions, or other autoimmune diseases such as lupus erythosus, Muller' s sclerosis, glomerulonephritis and chronic uveitis, insulin-dependent diabetes mellitus and dementia.

In addition, the compounds of the invention may also be used to treat infections such as viral and parasitic infections, such as malaria, leishmaniasis, infection-related fever, infection-related muscle pain, AIDS and cachexia.

The compounds of the invention are inhibitors of phosphodiesterase 4.

The compounds of the invention can therefore be used to inhibit phosphodiesterase 4.

Therefore, the purpose of this invention is to demonstrate that the compounds of formula 1 and their salts, and pharmaceutical preparations containing these compounds or their salts, can be used to treat diseases in which inhibition of phosphodiesterase 4 is useful.

The compounds of the invention can be used as bronchodilators and as asthma prophylaxis. The compounds of formula 1 continue to inhibit the accumulation and activity of eosinophils. Consequently, the compounds of the invention can also be used in diseases in which eosinophils play a role, such as inflammatory respiratory diseases such as bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, eczema, allergic angina, inflammations caused by eosinophils such as eosinophil fasciitis, eosinophil pneumonia and PIE (pulmonary infiltration with eosinophil), urticaria, colitis, ulcerative colitis and ulcerative colitis such as Crohn's disease.

The present invention is based on the fact that the compounds of 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 combination of these pharmacologically significant properties demonstrates that the compounds of formula 1 and their salts and pharmaceutical preparations containing these compounds or their salts can be used therapeutically to treat chronic obstructive pulmonary disease.

The compounds of the invention continue to have neuroprotective properties and can be used to treat diseases in which neuroprotection is useful, such as senile dementia (Alzheimer's disease), memory loss, Parkinson's disease, depression, stroke and claudication intermittens.

Other applications of the compounds of the invention are the prophylaxis and treatment of prostatic diseases such as benign prostatic hyperplasia, pollaxisuria, nocturia, and the treatment of incontinence, urinary stone colic and male and female sexual dysfunction.

Finally, the compounds of the invention can also be used to inhibit the development of drug dependence on repeated use of analgesics such as morphine and to reduce the development of tolerance to repeated use of these analgesics.

In addition to the usual excipients, carriers and additives, an effective dose of the compounds or their salts is used in the manufacture of the medicinal products.

The dosage of the active substances may vary depending on the route of administration, the patient' s age, weight, the nature and severity of the conditions being treated and similar factors.

The daily dose can be given as a single dose or divided into 2 or more daily doses and is usually 0.001-100 mg.

The preferred application form is oral, parenteral, intravenous, transdermal, topical, inhaled and intranasal.

The usual galenic preparations are used, such as tablets, dragees, capsules, dispersible powder, granules, aqueous solutions, aqueous or oily suspensions, syrups, juices or drops.

Solid forms of medicinal products may contain inert ingredients and carriers such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannite, alginate, gelatine, guar gum, magnesium or aluminium stearate, methyl cellulose, talcum, highly dispersible silica acids, silicone oil, higher molecular fatty acids (such as stearic acid), gelatine, agar or vegetable or animal fats and oils, solid high molecular polymers (such as polyethylene glycol); preparations suitable for oral application may contain additional flavourings and/or sweeteners if desired.

Liquid forms of medicinal products may be sterilised and/or contain, where appropriate, excipients such as preservatives, stabilizers, net agents, penetrants, emulsifiers, dispersants, solvents, salts, sugars or sugar alcohols to regulate osmotic pressure or buffering and/or viscosity regulators.

Such additives are, for example, tartrate and citrate buffers, ethanol, complexes (such as ethylene-diamine tetracyclic acid and its non-toxic salts). To regulate viscosity, high-molecular polymers are suitable, such as liquid polyethylene oxide, microcrystalline cellulose carboxymethyl cellulose, polyvinylpyrrolidone, dextrane or gelatine. Solid carriers are, for example, starch, lactose, mannite, methyl cellulose, talcum, high-dissolving silica acids, higher molecular fluorine (molecular stearic acid), gelatine, agar agar, calcium, polyphosphate, magnesium, animal and plant-based polymers, such as high-molecular polyethylene.

Oily suspensions for parenteral or topical applications may be vegetable synthetic or semisynthetic oils such as liquid fatty acid esters with 8 to 22 C in each fatty acid chain, e.g. palmitin, laurine, tridecyl, margarine, stearin, arachin, myristin, benzoyl, pentadecyl, linol, elaidin, brasidine, eruca or oleic acid, which may be esterified with one to three C alcohols such as methanol, ethanol, sesame, propanol, beta, capanol or their esters, polybutylene, glycol or glycerol. The further uses of polybutylene are for example commercial oleic acid, coenzyme cyclohexanol, risopropyl, isopropyl, isopropyl/ethyl esterol, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopropyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isopyl, isop

The solvent, gel-forming agent and solvent intermediate are water or water-mixable solvents, such as alcohols such as ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldecanol, polyethylene glycol, phthalates, adipate, propylene glycol, glycerin, di- or tripropylene glycol, waxes, methyl cellulose solvents, cellulose esters, morpholine, dioxane, dimethylfoxide, dimethylform, tetrahydrofuran, cyclohexanamide, etc.

Cellulose ethers which are soluble or soluble in water and in organic solvents, such as hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose or soluble starches, may be used as film formers.

Mixtures between gel and film formers are also quite possible, and ionic macromolecules are used, such as sodium carboxymethylcellulose, polyacrylic acid, polymethacrylic acid and its salts, sodium myleptopectin semiglycolate, alginic acid or propylene glycol alginate as sodium salt, gum arabic, xanthan gum, guar gum or carrageenan.

The use of surfactants, emulsifiers or net agents may also be necessary for the formulation, such as Na-lauryl sulphate, fatty alcohols sulphates, Di-Na-N-lauryl-β-iminodipronate, polyoxyethylene oil or sorbitol monolate, sorbitol monosodium, polysorbates (e.g. Tween), chlorine alcohol, lecithin, glycerol monosodium, polyoxystenyl monolamine, alkylphenol polyethylene, cetyltrimethyl chloride, or monosodium dihydroxyethylene, or may also be necessary for the activation of preservatives such as butyl or butyl phospholipids, or for the reduction of staphylococcus or other active substances such as butyl or butyl phospholipids.

Preparations for parenteral application may be in separate unit dosage forms such as ampoules or vials. Solutions of the active substance, preferably aqueous solutions and especially isotonic solutions, but also suspensions, are preferred. These injection forms may be provided as a finished product or only immediately prior to use by mixing the active substance, e.g. the lyophilisate, with other solid carriers, if necessary, to prepare the solvent or suspension of choice.

Intra-nasal preparations may be available as aqueous or oily solutions or aqueous or oily suspensions or as lyophilisates prepared with the appropriate solvent or suspension prior to administration.

The preparations shall be manufactured, packaged and sealed under normal antimicrobial and aseptic conditions.

The invention also relates to processes for the manufacture of the compounds of the invention.

According to the invention, the compounds of the general formula 1 are obtained from the meanings of R1, R2, R3 and n = 1 shown above, by converting 7-azaindol-3-carbon acids of formula 2 with identical meanings as R1 in an inherently known manner by acid chlorides, preferably with thionyl chloride or oxalic chloride, first into the 7-azaindol-3-carbon acid chloride analogues of formula 3. Other

The compounds of the invention of general formula 1 are then obtained from the isolated 7-azaindol-3-carbonic acid chlorides of formula 3 by transformation with a primary or secondary amine, with the meanings of R1, R2, R3 and n = 1 shown above. The reaction is favourable in the presence of an auxiliary base. An excess of the amine used as a reaction partner, a tertiary amine, preferably pyridine or triethylamine, and inorganic bases, preferably alkali hydroxides or alkali hydrides, may be used as auxiliary bases.

According to the invention, the compounds of general formula 1 with the meanings of R1, R2, R3 and n = 2 shown above are obtained by first converting 7-azinodols of formula 4 with identical meanings of R1 into the analogues of formula 5 by acylation with oxalic chloride in a known manner. Other

The compounds of the invention of general formula 1 with the meanings of R1, R2, R3 and n = 2 shown above are then obtained from the isolated 7-azaindol-3-yl-glyoxylic acid chlorides of formula 5 by transformation with a primary or secondary amine. The reaction is preferably carried out in the presence of an auxiliary base. An excess of the amine used as a reaction partner, a tertiary amine, preferably pyridine or triethylamine, and inorganic bases, preferably alkali hydroxides or alkali hydrides, may be used as auxiliary bases.

Examples of implementation

Model manufacturing process for compounds of formula 1 with n = 1:

The test chemical is used to determine the concentration of the active substance in the test chemical.

1.87 g 1-cyclopropylmethyl-7-azaindol-3-carbonic acid (8.6 mmol) is suspended in 15 ml of dichloromethane. 1.8 ml of oxalic chloride (17.4 mmol) is added under water cooling. The reaction mixture is stirred for 8 hours.

After about 15 minutes, the previously prepared solution of 1-Cyclopropylmethyl-7-azaindol-3-carbonate chloride is added to the reaction mixture. The whole is then boiled for 3 hours on the back stream. After cooling, the reaction mixture is mixed with 36 ml of acetic acid ethyl ester and 36 ml of water. The phases are separated and the organic phase is washed with water. The solvent is distilled and the residue is decrystallized from ethanol. The yield is 1.3 g (50% d. theory) The melting point is 187 to 189 °C.

The following are examples of many other compounds of formula 1 with n = 1 which can be produced using the manufacturing process described: Other

Beispiel			n	Schmelzpkt. [°C]
1	Cyclopropylmethyl-	4-Pyridylmethylamino-	1	187-189 Ethanol
2	Isobutyl-	3,5-Dichlor-4-pyridylamino-	1	168-170 Ethanol
3	n-Hexyl-	3,5-Dichlor-4-pyridylamino-	1	136-137 Methanol
4	Cyclopropylmethyl-	3,5-Dichlor-4-pyridylamino	1	186-187 Ethanol
5	4-Fluorbenzyl-	4-Pyridylmethyl-amino-	1	189-191 Ethanol
6	4-Fluorbenzyl-	3, 5-Dichlor-4-pyridylamino-	1	232-233 Ethanol
7	4-Methoxy-benzyl	3,5-Dichlor-4-pyridylamino-	1	193-195 Ethanol
8	4-Chlorbenzyl-	4-Pyridylamino-	1	192-194 Methanol
9	4-Fluorbenzyl-	Morpholino-	1	182-184 Ethanol
10	2-Methylpropen-3-yl-	2,6-Dichlorphenylamino-	1	171-174 Ethanol
11	4-Pyridylmethyl-	3, 5-Dichlor-4-pyridylamino	1	190-192 Methanol

Model manufacturing process for compounds of formula 1 with n = 2:

Example 12 N- ((3,5-Dichlorpyridine-4-yl) -[1- ((3-Methoxybenzyl) -7-Azaindol-3-yl]-Gyoxylic acid amide

At 0 °C, a solution of 1.54 ml of oxalic chloride (18 mmol) is added to 10 ml of butyl methyl ether by stirring. The mixture is then boiled for 2 hours at the return flow. The solvent is then distilled in a vacuum. The resulting 1-(3-methoxybenzyl) -7-azaindol-3-yl-glyoxychloroacid is obtained as a solid residue suspended in 50 ml of tetrahydrofuran (THF).

To make a suspension of 2 g sodium hydride in 20 ml THF, a solution of 2.4 g 4-amino-3,5-dichlorpyridine (15 mmol) is dripped at -5 °C in 30 ml THF. The mixture is then tempered to 20 °C for 1 hour during stirring. The previously prepared suspension of 1- ((3-methoxybenzyl) -7-azaindol-3-glyoxylyl chloride is then dripped at about 0 °C. Finally, the reaction mixture is boiled for 4 hours at the return flow. The solvent is removed in a vacuum. The residue is stirred with 50 ml of ethyl acid ester and 50 ml of water. The phases are separated. The organic phase is washed with water. The solvent is distilled in a vacuum. The residue is is isopropyl ether crystallised. The yield is 3.5 g (51.5 % d. theory) The melting point is 165 to 167 °C.

The following are examples of many other compounds of formula 1 with n = 2 which can be produced using the manufacturing process described: Other

The compounds of the invention are potent inhibitors of phospho-diesterase 4 and TNFα release and their therapeutic potential is demonstrated in vivo, for example by inhibiting the late asthmatic phase response (eosinophilia) and by influencing allergen-induced vascular permeability in actively sensitised Brown Norway rats.

Inhibition of phosphodiesterase

PDE4 activity is determined in enzyme preparations from human polymorphic nucleic lymphocytes (PMNL), PDE2, 3 and 5 activity with PDE from human thrombocytes. Human blood was anticoagulated with citrate. Centrifugation at 700 x g for 20 minutes at RT separates the platelet-rich plasma in the plasma from the erythrocytes and leukocytes. The platelets are lysified by ultrasound and inserted into the PDE3 and PDE5 assay. For determination of PDE2 activity, the cytosolic thrombocyte reaction is performed on an anion column by means of NaCl-gradient exchange and the PDE2 is obtained for the NaCl-gradient. The hypothetical pH of the PMNL is 0.4 g/ m3 for PMNL 4 × 4 × 10 mL. The resulting pH is determined by a second ultrasound and the resulting PDE4 is inserted into the PDE4 at 6 °C. The resulting PDE4 is then added to the PDE4 at a pH of 0.4 g/ m3 for the PDE4 at 10 °C. The resulting PDE4 is then added to the PDE4 at a pH of 0.4 g/ m3 for the PMNL 4 × 10 °C. The resulting PDE4 is inserted into the PDE4 at a pH of 0.4 g/ m3 and the resulting PDE4 is inserted into the PDE4 at a pH of 0.4 g/ m3 at 10 °C.

Phosphodiesterase activity is determined with some modifications according to the method described by Thompson et al. (Thompson, W.J.; Appleman, M.M., Assay of cyclic nucleotide phosphodiesterase and resolution of multiple molecular forms of the enzyme.

The final volume is 100 ml. Test substances are added as stock solutions in DMSO. The DMSO concentration in the reaction medium is 1 % v/v, the corresponding enzyme preparation and the additional components necessary to detect the individual isoenzymes (see below). The addition of the substrate 0,5 μM [3H]-cAMP or [3H]-cGMP (approximately 6000 CPM/test) starts the reaction. The final volume is 100 ml. Test substances are introduced as stock solutions in DMSO. The DMSO concentration in the variable concentrations, the corresponding enzyme preparation and the additional components necessary to detect the individual isoenzymes (see below). The start of the reaction is by means of a substrate of 0,5 μM [3H]-cAMP or [3H]-cGMP (approximately 6000 CPM/test). The final volume is 100 ml. The test substances are placed as stock solutions in DMSO. The DMSO concentration in the reaction medium is 1 % v/v. At this DMSO concentration, the PDE activity is not re-infused. The start of the reaction is followed by an incubation of 200 μl of S-glucose at 37 μl+ C. The samples are incubated for another 10 minutes. The test substance is then cooled for 10 minutes (1 minute) and the remaining samples are placed in an ice-free container for 10 minutes. The remaining samples are then placed in an ice-free container for another 10 minutes (1 minute) and the test substance is stopped.

The non-specific enzyme activities are determined in the presence of 100 μM rolipram at PDE 4 and 100 μM IBMX at PDE 3 and 5 and subtracted from the test values. The incubation approaches of the PDE 3 assay contain 10 μM rolipram to inhibit possible contamination by PDE 4. The PDE 2 is tested with an SPA assay from Amersham. The assay is performed in the presence of the PDE 2 activator (5 μM cGMP).

For the compounds of the invention, IC50 values in the range 10-9 to 10-5 M have been determined for the inhibition of phosphodiesterase 4 and selectivity for PDE types 2, 3 and 5 is a factor of 100 to 10,000.

For example, the results of PDE 4 inhibition for selected application areas have been summarised in the following table: Other

Beispiel
1	0.710
2	1.400
12	0.005
13	0.058
14	0.004
15	0.031
16	0.002
17	0.008
18	0.031
22	0.002
23	0.001
24	0.003
25	0.004
26	0.021
27	0.002
28	0.003
32	0.113
37	0.987

Inhibition of TNFα release from nasal polype cells

The test design is essentially the same as that described by Campbell, A.M. and Bousquet J. (Anti-allergic activity of H1-blockers. Int. Arch. Allergy Immunol., 1993, 101, 308-310).

The resulting cells, a mixture of epithelial cells, monocytes, macrophages, lymphocytes, fibroblasts and granulocytes, are filtered and washed by repeated centrifugation in nutrient solution, passively sensitized by addition of human IgEISA (0.75 mg/ ml) and the centrifugation is carried out at a concentration of 2 cells/ ml in RNF 1640 (followed by a 10 μl beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta beta

Non-IgE stimulated cells produce little TNFα, but stimulated cells secrete large amounts of TNFα, which can be reduced by, for example, PDE4 inhibitors, depending on the dose.

For the compounds of the invention, IC50 values were determined in the range 10-7 to 10-5 M.

For example, for selected application areas, the results on inhibition of TNFα release were summarized in the following table: Other

Beispiel	Hemmung der TNFα Freisetzung
	Konzentration	Hemmung
14	0,3 µmol/l	92
16	1,0 µmol/l	90
17	1,0 µmol/l	91
27	1,0 µmol/l	91

Inhibition of late-stage eosinophilia 48 h after inhaled ovalbumin inactivated in actively sensitised Brown Norway rats

Inhibition of pulmonary eosinophil infiltration by the substances of the invention is being investigated in actively sensitised male Brown Norway rats (200-250 g) to ovalbumin (OVA). Sensitisation is achieved by subcutaneous injection of a suspension of 10 μg OVA together with 20 mg aluminium hydroxide as adjuvant in 0.5 ml saline per animal on days 1, 14 and 21. In addition, the animals are injected with Bordetella CAussis vaccine at the same times, diluting 0.25 ml per animal i.p. On day 28 the animals are injected individually into 1 I open plexiglass glands connected to a head-on air-exposure. The animals are exposed to a 0.09% Aerosol-Nebulizer (0.9% Aerosol-Nebulizer) for 1 hour. The animals are also exposed to a new Aerosol-Albumin (Aerosol-Chlorotrifluor) 1 hour after exposure.

48 hours after the allergen challenge, a massive influx of eosinophilic granulocytes into the animals' lungs occurs. At this point, the animals are anesthetized with an overdose of ethylurethane (1.5 g/kg body weight i.p.) and a bronchoalveolar lavage (BAL) is performed with 3 × 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 with an automatic cell differentiation device (Bayer Diagnostics Technicon H 1 E). For each animal, the eosinophils (EOS) in the BAL are calculated in E/million: EOS/μl × BAL-recovery (μl) = EOS/tier.

The test chemical is then applied to the test chemical and the test chemical is then removed.

The percentage inhibition of eosinophilia in the treated group is calculated using the following formula: $\text{{((OVAC - SC) - (OVAD - SC)) / (OVAC - SC)} × 100 \% = \% Hemmung}$ (SC = vehicle treated control group with 0,9% saline solution; OVAC = vehicle treated control group with 1% ovalbumin suspension; OVAD = substance treated control group with 1% ovalbumin suspension)

The test substances are applied intraperitoneally or orally as a suspension in 10% polyethylene glycol 300 and 0.5% 5-hydroxyethyl cellulose 2 hours before the allergen challenge.

The compounds of the invention inhibit late-stage eosinophilia by 30% to 100% after intraperitoneal administration of 10 mg/kg and by 30% to 75% after oral administration of 30 mg/kg.

The compounds of the invention are therefore particularly suitable for the manufacture of medicinal products for the treatment of diseases associated with the action of eosinophils.

For example, the results on the inhibition of eosinophilia for selected application sites are summarised in the following table: Other

Beispiel	Hemmung der Eosinophilie
	Dosis/Applikation	Hemmung [%]
14	10 mg/kg i.p.	62
	10 mg/kg p.o.	59
16	10 mg/kg i.p.	100
	10 mg/kg p.o.	70
17	10 mg/kg i.p.	75
	10 mg/kg p.o.	32
27	10 mg/kg i.p.	50
	10 mg/kg p.o.	70

Inhibition of lipopolysaccharide (LPS) induced pulmonary neutrophily in Lewis rats

The inhibition of pulmonary neutrophil infiltration by the substances of the invention is being tested in male Lewis rats (250-350 g). On the day of the test, the animals are placed individually in open 1 l plexiglass boxes connected to a head-nose exposure device. The animals are exposed to an aerosol from a lipopolysaccharide suspension (100 μg LPS/ml 0.1% hydroxylamine solution) in PBS (LPS provocation). The LPS/hydroxylamine aerosol is produced by a compressed air (0.2 MPa) powered nebulizer (Bird micro nebulizer, CA, Palm Springs, USA). The exposure time is 40 minutes, with a normal 0.1% hydroxylamine aerosol also being nebulized in 40 minutes with a PBS 0.1% controlled aerosol.

6 hours after the LPS challenge, the animals reach a maximum mass inflow of neutrophils into their lungs. At this point, the animals are anesthetized with an overdose of ethylurethane (1.5 g/kg i.p.) and a bronchoalveolar lavage (BAL) with 3 × 4 ml of Hank's Balance solution is performed. The total cell count and the number of neutrophils in the pooled BAL liquid are then determined by an automatic cell differentiator (Bayer Diagnostics Technicon H 1 E). For each animal, the neutrophils (NEUTRO) in the BAL are calculated in million/animal: NEUTRO/μL × BAL-Recovery (NEUTRO) = NEUTRO/ml.

The test chemical is then applied to the test chemical in the presence of a negative test chemical.

The percentage inhibition of neutrophils in the treated group is calculated as follows: $\text{{((LPSC - SC) - (LPSD - SC)) / (LPSC - SC)} × 100 \% = \% Hemmung}$ SC = vehicle treated control group with 0,1 per cent hydroxylamine solution; LPSC = vehicle treated control group with LPS (100 μg/ml 0.1 per cent hydroxylamine solution); LPSD = substance treated control group with LPS (100 μg/0,1 ml % hydroxylamine solution).

The test substances are administered orally as a suspension in 10% polyethylene glycol 300 and 0.5% 5-hydroxyethyl cellulose 2 hours prior to LPS provocation.

The compounds of the invention inhibit neutrophils by 40% to 90% after oral administration of 1 mg/kg and are therefore particularly suitable for the manufacture of medicinal products for the treatment of diseases associated with the action of neutrophils.

For example, the results on neutrophil inhibition for selected application sites are summarized in the following table: Other

Beispiel	Hemmung der Neutrophilie
	Dosis/Applikation	Hemmung [%]
14	1 mg/kg p.o	80
22	1 mg/kg p.o.	64
27	1 mg/kg p.o.	52

Claims (19)

1. 7-Azaindoles of the formula 1 in which n can be 1 or 2 and R ¹ represents -C₁ to -C₁₀ alkyl, linear or branched, unsubstituted or substituted one or more times with -OH, -SH, -NH₂, -NHC₁ to -NHC₆ alkyl, -N(C₁ to C₆-alkyl)₂, -NHC₆ to -NHC₁₄ aryl, -N(C₆ to C₁₄ aryl)₂, -N(C₁ to C₆ alkyl) (C₆ to C₁₄ aryl), -NO₂, -CN, -F, -Cl, -Br, -I, -O-C₁ to -O-C₆ alkyl, -O-C₆ to -O-C₁₄ aryl, -S-C₁ to -S-C₆ alkyl, -S-C₆ to -S-C₁₄ aryl, -SO₃H, -SO₂C₁ to -SO₂C₆ alkyl, -SO₂C₆ to -SO₂C₁₄ aryl, -OSO₂C₁ to -OSO₂C₆ alkyl, -OSO₂C₆ to -OSO₂C₁₄ aryl, -COOH, -(CO)C₁ to -(CO)C₅ alkyl, with mono-, bi- or tricyclic, saturated or monounsaturated or polyunsaturated carbocyclic compounds with 3 to 14 ring elements, with mono-, bi- or tricyclic saturated or monounsaturated or polyunsaturated heterocyclic groups with 5 to 15 ring elements and 1 to 6 hetero atoms, which preferably are N, 0 and S, it being possible for the C₆ to C₁₄ aryl groups and the carbocyclic and heterocyclic substituents, in turn, to be unsubstituted or monosubstituted or polysubstituted with R⁴, -C₂ to C₁₀ alkenyl, monounsaturated or polyunsaturated, linear or branched, unsubstituted or monosubstituted or polysubstituted with -OH, -SH, -NH₂, -NHC₁ to -NHC₆ alkyl, -N(C₁ to C₆-alkyl)₂, -NHC₆ to -NHC₁₄ aryl, -N(C₆ to C₁₄ aryl)₂, -N(C₁ to C₆ alkyl) (C₆ to C₁₄ aryl), -NO₂, -CN, -F, -Cl, -Br, -I, -O-C₁ to -O-C₆ alkyl, -O-C₆ to -O-C₁₄ aryl, -S-C₁ to -S-C₆ alkyl, -S-C₆ to -S-C₁₄ aryl, -SO₃H, -SO₂C₁ to -SO₂C₆ alkyl, -SO₂C₆ to -SO₂C₁₄ aryl, -OSO₂C₁ to -OSO₂C₆ alkyl, -OSO₂C₆ to -OSO₂C₁₄ aryl, -COOH, -(CO)C₁ to -(CO)C₅ alkyl, with mono-, bi- or tricyclic, saturated or monounsaturated or polyunsaturated carbocyclic compounds with 3 to 14 ring elements, with mono-, bi- or tricyclic saturated or monounsaturated or polyunsaturated heterocyclic groups with 5 to 15 ring elements and 1 to 6 hetero atoms, which preferably are N, O and S, it being possible for the C₆ to C₁₄ aryl groups and the carbocyclic and heterocyclic substituents, in turn, to be unsubstituted or monosubstituted or polysubstituted with R⁴, R ² and R ³ may be the same or different, it being possible for only one of the two to represent hydrogen and furthermore, R² and R³ can represent -C₁-C₅ alkyl, unsubstituted or monosubstituted or polysubstituted with -OH,-SH, -NH₂, -NHC₁ to -NHC₆ alkyl, -N(C₁ to C₆-alkyl)₂, -NO₂, -CN, -F, -Cl, -Br-, -I, -O-C₁ to -O-C₆ alkyl, -S-C₁ to -S-C₆ alkyl, -phenyl, -pyridyl -phenyl, unsubstituted or monosubstituted or polysubstituted with -OH, -SH, -NH₂, -NHC₁ to -NHC₃ alkyl, -N(C₁ to C₃-alkyl)₂, -NO₂, -CN, -COOH, -COOC₁ to -COOC₃ alkyl, -F, -Cl, -Br-, -O-C₁ to -O-C₃ alkyl, -S-C₁ to -S-C₃ alkyl, -pyridyl, unsubstituted or monosubstituted or polysubstituted with -NO₂, -CN, -COOH, -COOC₁ to -COOC₃ alkyl, -Cl, -Br-, -O-C₁ to -O-C₃ alkyl, -S-C₁ to -S-C₃ alkyl, as well as furthermore, the -NR²R³ group can represent together and R⁴ represents -H, -OH, -SH, -NH₂, -NHC₁ to -NHC₆ alkyl, -N(C₁ to C₆ alkyl)₂, NHC₆ to NHC₁₄ aryl, N(C₆ to C₁₄ aryl)₂, -N(C₁ to C₆ alkyl)(C₆ to C₁₄ aryl), -NHCOC₁ to -NHCOC₆ alkyl, -NO₂, -CN, -COOH, -COOC₁ to -COOC₆ alkyl, -(CO)C₁ to -(CO)C₆ alkyl, -(CS)C₁ to -(CS)C₆ alkyl, -F, -Cl, -Br, -I, -O-C₁ to -O-C₆ alkyl, -O-C₆ to -O-C₁₄ aryl, -S-C₁ to -S-C₆ alkyl, -S-C₆ to -S-C₁₄ aryl, -SOC₁ to -SOC₆ alkyl, -SO₂C₁ to -SO₂C₆ alkyl, with the proviso that when n = 1 there is no concurrent R₁ = -C₁ to C₆ alkyl R₂ = -H or -C₁ to C₅ alkyl and R₃ = where R and R' are independently -C₁ to C₆ alkyl with or without single or multiple halogen substitution, -C₂ to C₆ alkenyl, -C₃ to C₆ cycloalkyloxy, -C₃ to C₆ cycloalkyl-C₁ to C₆ alkoxy, -C₂ to C₆ alkynyl, -C₃ to C₆ cycloalkyl, -C₃ to C₆ cycloalkyl-C₁ to C₆ alkyl, -C₁ to C₆ alkylthio, -C₃ to C₆ cycloalkylthio, -C₃ to C₆ cycloalkyl-C₁ to C₆ alkylthio, -C₁ to C₆ alkoxy, hydroxyl, halogen, nitro, -CF₃, -C₂F₅, -OCF₃, -SCF₃, -SO₂CF₃, -SO₂F, formyl, -C₂ to C₆ alkanoyl, cyano, substituted or unsubstituted phenyl or thienyl, -NR''₂, -CONR''₂, -COOR'' or R + R' together are a 5-membered carbocycle or heterocycle, and R'' = -H or -C₁ to C₆ alkyl.
2. Physiologically tolerated salts of the compounds of formula 1 according to Claim 1, characterized by neutralization of the bases with inorganic or organic acids or neutralization of the acids with inorganic or organic bases or quaternization of tertiary amines to quaternary ammonium salts.
3. Compounds of formula 1 according to Claims 1 and 2 with an asymmetric carbon atom in the D form, the L form or in the form of D,L mixtures or, in the case of several asymmetric carbon atoms, the diastereoisomeric forms.
4. Compound of formula 1 according to any one of Claims 1 to 3 with n = 1, selected from the following compounds:

   N-(4-pyridylmethyl)-1-cyclopropylmethyl-7-azaindol-3-carboxylic acid amide

   N-(3,5-dichloropyridin-4-yl)-1-isobutyl-7-azaindol-3-carboxylic acid amide

   N-(3,5-dichloropyridin-4-yl)-1-hexyl-7-azaindol-3-carboxylic acid amide

   N-(3,5-dichloropyridin-4-yl)-1-cyclopropylmethyl-7-azaindol-3-carboxylic acid amide

   N-(4-pyridylmethyl)-1-(4-fluorobenzyl)-7-azaindol-3-carboxylic acid amide

   N-(3,5-dichloropyridin-4-yl)-1-(4-fluorobenzyl)-7-azaindol-3-carboxylic acid amide

   N-(3,5-dichloropyridin-4-yl)-1-(4-methoxybenzyl)-7-azaindol-3-carboxylic acid amide

   N-(4-pyridylmethyl)-1-(4-chlorobenzyl)-7-azaindol-3-carboxylic acid amide

   1-(4-fluorobenzyl)-7-azaindol-3-carboxylic acid morpholide

   N-(2,6-dichlorophenyl)-1-(2-methylpropen-3-yl)-7-azaindol-3-carboxylic acid amide and

   N-(3,5-dichloropyridin-4-yl)-1-(4-pyridylmethyl)-7-azaindol-3-carboxylic acid amide.
5. Compound of formula 1 according to any one of Claims 1 to 3 with n = 2, selected from 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]-glyoxylic acid amide hydrochloride

   N-(3,5-dichloropyridin-4-yl)-[1-(4-fluorobenzyl)-7-azaindol-3-yl]-glyoxylic acid amide

   N-(4-pyridyl)-[1-(4-chlorobenzyl)-7-azaindol-3-yl]-glyoxylic acid amide hydrochloride

   N-(3,5-dichloropyridin-4-yl)-[1-(4-chlorobenzyl)-7-azaindol-3-yl]-glyoxylic acid amide

   N-(3,5-dichloropyridin-4-yl)-[1-(4-methoxybenzyl)-7-azaindol-3-yl]-glyoxylic acid amide

   N-(2,6-dichlorophenyl)-[1-(9-chlorobenzyl)-7-azaindol-3-yl]-glyoxylic acid amide

   N-(4-carboxyphenyl)-[1-(4-fluorobenzyl)-7-azaindol-3-yl]-glyoxylic acid amide

   N-(4-ethoxycarbonylphenyl)-[1-(4-fluorobenzyl)-7-azaindol-3-yl]-glyoxylic acid amide

   N-(3,4-dimethoxyphenyl)-[1-(4-fluorobenzyl)-7-azaindol-3-yl]-glyoxylic acid amide

   N-(3,5-dichloropyridin-4-yl)-[1-(4-methylbenzyl)-7-azaindol-3-yl]-glyoxylic acid amide

   N-(3,5-dichloropyridin-4-yl)-[1-(4-hydroxybenzyl)-7-azaindol-3-yl]-glyoxylic acid amide

   N-(3,5-dichloropyridin-4-yl)-[1-(3-hydroxybenzyl)-7-azaindol-3-yl]-glyoxylic acid amide

   N-(3,5-dichloropyridin-4-yl)-(1-cyclopropylmethyl-7-azaindol-3-yl)-glyoxylic acid amide

   N-(3,5-dichloropyridin-4-yl)-(1-hexyl-7-azaindol-3-yl)-glyoxylic acid amide

   N-(3,5-dichloropyridin-4-yl)-(1-isobutyl-7-azaindol-3-yl)-glyoxylic acid amide

   N-(3,5-dichloropyridin-4-yl)-[1-(2-methylpropen-3-yl)-7-azaindol-3-yl]-glyoxylic acid amide

   N-(3,5-dichloropyridin-4-yl)-[1-(2-methoxyethyl)-7-azaindol-3-yl]-glyoxylic acid amide

   N-(3,5-dichloropyridin-4-yl)-[1-(1-naphthylmethyl)-7-azaindol-3-yl]-glyoxylic acid amide

   N-(3,5-dichloropyridin-4-yl)-[1-(4-pyridylmethyl)-7-azaindol-3-yl]-glyoxylic acid amide

   N-(3,5-dichloropyridin-4-yl)-[1-(3,5-dimethylisoxazole-4-ylmethyl)-7-azaindol-3-yl]-glyoxylic acid amide

   N,N-bis(2-methoxyethyl)-[1-(4-fluorobenzyl)-7-azaindol-3-yl]-glyoxylic acid amide

   [1-(4-fluorobenzyl)-7-azaindol-3-yl]-glyoxylic acid morpholide

   [1-(4-fluorobenzyl)-7-azaindol-3-yl]-glyoxylic acid (S,S-dioxo-thiomorpholide)

   [1-(4-fluorobenzyl)-7-azaindol-3-yl]-glyoxylic acid (4-methylpiperazide)

   N-(6-methyluracil-5-yl)-[1-(4-fluorobenzyl)-7-azaindol-3-yl]-glyoxylic acid amide

   N-(3,6-dimethyluracil-5-yl)-[1-(4-fluorobenzyl)-7-azaindol-3-yl]-glyoxylic acid amide

   N-(1,3,6-trimethyluracil-5-yl)-[1-(4-fluorobenzyl)-7-azaindol-3-yl]-glyoxylic acid amide and

   N-(1,2,4-4H-triazol-3-yl)-[1-(4-fluorobenzyl)-7-azaindol-3-yl]-glyoxylic acid amide.
6. Method of preparing compounds of formula 1 according to any one of Claims 1 to 4 with n = 1, characterized in that 7-azaindol-3-carboxylic acids are converted by means of acid chlorides into the analogous 7-azaindol-3-carboxylic acid chlorides and subsequently, by reaction with primary or secondary amines, converted to the inventive compounds of formula 1 with n = 1.
7. Preparation of compounds of formula 1 by the method according to Claim 6, characterized by the use of thionyl chloride or oxalyl chloride as acid chlorides for the synthesis of the 7-azaindol-3-carboxylic acid chlorides.
8. Preparation of compounds of formula 1 by the method according to Claim 6 or 7, characterized by the reaction of the 7-azaindol-3-carboxylic acid chlorides 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, of a tertiary amine, such as pyridine or triethylamine, as well as of inorganic bases, preferably alkali hydroxides or alkali hydrides.
9. Method for the preparation of compounds of formula 1 according to any one of Claims 1 to 3 and 5 with n = 2, characterized in that 7-azaindoles are converted into the analogous 7-azaindol-3-yl-glyoxylic acid chlorides with oxalyl chloride and subsequently into the compounds of formula 1, with n = 2, by reaction with primary or secondary amines.
10. Preparation of compounds of formula 1 by the method according to Claim 9, characterized by the reaction of 7-azaindol-3-yl-glyoxylic acid chlorides with primary or secondary amines in the presence of an auxiliary base, preferably in the presence of an excess of the amine used as the reactant, of a tertiary amine, such as pyridine or triethylamine, as well as of inorganic bases, preferably alkali hydroxides or alkali hydrides.
11. Use of compounds of formula 1 according to any one of Claims 1 to 5 as therapeutic active ingredients for the preparation of medicinal drugs for the treatment of diseases, for which the inhibition of TNFα is therapeutically useful.
12. Use of compounds of formula 1 according to any one of Claims 1 to 5 as therapeutic active ingredients for the preparation of medicinal drugs for the treatment of diseases for which the inhibition of phosphodiesterase 4 is therapeutically useful.
13. Use of the compounds of formula 1 according to Claims 1 to 5 as therapeutic active ingredients for the preparation of drugs for the treatment of diseases which are associated with the effects of eosinophiles.
14. Use of the compounds of formula 1 according to Claims 1 to 5 as therapeutic active ingredients for the preparation of drugs for the treatment of diseases which are associated with the effects of neutrophiles.
15. Use of a compound according to any one of Claims 1 to 5 as an active ingredient to produce a drug for treatment and/or prophylaxis of diseases where an inhibition of TNFα is beneficial, especially of joint inflammations, arthritis, rheumatoid arthritis, arthritic diseases, rheumatoid spondylitis, osteoarthritis, osteoperosis, sepsis, septic shock, Gram-negative sepsis, toxic shock syndrome, respiratory distress syndrome, asthma, chronic pulmonary diseases, bone resorption diseases, transplant rejection reactions, autoimmune diseases, lupus erythematosis, multiple sclerosis, glomerulonephritis, uveitis, insulin-dependent diabetes mellitus, chronic demyelination, of viral diseases, viral infections, parasite infections, malaria, leishmaniasis, infection-induced fever, infection-induced muscle pain, AIDS, cachexia, diseases which can be treated with an inhibition of phosphodiesterase 4, asthma, diseases associated with the effects of eosinophiles, bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, eczema, allergic angiitis, inflammations brought about by eosinophiles, eosinophilic fasciitis, eosinophilic pneumonia, PIE syndrome, urticaria, ulcerative colitis, Crohn's disease, proliferative skin diseases, psoriasis, keratosis, chronic obstructive lung diseases, diseases which can be treated by neuroprotection, senile dementia, Alzheimer's, memory loss, Parkinson's, depressions, strokes, intermittent claudications, prostata diseases, benign prostate hyperplasia, pollakiuria, nocturia, incontinence, colics, colics initiated by urinary calculus, male and female sexual dysfunctions and also as bronchodilators, for the inhibition of the development of drug dependence and also for reducing the development of tolerance.
16. Medicinal drugs, containing one or more compounds according to Claims 1 to 5 in addition to conventional, physiologically tolerated carriers and/or diluents or adjuvants.
17. Method for the preparation of a medicinal drug according to Claim 16, characterized in that one or more compounds according to any one of Claims 1 to 5, together with conventional pharmaceutical carrier materials and/or diluents or other adjuvants, are processed into pharmaceutical preparations or/and brought into a therapeutically usable form.
18. Use of compounds of the general formula 1 according to any one of Claims 1 to 5 and/or of pharmaceutical preparations according to Claims 16 and 17 alone or in combination with one another or in combination with carrier materials and/or diluents or other adjuvants, for the preparation of a medicament.
19. Compound of formula I according to any one of Claims 1 to 3, which is N-(3,5-dichloropyridin-4-yl)-[1-(4-fluorobenzyl)-7-azaindol-3-yl]glyoxylic acid amide.