EP1613627A1 - 7-azaindoles and use thereof as therapeutic agents - Google Patents

Abstract

The invention relates to substituted 7-azaindoles of formula (I), a method for the production thereof, pharmaceutical preparations comprising said compounds and the pharmaceutical use of said compounds which are inhibitors of phosphodiesterase 4, as active substances in the treatment of diseases which can be influenced by said inventive compounds by means of an inhibition of phosphodiesterase 4-activity, especially in immunocompetent cells (for example, macrophages and lymphocytes).

Description

 7-azaindole and their use as therapeutics

description

The invention relates to substituted 7-azaindoles, processes for their preparation, pharmaceutical compositions containing these compounds and the pharmaceutical use of these compounds, which are inhibitors of phosphodiesterase 4, as active ingredients for the treatment of diseases associated with inhibition of phosphodiesterase 4 activity in particular in immunocompetent cells (eg macrophages and lymphocytes) are to be influenced by the compounds of the invention.

The activation of receptors of the cell membrane by transmitters leads to the activation of the second messenger system. Adenylate cyclase synthesizes the active cyclic AMP (cAMP) or cyclic GMP (cGMP) from AMP and GMP. These lead eg in smooth muscle cells to relaxation or in inflammatory cells to inhibit mediator release or synthesis. The degradation of the second messenger cAMP and cGMP occurs through the phosphodiesterases (PDE). To date, 11 families of PDE enzymes (PDE1-11) are known that differ in their substrate specificity (cAMP, cGMP or both) and their dependence on other substrates (eg calmodulin). These isoenzymes have different functions in the body and are different in the individual cell types (Beavo, J, Conti, M. and Heaslip, RJ, Multiple cyclic nucleotide phosphodiesterases, Mol Pharmacol 1994, 46: 399-405; Isoenzyme selective phosphodiesterase inhibitors: Potential clinical uses, Br. J. clin Pharmacol., 1993, 35: 1-7). Inhibition of the various PDE isoenzyme types leads to an accumulation of cAMP or cGMP in the 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), the predominant PDE isoenzyme is type 4 (Torphy, JT and Undem, BJ, 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 to be an important approach to the therapy of a variety of allergic-induced diseases (Schudt, Ch., Dent, G., Rabe, K., Phosphodiesterase Inhibitors, Academic Press London 1996).

An important property of phosphodiesterase 4 inhibitors is the inhibition of the release of tumor necrosis factor α (TNFα) from inflammatory cells. TNFα is a major pro-inflammatory cytokine that affects a variety of biological processes. TNFα is released, for example, from activated macrophages, activated T lymphocytes, mast cells, basophils, fibroblasts, endothelial cells and astrocytes in the brain. It has a self-activating effect on neutrophils, eosinophils, fibroblasts and endothelial cells, releasing various tissue-destroying mediators. In monocytes, macrophages and T lymphocytes TNFα causes the increased production of other proinflammatory cytokines, such as GM-CSF (granulocyte macrophage colony-stimulating factor) or interleukin-8. Because of its proinflammatory and catabolic effects, TNFα plays a central role in a variety of diseases such as respiratory tract inflammation, inflammation of the joints, endotoxic shock, tissue rejection, AIDS and many other immunological disorders. Thus, inhibitors of phosphodiesterase 4 are also suitable for the therapy of such diseases associated with TNFα.

Chronic obstructive pulmonary diseases (COPD) are widespread in the population and also of great economic importance. How to cause COPD disorders Approximately 10-15% of all medical expenses in developed countries and approximately 25% of US deaths are attributable to this cause (Norman, P .: COPD: New developments and therapeutic opportunities, Drug News Perspect. 11 (7)). 431-437, 1998). The WHO estimates that COPD will be the third leading cause of death within the next 20 years.

The clinical picture of chronic obstructive pulmonary disease (COPD) summarizes various clinical pictures of chronic bronchitis with the symptoms of coughing and sputum, as well as progressive and irreversible worsening of lung function (especially expiration). The course of the disease is relapsing-remitting and often complicated by bacterial infections (Rennard, S. I .: COPD: Overview of Definitions, Epidemiology, and factors influencing its development., Chest, 113 (4) Suppl., 235S-241S, 1998). As the disease progresses, lung function steadily decreases, the lung becomes increasingly emphysematous, and patients' respiratory distress becomes apparent. This disease significantly affects the quality of life of patients (shortness of breath, low resilience) and significantly shortens their life expectancy. The main risk factor besides environmental factors is smoking (Kummer, F .: Asthma and COPD, Respiratory Pneumonia, 20 (5), 299-302, 1994; Rennard, SI: COPD: Overview of Definitions, Epidemiology, and factors influencing its development Chest, 113 (4) Suppl., 235S-241S, 1998) and therefore men are significantly more affected than women. However, changing the way people live and increasing the number of smokers will change this picture in the future.

The current therapy is aimed only at alleviating the symptoms without causally interfering with the progression of the disease. The use of long-acting beta2-agonists (eg salmeterol) possibly in combination with muscarinic antagonists (eg ipratropium) improves lung function through bronchodilation and is routinely used (Norman, P .: COPD: New developments and therapeutic opportunities, Drug News Perspect. 7), 431-437, 1998). A big role in the COPD Bouts play bacterial infections that need to be treated with antibiotics (Wilson, R .: The role of infection in COPD, Chest, 113 (4) Suppl., 242S-248S, 1998; Grossman, RF: The value of antibiotics and the outcomes of antibiotic therapy in exacerbations of COPD Chest, 113 (4) Suppl., 249S-255S, 1998). The treatment of this disease is still unsatisfactory, especially in view of the steady decline in lung function. New therapeutic approaches that target inflammatory mediators, proteases or adhesion molecules may be very promising (Barnes, PJ: Chronic obstructive disease: new opportunities for drug development, TiPS 10 (19), 415-423, 1998).

Regardless of the bacterial infections complicating the disease, chronic inflammation is found in the bronchi, which is dominated by neutrophilic granulocytes. For the observed structural changes in the respiratory tract (emphysema), among other things, the mediators and enzymes released by neutrophilic granulocytes are held responsible. The inhibition of neutrophil granulocyte activity is thus a rational approach to preventing or slowing the progression of COPD (worsening of pulmonary function parameters). An important stimulus for the activation of granulocytes is the pro-inflammatory cytokine TNFα (tumor necrosis factor). It is known that TNFα stimulates the formation of oxygen radicals by neutrophilic granulocytes (Jersmann, HPA; Rathjen, DA and Ferrante, A .: Enhancement of LPS-induced neutrophil oxygen radical production by TNFα, Infection and Immunity, 4, 1744- 1747, 1998). PDE4 inhibitors can very effectively inhibit the release of TNFα from a variety of cells and thus suppress neutrophil granulocyte activity. The nonspecific PDE inhibitor pentoxifylline is able to inhibit both the formation of oxygen radicals and the phagocytosis capability of neutrophils (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. These are predominantly xanthine derivatives, rolipram analogs or nitraquazone derivatives (reviewed in: Karlsson, JA, Aldos, D., Phosphodiesterase 4 inhibitors for the treatment of asthma, Exp. Opin. Ther. Patents 1997, 7: 989-1003). None of these compounds has yet been brought to clinical use. It had to be stated that the known PDE4 inhibitors also have various side effects, such as nausea and emesis, which hitherto could not be sufficiently suppressed. Therefore, the discovery of new PDE4 inhibitors with better therapeutic latitude is required.

Indol-3-ylglyoxylic acid amides and processes for their preparation have already been described several times. In all cases unsubstituted indoles synthesized by substitution in position 1 of a commercially available indole were converted by reaction with oxalyl halides into indole-3-ylglyoxylic acid halides in the 3-position, which were subsequently reacted by reaction with ammonia or with primary or tert secondary amines give the corresponding indole-3-ylglyoxylsäureamide. (Scheme 1)

Scheme 1:

X = halogen

For example, US Pat. Nos. 2,825,734 and 3,188,313 describe various indole-3-ylglyoxylic acid amides prepared according to the procedure illustrated in Scheme 1. These compounds were called Intermediates used for the preparation of indole derivatives resulting from reductions. Also in US Pat. No. 3,642,803, indole-3-ylglyoxylic acid amides are described.

Farmaco 22 (1967), 229-244 describes the preparation of 5-methoxyindol-3-ylglyoxylic acid amides. Again, the indole derivative used is reacted with oxalyl chloride and the resulting indole-3-ylglyoxylsäurechlorid reacted with an amine.

In addition, US Pat. No. 6,008,231 also describes indole-3-ylglyoxylic acid amides and processes for their preparation. Again, the reaction steps and conditions shown in Scheme 1 are used.

Substituted 5-hydroxyindolyl-glyoxylic acid amides and 6-hydroxyindolyl glyoxylic acid amides and processes for their preparation and their use as PDE4 inhibitors were described for the first time in the patent application DE 198 18 964 A1.

7-Azaindol-3-yl-glyoxylic acid amides are known as PDE4 inhibitors from the patent application DE 100 53 275 A1, which also describes their preparation and use as therapeutics.

4- or 7-hydroxyindole derivatives, their preparation and use as PDE4 inhibitors are proposed in the patent application DE 102 53 426.8.

The invention relates to substituted 7-azaindoles of the general formula I and their physiologically acceptable salts, wherein A, B, R \ R ² , R ³ and R ^{4 are} as defined in claim 1.

The compounds of the invention preferably include those compounds of formula 1, in which

A is an N-oxide group and B is carbon (ie, a CH group or a CR ^{3 group} as defined below) or nitrogen. These are the compounds of the formula 1a according to the invention

wherein

R ¹

(i) represents --C ^ o-alkyl, straight-chain or branched-chain, optionally mono- or polysubstituted with -OH, -SH, -NH ₂ , -NHC, _ ₆ -alkyl, -N (C _1.6 -alkyl) ₂ , -NHC ₆ . ₁₄ -aryl, -N _{(C6. 14,} aryl) _2> -N (C _{1. 6,} alkyl) (C. _{6 14} aryl), -NO _2, -CN, -F, -Cl, -Br , -I, -OC ^ -alkyl, -OC ^ -aryl, -SC ^ -alkyl, -SC ^ -aryl, -SO ₃ H, -SO.C ^ -alkyl, -SO ₂ C _6.14- aryl, - OSO ^ alkyl, -OSO ₂ C _M4 -aryl, -COOH, - (CO) C ^ -alkyl, -COO-C ^ -alkyl, -O (CO) C ,. _.5 alkyl, with mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles having 3-14 ring members or / and with mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles having 5-15 ring members and 1-6

Heteroatoms, which are preferably N, O and S, wherein the C ₆ . ₁₄ -aryl groups and the carbocyclic and heterocyclic substituents in turn optionally mono- or polysubstituted with -C ^ alkyl, -OH, -NH ₂ , -NHC ^ alkyl, -NfC ^ -Alky!) ,, ,, NO ₂ , -CN, -F, -Cl, -Br, -I, -OC ^ -alkyl, -S-. _g -alkyl, -SO ₃ H,

-SO.C ^ -alkyl, -OSO ₂ C _M -alkyl, -COOH, - (CO) C _M -alkyl,

-COO-C ^ -alkyl or / and -O COJC ^ -alkyl may be substituted, and wherein the alkyl groups on the carbocyclic and heterocyclic substituent in turn optionally mono- or polysubstituted with -OH, -SH, -NH ₂ , -F, -Cl, -Br, -I, -SO ₃ H or / and -COOH may be substituted, or

(ii) for -C ₂ . ₁₀ alkenyl, mono- or polyunsaturated, straight-chain or branched-chain, optionally mono- or polysubstituted with -OH, -SH, -NH ₂ ,

-NHC ^ -alkyl, -N (C _{1. 6,} alkyl) _2, -NHC _6.14 -aryl, -N (C _W4 aryl) _2,

-N (C _{1. 6,} alkyl) (C _6.14 -aryl), -NO _2> is -CN, -F, -Cl, -Br, -I, -OC ^ alkyl,

-OC ₆ . ₁₄ -aryl, -SC ^ -alkyl, -SC ₆ . ₁₄ -aryl, -SO ₃ H, -S0 ₂ C _M -alkyl.

-SO ₂ C ₆ . ₁₄ -aryl, -OSO.C ^ -alkyl, -OSO ₂ C ₆ . ₁₄ -aryl, -COOH, - (CC C ^ alkyl, -COO-C ^ alkyl or / and -0 (CO) C ^ alkyl, with mono-, bi- or tricyclic saturated or mono- or polyunsaturated Carbocycles having 3-14 ring members or / and with mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles having 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 optionally mono- or polysubstituted with -C ^ alkyl, -OH, -NH ₂ , -NHC ^ alkyl, -N (C _1.6 alkyl) ₂ , -NO ₂ , -CN, -F, -Cl , -Br, -I, -OC ^ alkyl, -SC ^ alkyl, -SO ₃ H, -S0 ₂ C ^ alkyl, -OSO. .g-alkyl, -COOH, - (CO) C _M alkyl.

-COO-C., _.5 alkyl and / or -O (CO) C _{1. 5-} alkyl may be substituted, and wherein the alkyl groups on the carbocyclic and heterocyclic substituent in turn optionally mono- or polysubstituted with -OH, -SH, -NH ₂ , -F, -Cl, -Br, -I, -SO ₃ H and / or -COOH can be substituted,

R ^{2 is} hydrogen or C _1-3 -alkyl,

R ³ and R ^{4 may be the} same or different and for

Hydrogen, -Cι _-6 alkyl, -OH, -SH, -NH _2, -NHCι _-6 -alkyl, -N (Cι _-6 alkyl) _2, -NO _2, -CN, -SO ₃ H, - SO ₃ -Cι _-6 alkyl, -COOH, -COO-Cι _-6 alkyl, -O (CO) -Cι _-5 alkyl, -F, -Cl, -Br, -I, -Od _-6 - Alkyl, -SC _1-6 alkyl, phenyl or pyridyl, wherein the phenyl or pyridyl substituents in turn optionally mono- or polysubstituted with -C _1-3 alkyl, -OH, -SH, -NH ₂ , -NHC _1-3 alkyl, -N (C _1-3 alkyl) ₂ , -NO ₂ , -CN, -SO ₃ H, -SOsd-α-alkyl, -COOH, -COOC _1-3 alkyl, -F , -Cl, -Br, -I, -O-Cι _-3 alkyl, -S-Cι _-3 alkyl and / or -O (CO) -Cι _-3 alkyl may be substituted and wherein the alkyl substituents in turn optionally mono- or polysubstituted by -OH, -SH, -NH ₂ , -F, -Cl, -Br, -I, -SO ₃ H, -SO ₃ -C ₃ -alkyl, -COOH, -COOC _1-3 - Alkyl, -O-Cι- ₃ alkyl, -SC _1-3 alkyl and / or -O (CO) -Cι _-3 alkyl may be substituted.

Furthermore, compounds of the invention preferably include those N-oxides of the formula I in which

B stands for an N-oxide group. These are the compounds of the formula 1b according to the invention

wherein

A nitrogen means

R ¹

(i) -C ^ _Q alkyl is straight or branched, optionally mono- or polysubstituted by -OH, -SH, -NH _2, -NHC., _ 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 ^ -alkyl, -OC ₆ . ₁₄ -aryl, -SC ^ -alkyl,

-SC _6.14 -aryl, -SO ₃ H, -SO ^ -alkyl, -SO - ^ - aryl, -OSO-.C-. _g -alkyl, -OSO ₂ C _6.14 -aryl, -COOH, - (CO) C ₁₅ -alkyl, -COO-C ^ -alkyl, -O ^ OJC ^ -alkyl, with mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles having 3-14 ring members or / and with mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles having 5-15 ring members and 1-6 heteroatoms, which are preferably N, O and S. where the C _g . ₁₄ -aryl groups and the carbocyclic and heterocyclic substituents in turn, optionally mono- or polysubstituted with -C ^ alkyl, -OH, -NH ₂ , -NHC ^ alkyl, -N ^ -Alky!) ,,

-NO ₂ , -CN, -F, -Cl, -Br, -I, -OC ^ alkyl, -SC ^ _g alkyl, -SO ₃ H, -SO ^ alkyl, -OSO ^. _g -alkyl, -COOH, - (COJC ^ -alkyl, -COO-C- _.g- alkyl or / and -O (CO) C., _ ₅ alkyl may be substituted, and wherein the alkyl groups on the carbocyclic and heterocyclic substituents in turn optionally on or may be substituted several times with -OH, -SH, -NH ₂ , -F, -Cl, -Br, -I, -SO ₃ H or / and -COOH, or

(ii) for -C ₂ . ₁₀ alkenyl, mono- or polyunsaturated, straight-chain or branched-chain, optionally mono- or polysubstituted with -OH, -SH, -NH ₂ ,

-NHC ^ alkyl, -N (C _{1. 6,} alkyl) _2, -NHς, ₁₄ -aryl, -N _{(C6. 14,} aryl) _2,

-N (C _1.6 -alkyl) (C. _{6 l4} aryl), -NO _2> is -CN, -F, -Cl, -Br, -I, -OC ^ alkyl,

-OC ₆ . ₁₄ -aryl, -SC ^ -alkyl, -SC _6.14 -aryl, -SO ₃ H, -SO.C ^ -alkyl, -SO ^^ - aryl, -OSO - ^ - alkyl, -OSO ₂ C ₆ . ₁₄ -aryl, -COOH,

- (CO) C, _.5 alkyl, -COO-C ^ alkyl, -O (CO) C _{1.. 5} -alkyl, with mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles having 3-14 ring members or / and with mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles having 5-15 ring members and 1-6 heteroatoms, which are preferably N, O and S, wherein the C ₆ . ₁₄ -aryl groups and the carbocyclic and heterocyclic substituents in turn optionally mono- or polysubstituted with -C ^ alkyl-OH, -NH ₂ , -NHC ^ alkyl, -N ^. _g -alkyl), -NO ₂ , -CN, -F, -Cl, -Br, -I, -OC ^ -alkyl, -SC-. _g -alkyl, -SO ₃ H,

-SO ^ alkyl, -OSO.C ^ alkyl, -COOH, - (COJC ^ alkyl, -COO-C, _ ₅ alkyl and / or -O ^ OJC ^ alkyl may be substituted, and wherein. the alkyl groups on the carbocyclic and heterocyclic substituents in turn optionally mono- or polysubstituted with -OH, -SH, -NH ₂ , -F, -Cl, -Br, -I, -SO ₃ H or / and

-COOH can be substituted,

R ^{2 is} hydrogen or -Cι ₃ alkyl,

R ³ and R ^{4 may be the} same or different and for

Hydrogen, -Cι _-6- alkyl, -OH, -SH, -NH ₂ , -NHCι _-6- alkyl, -N (C _{1, 6} -alkyl) ₂ , -NO _2, -CN, -S0 ₃ H, -SO ₃ -C _1-6 alkyl, -COOH, -COO-C _1-6 alkyl, -O (CO) -Cι _-5 alkyl, -F , -Cl, -Br, -I, -O-Cι _-6 alkyl, -S-Cι _-6 alkyl, phenyl or pyridyl, where the phenyl or pyridyl substituents in turn optionally one or more times with -Cι _3- alkyl, -OH, -SH, -NH ₂ , -NHCι- _3- alkyl, -N (C _{1, 3} -alkyl) ₂ , -NO ₂ , -CN, -COOH, -SO ₃ H, - SO ₃ Cι _-3 alkyl, -COOCι _-3 alkyl, -F, -Cl, -Br, -I, -O-Cι _-3 alkyl, -S-Cι _-3 alkyl and / or -O ( CO) -Cι _-3 alkyl may be substituted and wherein the alkyl substituent in turn optionally mono- or polysubstituted by -OH, -SH, -NH _2, -F, -Cl, -Br, -I, -SO _s H, - SO ₃ Cι _-3 alkyl, -COOH, -COOC _1-3 alkyl, -O-Cι _-3 alkyl, -S-Cι _-3 alkyl and / or -O (CO) -Cι _-3 alkyl may be substituted.

Furthermore, the compounds according to the invention include those N-oxides of the formula 1 in which

A and B represent an N-oxide group. These are the compounds of the formula 1c according to the invention

wherein

R

(i) represents -C -.- _Q- alkyl, straight-chain or branched-chain, optionally mono- or polysubstituted with -OH, -SH, -NH ₂ , -NHC, _ ₆ -alkyl,

-N (C _{1. 6,} alkyl) _2> -NHC ^ -aryl, -N (C _6.14 -aryl) _2, -N (C _1.6 -alkyl) (C _{6. 14,} aryl),

-NO ₂ , -CN, -F, -Cl, -Br, -I, -OC ^ -alkyl, -OC ^ -aryl, -SC ^ -alkyl, -SC ₆ . ₁₄ -aryl, -SO ₃ H, -SO - ^ - alkyl, -SO ₂ C ₆ . ₁₄ -aryl, -OSO ^ -alkyl, -OSO ₂ C _6.14 -aryl, -COOH, - (CO) C ₁₅ -alkyl, -COO-C 1-4 -alkyl, -O (CO) C ,. _.5 alkyl, with mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles having 3-14 ring members or / and with mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles having 5-15 ring members and 1-6

Heteroatoms, which are preferably N, O and S, wherein the C _g _ ₁₄ aryl groups and the carbocyclic and heterocyclic substituents in turn optionally mono- or polysubstituted with -C ^ alkyl, -OH, -NH ₂ , -NHC ^ -Alkyl, -N (C _1.6 -alkyl) ₂ , -NO ₂ , -CN, -F, -Cl, -Br, -I, -OC ^ -alkyl, -SC ^ -alkyl, -SO ₃ H,

-SO. _.g- alkyl, -OSO ₂ C, _.6- alkyl, -COOH, - (CO) C can be substituted by _1.5- alkyl, -COO-C ^ -alkyl or / and -0 (CO) C ^ -alkyl, and wherein the alkyl groups on the carbocyclic and heterocyclic substituent in turn optionally mono- or polysubstituted with -OH, -SH, -NH ₂ , -F, -Cl, -Br, -I, -SO ₃ H or / and

-COOH may be substituted, or

(ii) for -C ₂ . ₁₀ alkenyl, mono- or polyunsaturated, straight-chain or branched-chain, optionally mono- or polysubstituted with -OH, -SH, -NH ₂ ,

-NHC ^ alkyl, -N (C _{1. 6,} alkyl) _2, -NHC _6.14 -aryl, -N (C _6.14 -aryl) _2,

-N (C _{l. 6} alkyl) (C _{6. 14} aryl), -NO _2, -CN, -F, -Cl. -Br, -I, -OC ^ -alkyl,

-OC ₆ . ₁₄ -aryl, -SC ^ -alkyl. -SC ₆ . ₁₄ -aryl, -SO ₃ H, -SO ₂ C ^ -alkyl,

-SO ₂ C ₆ . ₁₄ -aryl, -OSO ₂ C _w -alkyl, -OSO ₂ C ₆ . ₁₄ -aryl, -COOH, - (CO) C., _.5- Alkyl, -COO-C ^ -alkyl, -O (CO) C ₁ . ₅ -alkyl, with mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles having 3-14 ring members or / and with mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles having 5-15 ring members and 1-6 heteroatoms, which are preferably N, O and S, wherein the C ^ aryl groups and the carbocyclic and heterocyclic substituents in turn optionally mono- or polysubstituted with -C ^ alkyl, -OH, -NH ₂ , -NHC-. _g -alkyl, -N _.g- alkyl)., -NO ₂ , -CN, -F, -Cl, -Br, -I, -OC ^ -alkyl, -SC ^ -alkyl, -SO ₃ H, -SO ^ -alkyl, -OSO ^ -alkyl, -COOH, - (COJC ^ alkyl, -COO-C-.s-alkyl and / or -O (CO) C,. ₅ alkyl may be substituted, and wherein the alkyl groups on the carbocyclic and heterocyclic substituent in turn may optionally be mono- or polysubstituted by -OH, -SH, -NH ₂ , -F, -Cl, -Br, -I, -SO ₃ H or / and -COOH .

R ^{2 is} hydrogen or -Cι ₃ alkyl,

R ³ and R ^{4 may be the} same or different and for

Hydrogen, -Cι _-6 alkyl, -OH, -SH, -NH _2, -NHC _1-6 alkyl, -N (Cι _-6 alkyl) _2, -NO ₂₎ -CN, -SO ₃ H, -SO ₃ -C _1-6 alkyl, -COOH, -COO-Cι _-6 alkyl, -0 (CO) -Cι _-5 alkyl, -F, -Cl, -Br, -I, -O- Cι _-6 alkyl, -S-Cι _-6 alkyl, -phenyl or -pyridyl stand, wherein the phenyl or pyridyl substituent in turn optionally mono- or polysubstituted with -Cι _-3 -AlkyI, -OH, -SH, -NH _2, -NHCι _-3 alkyl, -N (C _1-3 alkyl) _2, -NO _2, -CN, -SO ₃ H, -SO ₃ Cι_ ₃ alkyl, -COOH, -COOC _1-3 - alkyl, -F, -Cl, -Br, -I, -O-Cι _-3 alkyl, -S-Cι _-3 alkyl and / or -O (CO) -Cι _-3 alkyl may be substituted and wherein the alkyl substituents, in turn, optionally mono- or polysubstituted by -OH, -SH, -NH ₂ , -F, -Cl, -Br, -I, -SO ₃ H, -SO ₃ -C ₃ alkyl, -COOH, -COOCι _-3 alkyl, -O-Cι _-3 alkyl, -S-Cι _-3 alkyl or / and -O (CO) -Cι _-3 alkyl may be substituted.

Preference is given to compounds of the formula I in which R ^{1 is} an optionally substituted particularly preferred is a d-radical having a cyclic substituent. The cyclic substituents are preferably C _3-8 -cycloalkyl groups or Cs-io-aryl or heteroaryl groups, for example phenyl or naphthyl groups, which have at least one substituent selected from halogen, ie -F, -Cl, -Br or -I, -OH , -NO ₂ , -CN, -CH ₃ , -OCH ₃ and -CF ₃ . R ² is preferably H or -CH ₃ . At least one of R ³ and R ⁴ is preferably halogen, ie -F, -Cl, -Br, or -I. R ³ and R ⁴ are particularly preferably halogen, for example -Cl.

Furthermore, the invention relates to the physiologically acceptable salts of the compounds according to formula 1.

The physiologically acceptable salts are obtained in a customary manner by neutralization of the bases with inorganic or organic acids or by 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 carboxylic, sulfonic or sulfonic acids, 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-

Hydroxyethanesulfonsäure, ethane-1, 2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid or naphthalene-2-sulfonic acid, in question. Examples of inorganic bases are 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 acceptable salts of the compounds according to formula 1 can be obtained by converting derivatives having tertiary amino groups into the corresponding quaternary ammonium salts in a manner known per se with quaternizing agents. As a quaternizing come for example Alkyl halides, such as methyl iodide, ethyl bromide and n-propyl chloride, but also arylalkyl halides, such as benzyl chloride or 2-phenylethyl bromide, in question.

Furthermore, the invention relates to the compounds of 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 are generally obtained as racemates can be separated into the optically active isomers in a manner known per se, for example with an optically active acid. However, it is also possible to use an optically active starting substance from the outset, in which case the end product obtained is a corresponding optically active or diastereomeric compound.

For the compounds according to the invention pharmacologically important properties were found that can be used therapeutically. The compounds according to formula I can be used alone, in combination with one another or in combination with other active substances.

The compounds according to the invention are phosphodiesterase 4 inhibitors. It is therefore an object of this invention that the compounds according to formula I and their salts as well as pharmaceutical preparations containing these compounds or their salts can be used for the treatment of diseases in which an inhibition of the Phosphodiesterase 4 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 are the treatment of patients suffering from osteoporosis, sepsis, septic shock, gram negative sepsis, toxic Shock syndrome, respiratory distress syndrome, asthma or other chronic pulmonary disease, bone resorption disease or transplant 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 the treatment of malaria, leishmaniasis, infection-related fever, infection-related muscle pain, AIDS and cachexia, as well as non-allergic rhinitis.

The compounds according to the invention can likewise be used for the therapy of hyperproliferative disorders, in particular of cancers, for example for the therapy of melanomas, breast cancer, lung cancer, colon cancer, skin cancer and leukemia.

The compounds of the invention may also be used as bronchodilators and for the treatment of asthma, e.g. used for asthma prophylaxis.

The compounds according to formula 1 are further 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, eosinophil mediated inflammation such as eosinophilic fasciitis, eosinophilic pneumonia and PIE syndrome (pulmonary infiltration with eosinophilia), urticaria. 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 also inhibit LPS-induced pulmonary neutrophil infiltration in rats in vivo. The pharmacologically important properties found prove that the compounds according to formula 1 and their salts as well as pharmaceutical preparations containing these compounds or their salts can be used therapeutically for the treatment of chronic obstructive pulmonary diseases.

The compounds of the invention also possess neuroprotective properties and can be used to treat diseases in which neuroprotection is useful. Such disorders include senile dementia (Alzheimer ^'s disease), memory loss, Parkinson ^'s disease, depression, strokes and intermittent claudication.

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

Finally, the compounds according to the invention can likewise be used for inhibiting the development of a drug dependence with repeated use of analgesics, such as, for example, morphine, and for reducing the development of tolerance in the repeated use of these analgesics.

For the preparation of the medicaments, in addition to the customary auxiliaries, carriers and additives, an effective dose of the compounds according to the invention or salts thereof is used. The dosage of the active ingredients may vary depending on the route of administration, age, weight of the patient, and type The severity of the diseases to be treated and similar factors vary. The daily dose may be given as a single dose to be administered once, or divided into 2 or more daily doses, and is usually 0.001-100 mg. Particularly preferred daily dosages of 0.1-50 mg are administered.

The form of administration can be oral, parenteral, intravenous, transdermal, topical, inhalative and intranasal preparations. Particular preference is given to using topical, inhalative and intranasal preparations of the compounds according to the invention. The usual pharmaceutical preparation forms, such as tablets, dragees, capsules, dispersible powders, granules, aqueous solutions, aqueous or oily suspensions, syrups, juices or drops, are used.

Solid dosage forms may contain inert ingredients and carriers, e.g. Calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatin, guar gum, magnesium or aluminum stearate, methyl cellulose, talc, fumed silica, silicone oil, higher molecular weight fatty acids (such as stearic acid), gelatin, agar-agar or vegetable or animal Fats and oils, solid high molecular weight polymers (such as polyethylene glycol); If desired, preparations suitable for oral administration may contain additional flavorings and / or sweeteners.

Liquid dosage forms may be sterilized and / or optionally contain excipients, such as preservatives, stabilizers, wetting agents, penetrating agents, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols, for controlling the osmotic pressure or for buffering and / or viscosity regulators.

Such additives include tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediamine tetraacetic acid and its non-toxic salts). To control the viscosity are high molecular weight polymers in Question, such as liquid polyethylene oxide, microcrystalline celluloses, carboxymethylcelluloses, polyvinylpyrrolidones, dextrans or gelatin. Solid carriers are, for example, starch, lactose, mannitol, methylcellulose, talc, highly disperse silicas, higher molecular weight fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular weight polymers such as polyethylene glycol.

Oily suspensions for parenteral or topical applications may include vegetable synthetic or semisynthetic oils, such as, for example, fatty fatty acid esters each having 8 to 22 C atoms in the fatty acid chains, for example palmitic, lauric, tridecyl, margarine, stearic, arachin , Myristic, behenic, pentadecyl, linoleic, elaidic, brasidic, erucic or oleic acid, which are reacted with monohydric to trihydric alcohols having 1 to 6 carbon atoms, such as, for example, methanol, ethanol, propanol, butanol, Pentanol or their isomers, glycol or glycerol are esterified. Such fatty acid esters are, for example, commercial miglyols, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG 6 capric acid, caprylic / capric acid esters of saturated fatty alcohols, polyoxyethylene glycerol trioleates, ethyl oleate, waxy fatty acid esters, such as artificial duckbald gland fat, isopropyl coconut fatty acid,

Oleic acid oleyl ester, oleic acid dicylate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol fatty acid esters, and the like. Also suitable are silicone oils of different viscosity or fatty alcohols, such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or oleyl alcohol, fatty acids, such as oleic acid. Further, vegetable oils such as castor oil, almond oil, olive oil, sesame oil, cottonseed oil, peanut oil or soybean oil may be used.

Suitable solvents, gelling agents and solubilizers are water or water-miscible solvents. Suitable examples are alcohols, such as, for example, ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, Glycerol, di- or tripropylene glycol, waxes, methyl cellosolve, cellosolve, esters, morpholines, dioxane, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, etc.

Cellulose ethers which can dissolve or swell both in water and in organic solvents, such as, for example, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose or soluble starches, can be used as film formers.

Mixed forms between gel and film formers are also possible. Here are mainly ionic macromolecules used, such. Sodium carboxymethyl cellulose, polyacrylic acid, polymethacrylic acid and its salts, sodium amylopectin monoglycolate, alginic acid or propylene glycol alginate as the sodium salt, gum arabic, xanthan gum, guar gum or carrageenan.

Other formulation auxiliaries may be used: glycerol, paraffin of different viscosity, triethanolamine, collagen, allantoin, novantisolic acid.

The use of surfactants, emulsifiers or wetting agents may also be necessary for the formulation, e.g. of Na lauryl sulfate, fatty alcohol ether sulfates, di-Na-N-lauryl-.beta.-iminodipropionate, polyoxyethylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (eg Tween), cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ethers, cetyltrimethyl ammonium chloride or mono- / Dialkyipolyglykoletherorthophosphorsäure- monoethanolamine salts.

Stabilizers, such as montmorillonites, or colloidal silicas for stabilizing emulsions or preventing the degradation of active substances, such as antioxidants, for example tocopherols or butylated hydroxyanisole, or preservatives, such as p-hydroxybenzoic acid. acid esters, may also be necessary to prepare the desired formulations.

Preparations for parenteral administration may be in separate dosage unit forms, such as e.g. Ampoules or vials are present. 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 finished preparation or just before use by mixing the active compound, e.g. of the lyophilizate, optionally with further solid carriers, with the desired solvent or suspending agent.

Intranasal preparations may be present as aqueous or oily solutions or as aqueous or oily suspensions. They may also be present as lyophilisates, which are prepared before use with the appropriate solvent or suspending agent.

The preparation, filling and sealing of the preparations is carried out under the usual antimicrobial and aseptic conditions.

The invention further relates to processes for the preparation of the compounds of the invention.

According to the invention, the compounds of general formula 1 having the meanings of A, B, R ¹ , R ² , R ³ and R ^{4 described} above are prepared,

in that compounds of the formula 1 with the above-described meaning of R ¹ , R ² , R ³ and R ⁴ , in which A is nitrogen and B may be nitrogen or carbon, in a conventional manner by treatment with an oxidizing agent, for example a organic peracid, preferably with m-chloroperbenzoic acid or / and peracetic acid to give the compounds of the formula Ia 1b or 1c according to the invention. Optionally resulting mixtures of N-oxides can be separated in a manner known per se by crystallization or chromatographic methods into the pure compounds of formula Ia 1b or 1c.

Examples

Example 1:

Exemplary production process for inventive

Compounds of the formula 1a:

1.1 N- (3 _J 5-Dichloropyridin-4-yl) - [1- (4-fluorobenzyl) -7-oxo-7-azaindol-3-yl] -glyoxylic acid amide

3 g of N- (3,5-dichloropyridin-4-yl) - [1- (4-fluorobenzyl) -7-azaindol-3-yl] -glyoxylic acid amide are dissolved in 180 ml of dichloromethane. With stirring, a solution of 6 g of m-chloroperbenzoic acid in 12 ml of acetic acid is added dropwise. The reaction mixture is stirred at room temperature for 7 days. By adding a potassium carbonate solution, the mixture is at pH 8 to 9 posed. The phases are separated and the organic phase washed with 100 ml of water. The solvent is distilled off under vacuum. The residue is stirred in 10 ml of isopropanol. The crystals are separated and dried at room temperature. The crude product is purified by preparative HPLC. The solvent system used is a mixture of ethyl acetate and methanol in the ratio 85:15.

From the fraction containing the product, the solvent mixture is distilled off in vacuo and the residue recrystallized from isopropanol.

Yield: 0.3 g (9.4% of theory) Melting point: 205 ° -208 ° C.

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

3.1 g of N- (3,5-dichlorophenyl) - [1- (2-chlorobenzyl) -7-azaindol-3-yl] -glyoxylic acid amide are dissolved in 180 ml of dichloromethane While stirring, a solution of 6 g of m Chloro perbenzoic acid added dropwise in 12 ml of acetic acid. The reaction mixture is stirred at room temperature for 7 days. By adding a potassium carbonate solution, the mixture is adjusted to pH 8 to 9. The phases are separated and the organic phase washed with 100 ml of water. The solvent is distilled off under vacuum. The residue is stirred with 30 ml of water at 50 ° C, filtered off with suction and recrystallized from 100 ml of isopropanol.

Yield: 1.3 g (40% of theory) Melting point: 165-168 ° C Example 2:

Exemplary production method for inventive

Compounds of the formula 1b:

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

3 g of N- (3,5-dichloropyridin-4-yl) - [1- (4-fluorobenzyl) -7-azaindol-3-yl] -glyoxylic acid amide are dissolved in 180 ml of dichloromethane. With stirring, a solution of 6 g of m-chloroperbenzoic acid in 12 ml of acetic acid is added dropwise. The reaction mixture is stirred at room temperature for 7 days. By adding a potassium carbonate solution, the mixture is adjusted to pH 8 to 9. The phases are separated and the organic phase washed with 100 ml of water. The solvent is distilled off under vacuum. The residue is stirred in 10 ml of isopropanol. The crystals are separated and dried at room temperature. The crude product is purified by preparative HPLC. The solvent system used is a mixture of ethyl acetate and methanol in the ratio 85:15.

From the fraction containing the product, the solvent mixture is distilled off in vacuo and the residue is recrystallized from ethanol.

Yield: 1.2 g (37.5% of theory) Melting point: 233-236 ° C.

Example 3:

Exemplary production method for inventive

Compounds of the formula Ic:

3.1 N- (3,5-dichloro-1-oxopyridin-4-yl) - [1- (4-fluorobenzyl) -7-oxo

7-azaindol-3-yl] -glyoxylsäureamid

3 g of N- (3,5-dichloropyridin-4-yl) - [1- (4-fluorobenzyl) -7-azaindol-3-yl] -glyoxyl acid amide are dissolved in 180 ml of dichloromethane. With stirring, a solution of 6 g of m-chloroperbenzoic acid in 12 ml of acetic acid is added dropwise. The reaction mixture is stirred at room temperature for 7 days. By adding a potassium carbonate solution, the mixture is adjusted to pH 8 to 9. The phases are separated and the organic phase washed with 100 ml of water. The solvent is distilled off under vacuum. The residue is stirred in 10 ml of isopropanol. The crystals are separated and dried at room temperature. The crude product is purified by preparative HPLC. The solvent system used is a 90:10 mixture of ethyl acetate and methanol.

From the fraction containing the product, the solvent mixture is distilled off in vacuo and the residue is recrystallized from ethanol.

Yield: 0.2 g (6.3% of theory) Melting point: 254-257 ° C

Example 4:

Preparation of further compounds

Numerous other compounds of formula 1 can be prepared using the indicated preparation methods, the following being exemplified:

The compounds according to the invention are potent inhibitors of phosphodiesterase 4. Their therapeutic potential is demonstrated in vivo, for example, by the inhibition of the asthmatic late-phase reaction (eosinophilia) and by the inhibition of LPS-induced neutrophilia in rats.

Example 5:

Inhibition of phosphodiesterase 4

PDE4 activity is determined with enzyme preparations from human polymorphonuclear lymphocytes (PMNL). Human blood (buffy coats) was anticoagulated with citrate. Centrifugation at 700 xg for 20 minutes at room temperature (RT) separates the platelet-rich plasma in the supernatant from the erythrocytes and leukocytes. The PMNLs for the PDE4 determination are characterized by a following dextran sedimentation and subsequent gradient centrifugation with Ficoll-Paque isolated. After a two-time washing of the cells, the erythrocytes still contained by the addition of 10 ml of hypotonic buffer (155 mM NH ₄ Cl, 10 mM NaHCO ₃ , 0.1 mM EDTA, pH = 7.4) within 6 minutes at 4 ° C lysed. The still intact PMNLs are washed twice with PBS and lysed by ultrasound. The supernatant from a one-hour centrifugation at 4 ° C at 48,000 xg contains the cytosolic fraction of PDE 4 and is used for the PDE4 measurements.

The phosphodiesterase activity is determined by a modified method of Amersham Pharmacia Biotech, a SPA (Scintillation Proximity Assay).

The reaction mixtures contain buffer (50 mM Tris-HCl (pH 7.4), 5 mM MgCl ₂ , 100 μM cGMP), the inhibitors in variable concentrations and the corresponding enzyme preparation. By adding the substrate, 0.5 μM

[ ³ H] -cAMP, the reaction is started. The final volume is 100 μl.

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 the start of the

Reaction by substrate addition, the samples are incubated at 37 ° C for 30 minutes. By adding a defined amount of SPA beads is the

Reaction stopped and the samples measured after one hour in the beta counter. The non-specific enzyme activity (the blank) is determined in the presence of 100 μM Rolipram and subtracted from the test values. The

Incubation approaches of the PDE4 assay contain 100 μM cGMP to detect any

Impurities by the PDE 3 to inhibit.

For the compounds according to the invention, IC ₅ O values in the range from 10 ^-10 to 10 ⁵ M were determined with respect to the inhibition of phosphodiesterase 4. The selectivity to PDE types 3, 5 and 7 is from 100 to 10,000. As an example, the results for the inhibition of PDE4 were summarized in the following table for selected application examples:

Example 6:

Inhibition of late-phase eosinophilia 48 h after inhalation of ovalbuminchallenge on actively sensitized Brown Norway rats

The inhibition of pulmonary eosinophil infiltration by the substances according to the invention is tested on actively against ovalbumin (OVA) sensitized male Brown Norway rats (200-250 g). Sensitization is by subcutaneous injection of a suspension of 10 μg OVA together with 20 mg of aluminum hydroxide as adjuvant in 0.5 ml of physiological saline per animal on days 1, 14 and 21. In addition, the animals will receive Bordetella pertussis vaccine dilution at the same times Animal injected 0.25 ml ip. On the 28th day of the experiment, the animals are placed individually in open 1 l Plexiglas boxes connected to a head-nose exposure device. The animals are exposed to an aerosol of 1, 0% Ovalbuminsuspension (allergen Challenge). The ovalbumin aerosol is generated by a compressed air (0.2 MPa) nebulizer (Bird micro nebulizer, Palm Springs CA, USA). Exposure time is 1 hour, with normal controls aerosolized with 0.9% saline also nebulized for 1 hour. 48 hours after the allergen challenge, massive eosinophilic granulocyte migration into the lungs occurs. At this time, the animals are anesthetized with an overdose of ethyl urethane (1, 5 g / kg body weight ip) and a bronchoalveolar lavage (BAL) with 3 x 4 ml Hank's Balanced solution. The total cell number and the number of eosinophilic granulocytes of the pooled BAL fluid are then determined with an automatic cell differentiation device (Bayer Diagnostics Technicon H1E). Eosinophils (EOS) in the BAL are calculated in millions / animal for each animal: EOS / μl x BAL recovery (ml) = EOS / animal.

For each test, 2 control groups (nebulization with saline and nebulization with OVA solution) are included.

The percent inhibition of eosinophilia of the substance-treated experimental group is calculated according to the following formula:

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

(SC = vehicle treated and 0.9% saline challenged control group, OVAC = vehicle treated and challenged with 1% ovalbumin suspension, OVAD = drug treated 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 the allergen challenge. The control groups are treated according to the application form of the test substance with the vehicle. The compounds according to the invention inhibit the late phase eosinophilia after intraperitoneal administration of 10 mg / kg by 30% to 100% and after oral administration of 30 mg / kg by 30% to 80%.

The compounds of the invention are therefore particularly suitable for the preparation of medicaments for the treatment of diseases associated with the action of eosinophils.

Example 7: Inhibition of lipopolysaccharide (LPS) -induced lung neutrophilia in Lewis rats

The inhibition of pulmonary neutrophil infiltration by the substances according to the invention is tested on male Lewis rats (250-350 g). On the day of the experiment, the animals are placed individually in open 1 l Plexiglas 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 generated by a nebulizer (Bird micro nebulizer, Palm Springs CA, USA) operated with compressed air (0.2 MPa). Exposure time is 40 minutes, normal controls being aerosolized with 0.1% hydroxylamine solution aerosol in PBS also for 40 minutes.

6 hours after the LPS provocation, there is a maximum, massive immigration of neutrophils into the lungs of the animals. At this time, the animals are anesthetized with an overdose of ethyl urethane (1, 5 g / kg body weight ip) and a bronchoalveolar lavage (BAL) with 3 x 4 ml Hank's Balanced solution. The total cell count and the number of neutrophil granulocytes of the pooled BAL fluid are then determined with an automatic cell differentiation device (Bayer Diagnostics Technicon H1 E). For each animal the neutrophils (NEUTRO) in the BAL in Mio / animal calculated: NEUTRO / μl x BAL recovery (ml) = NEUTRO / animal.

For 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) are carried.

The percentage inhibition of neutrophilia of the substance-treated experimental group is calculated according to the following formula:

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

% Inhibition

SC = vehicle treated and challenged with 0.1% hydroxylamine solution; LPSC = vehicle treated and challenged with LPS (100 μg / ml 0.1% hydroxylamine solution) control group; LPSD = substance-treated and challenged with LPS (100 μg / ml 0.1% hydroxylamine solution) experimental group.

The test substances are administered orally as a suspension in 10% polyethylene glycol 300 and 0.5% 5-hydroxyethyl cellulose 2 hours before the LPS provocation. The control groups are treated according to the application form of the test substance with the vehicle.

The compounds of the invention inhibit the neutrophilia after oral administration of 1 mg / kg by 30% to 90% and are therefore particularly suitable for the preparation of medicaments for the treatment of diseases associated with the action of neutrophils.

Claims

Expectations

1. Compounds of the general formula 1,

wherein

A can represent nitrogen or an N-oxide group, B can be carbon, nitrogen or an N-oxide group,

R

(i) for -C ,. ₁₀ -alkyl, straight-chain or branched-chain, optionally mono- or polysubstituted with -OH, -SH, -NH ₂ , -NHC ^ -alkyl, -N (C _1.6 alkyl) ₂ , -NHC ₆ . _14- aryl, -N (C _M4- aryl) ₂ , -N (C _1.6 -alkyl) (C _6.14- aryl),

-NO ₂ , -CN, -F, -Cl, -Br, -I, -OC ^ alkyl, -OC _6.14 -Aryl, -SC ^ alkyl, -SC ^ aryl, -SO ₃ H, -SO .C ^ -alkyl, SO - ^ - aryl, -OSO ^ -alkyl, -OSO.C ^ -aryl, -COOH, - (COJC ^ -alkyl, -COO-C ^ -alkyl, - © (COJC ^ - Alkyl, with mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3-14 ring members or / and 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, the C ^ -Arvl groups and the carbocyclic and heterocyclic substituents in turn, if appropriate, one or more times with - _.g -alkyl, -OH, -NH ₂ , -NH _{. g} -alkyl, -NC ^ -alkyl) ,, -NO _2> -CN, -F, -Cl, -Br, -I, -OC ^ -alkyl, -SC ^ -alkyl, -SO ₃ H, -S0 ₂ C ^ alkyl. -OS0 ₂ C ^ alkyl. -COOH, - (CO) C ^ -alkyl. -COO-C-.s-alkyl or / and -0 (CO) C _M alkyl may be substituted, and wherein the alkyl groups on the carbocyclic and heterocyclic substituents in turn, if necessary, one or more times with -OH, -SH, -NH ₂ , -F, -Cl, -Br, -I, -SO ₃ H or / and

-COOH can be substituted, or

(ii) represents -C _2.10 alkenyl, mono- or polyunsaturated, straight-chain or branched-chain, optionally mono- or polysubstituted with -OH, -SH, -NH ₂ ,

-NHC ^ alkyl, -N (C _{1. 6,} alkyl) _2, -NHC ^ -aryl, -N (C _6.14 -aryl) _2, -N (C _{1. 6,} alkyl) (C _6.14 -aryl) , -NO ₂ , -CN, -F, -Cl, -Br, -I, -OC ^ alkyl, -OC _6.14 aryl, -SC ^ alkyl, -SC ^ aryl, -SO ₃ H, - SO ₂ C _1.6 alkyl, -SO ₂ C _6.14 aryl, -OSO-C ^ alkyl, -OSC ^ C ^ aryl, -COOH, - (CO) C, _.5 alkyl, -COO-C ^ -AIkyl, -0 (CO) C ^ -alkyl, with mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3-14 ring members and / or 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, the C _g . ₁₄ aryl groups and the carbocyclic and heterocyclic substituents in turn, if appropriate, one or more times with -C ^ alkyl, -OH, -NH ₂ , -NHC ^ alkyl, -N (C ₆ alkyl) ₂ , -NO ₂ , -CN, -F, -Cl, -Br, -I, -OC ^ alkyl, -SC ^ alkyl, -SO ₃ H, -SO.C ^ alkyl, -OS0 ₂ C ₁ _ ₆ alkyl , -COOH, - (COJC ^ alkyl,

-COO-G ^ -alkyl or / and -O (CO) C ₁ . ₅ -Alkyl may be substituted, and the alkyl groups on the carbocyclic and heterocyclic substituents in turn, if appropriate, one or more times with -OH, -SH, -NH ₂ , -F, -Cl, -Br, -I, -SO ₃ H or / and -COOH can be substituted, R ^{2 represents} hydrogen or -Cι- ₃ alkyl,

R ³ and R ^{4 may be the} same or different and are for

Hydrogen, -Cι _-6- alkyl, -OH, -SH, -NH ₂₎ -NHC _1-6 -alkyl, -N (d _-6 -alkyl) ₂ , -NO ₂ , -CN, -SO ₃ H, -SO ₃ -Cι-6-alkyl, COOH, -COO-de-alkyl, -O (CO) -

Ci-s-alkyl, -F, -Cl, -Br, -I, -OC _1-6 -alkyl, -Sd _-6- alkyl, -phenyl or -pyridyl, the phenyl or pyridyl substituents in turn optionally being or several times with -Cι _-3 alkyl, -OH, -SH, -NH ₂ , -NHCι _-3 alkyl, -N (C _1-3 -AlkyI) ₂ , -NO ₂ , -CN, -SO ₃ H , -SO ₃ Cι, ₃ -AlkyI, -COOH, -COOCι-3-AlkyI, -F, -Cl, -Br, -I, -O-Cι. ₃ -alkyl, -S-Cι _-3 alkyl or / and

-O (CO) -Cι _-3 alkyl can be substituted and the alkyl substituents in turn, if necessary, one or more times with -OH, -SH, -NH ₂ , -F, -Cl, -Br, -I, -SO ₃ H, -SO ₃ Cι _-3 alkyl, -COOH, COOCi-s-alkyl, -O-Ci.g-alkyl, -S-Cι _-3 alkyl or / and -O (CO) -C _1-3 -Alkyl can be substituted.

or salts of the compounds of formula 1.

2. Compounds according to claim 1 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.

3. Compounds according to claim 1 or 2, characterized in that A is N and B is N-O.

4. Compounds according to claim 3, characterized in that R ^{2 is} -H or -CH ₃ .

5. Compounds according to claim 4, characterized in that at least one of R ³ and R ⁴ each represents a halogen atom.

6. Compounds according to claim 1 or 2, characterized in that A is NO and B is CH, CR ³ or N.

7. Compounds according to claim 6, characterized in that R ^{2 is} -H or -CH ₃ .

8. Compounds according to claim 7, characterized in that at least one of R ³ and R ⁴ each represents a halogen atom.

9. Compounds according to one of claims 1 to 8 selected from:

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

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

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

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

N-phenyl- [1- (4-fluorobenzyl) -7-oxo-7-azaindol-3-yl] glyoxylic acid amide N- (3,5-dichloro-1-oxopyridin-4-yl) - [1- (2-fluorobenzyl) -7-azaindol-3-yl] glyoxylic acid amide

N- (3,5-dichloro-1-oxopyridin-4-yl) - [1- (3-nitrobenzyl) -7-azaindol-3-yl] glyoxylic acid amide

N- (3,5-dichloro-1-oxopyridin-4-yl) - [1- (2,6-difluorobenzyl) -7-azaindol-3-yl] glyoxylic acid amide

N- (3,5-dichloro-1-oxopyridin-4-yl) - [1- (2,4-dichlorobenzyl) -7-azaindoI-3-yl] glyoxylic acid amide

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

N- (3,5-dichloro-1-oxopyridin-4-yl) - [1- (2-chlorobenzyl) -7-azaindol-3-yl] glyoxylic acid amide

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

N- (3,5-dichloro-1-oxopyridin-4-yl) - [1- (2-chlorobenzyl) -7-oxo-7-azaindol-3-yl] glyoxylic acid amide

N- (3,5-dichloropyridin-4-yl) -N-methyl- [1- (2-chlorobenzyl) -7-oxo-7-azaindole-

3-yl] glyoxylic acid amide

N- (3,5-dichloro-1-oxopyridin-4-yl) -N-methyl- [1- (2-chlorobenzyl) -7-azaindole-3-yl] glyoxylic acid amide

N-Methyl-N- (1-oxopyridin-4-yl) - [1- (2-chlorobenzyl) -7-azaindol-3-yI] glyoxylic acid amide N- (3,5-dichloro-1-oxopyridin-4-yl) - [1- (2,6-dichlorobenzyl) -7-azaindol-3-yl] glyoxylic acid amide

N- (3,5-dichloro-1-oxopyridin-4-yl) - [1- (2-methylbenzyl) -7-azaindol-3-yl] glyoxylic acid amide

N- (3,5-dichloro-1-oxopyridin-4-yl) - [1- (2,6-dimethylbenzyl) -7-azaindol-3-ylj-glyoxylic acid amide

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

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

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

N- (3,5-dichloro-1-oxopyridin-4-yl) - [1 - (naphth-1-yl-methyl) -7-azaindol-3-yl] - glyoxylic acid amide

N- (3,5-dichloropyridin-4-yl) - [1- (2-chloro-6-fluorobenzyl) -7-oxo-7-azaindole-3-yl] glyoxylic acid amide

N- (3,5-dichloro-1-oxopyridin-4-yl) - [1- (2-chloro-6-fluorobenzyl) -7-azaindole-3-yl] glyoxylic acid amide

N- (3,5-dichloro-1-oxopyridin-4-yl) - [1- (2-chloro-6-fluorobenzyl) -7-oxo-7-azaindol-3-yl] glyoxylic acid amide

N- (3,5-dichloro-1-oxopyridin-4-yl) - [1 - (2-difluoromethylbenzyl) -7-azaindole-3-yl] -glyoxylic acid amide N- (3,5-dichloro-1-oxopyridin-4-yl) - [1- (2-cyanobenzyl) -7-azaindol-3-yl] glyoxylic acid amide

and physiologically acceptable salts thereof.

10. A process for the preparation of compounds of formula 1, characterized in that compounds in which A is nitrogen and B can be nitrogen or carbon, by treatment with an oxidizing agent to give the compounds of formula 1a ,. 1b or 1c oxidized.

11. The method according to claim 10, characterized in that a peracid, in particular m-

Chloroperbenzoic acid and / or peracetic acid.

12. The method according to claim 10, characterized in that resulting mixtures of N-oxides by crystallization and / or chromatographic methods in the pure compounds of formula IJ. 1b or 1c.

13. The method according to any one of claims 10 to 12, characterized in that for the separation of mixtures of N-oxides by chromatographic methods, mixtures of the solvents ethyl acetate and methanol are preferably used in mixing ratios between 50:50 and 99: 1.

14.Use of the compounds of formula 1 according to one of claims 1 to 9 as therapeutic agents for the manufacture of medicaments for the treatment of diseases in which the Inhibition of phosphodiesterase 4 is therapeutically useful.

15. Use of the compounds of formula 1 according to any one of claims 1 to 9 as therapeutic agents for the manufacture of medicaments for the treatment of diseases associated with the action of

Eosinophils are linked.

16.Use of the compounds of formula 1 according to any one of claims 1 to 9 as therapeutic agents for the manufacture of medicaments for the treatment of diseases associated with the action of

Neutrophils are linked.

17. Use of the compounds of formula 1 according to any one of claims 1 to 9 as therapeutic agents for the manufacture of medicaments for the treatment of hyperproliferative diseases.

18.Arzneimitt.el, containing one or more compounds according to claims 1 to 9 in addition to the usual physiologically compatible carriers and / or diluents or auxiliaries.

19. A method for producing a medicament according to claim 18, characterized in that one or more compounds according to one of claims 1 to 9 are processed with common pharmaceutical carriers and / or diluents or other auxiliaries to give pharmaceutical preparations or are brought into a therapeutically usable form.

20. Use of compounds of general formula 1 according to one of claims 1 to 9 and / or of medicaments according to claim 18 alone or in combination with one another or in combination with other active pharmaceutical ingredients.