HK1035183B - New hydroxyindoles, their use as phosphodiesterase 4 inhibitors and method for producing same - Google Patents

Description

Technical field

The invention relates to substituted hydroxyindoles of general formula 1 , 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)Conti M and Heaslip RJ. Multiple cyclic nucleotide phosphodiesterases. Mol. Pharmacol. 1994, 46:399-405; Hall IP. Isoenzyme selective phosphodiesterase inhibitors: potential clinical uses, Br. J. clin. Pharmacol. 1993, 35-1-7). Inhibition of the different PDE isoenzyme types leads to a buildup 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, eosinophil granulocytes, macrophages), the predominant PDE isoenzyme is type 4 (Torphy, JT and Undem, BJ 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 the inhibition of the release of tumor necrosis factor a (TNFα) from inflammatory cells. TNFα is a major pro-inflammatory cytokine that influences a variety of biological processes. TNFα is released from, for example, activated macrophages, activated T-lymphocytes, mast cells, basophils, fibroblasts, endothelial cells and astrocytes in the brain. It acts actively on neutrophils, eosinophils, fibroblasts and endothelial cells, releasing various tissue-destructive mediators.Macrophages and T-lymphocytes cause TNFα to increase the production of other pro-inflammatory cytokines such as granulocyte macrophage colony-stimulating factor (GMSF) or interleukin-8. Due to its pro-inflammatory and catabolic effects, TNFα plays a key role in a wide range of diseases, including respiratory tract inflammation, joint inflammation, endotoxic shock, tissue rejection, AIDS and many other immunological diseases.

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), although patients are usually over 55 years old at the time of death (Nolte D.: Chronic bronchitis - a folk disease of multifactorial genesis.

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 changes steadily decrease, and the lung becomes increasingly emphysema and the asthma of the patients is obviously reduced. This number significantly affects the quality of life of patients (S. S. 1132, Epidemiology and Disease Definition: Smoking and respiratory disease) and the quality of life of patients (S. S. 239 and Epidemiology: Smoking and respiratory disease) (5 F. 1994; Supplement, 239 and 239 F. 1994); however, the number of patients whose lung function changes significantly decreases, the lung becomes increasingly emphysema and the asthma of the patients is obviously reduced.

The use of long-acting beta-2 agonists (e.g. salmeterol) may be combined with muscarinic antagonists (e.g. ipratropium) to improve lung function by 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 require antibiotic therapy (Wilson R.: The role of infection in chest disease, Chest, 113 (4) Supplement, 242S48-23, 1998; Grossman F. The value of antibiotics for inflammation and the development of new antibiotic agents, especially in the development of COPD, may be significantly reduced by the use of antibiotics, especially in the development of new drugs, such as L.S. 11-159 (1915), or L.S. 11-159 (1915), Supplement, 113-135).

In addition to the bacterial infections that complicate the disease, chronic inflammation is present in the bronchi, which is dominated by neutrophil granulocytes. The structural changes observed in the respiratory tract (emphysema) are caused, among other things, by mediators and enzymes released by neutrophil granulocytes. Inhibition of neutrophil granulocyte activity is thus a rational approach to preventing or slowing the progression of COPD (degradation of lung function parameters). A very important stimulant for activating granulocyte activity is the pro-inflammatory cytokine granulocyte TNFα (TNFα granulocyte necrosis). It is known that the formation of granulocyte TNFα by neutrophil granulocyte is stimulated by the production of free oxygen. The active substance is known to inhibit the production of granulocyte granulocyte and granulocyte P.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.

Various PDE4 inhibitors are already known, primarily xanthine derivatives, rolipram analogues or nitracuazone 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 has been able to reach clinical use. It has been found that the known PDE4 inhibitors also have various side effects such as nausea and emesis which have not been sufficiently reversed so far.

Although indoles have been important in the development of new drugs for various indications for many years, hydroxyindoles as inhibitors of PDE4 are completely unknown.

Description of the invention

The invention relates to substituted hydroxyindoles of general formula 1, In which R1 for - C1...12-alkyl, straight or branched chain, where appropriate, replaced by -OH, -SH, -NH2, -NHC1...6-alkyl, -N(C1...6-alkyl) 2, -NHC6...14Aryl, -N(C6...14Aryl) 2, -N(C1...6Alkyl) -C6...14Aryl), -N(C1...6Alkyl) -N(C6...14Aryl), -N(C1...6Alkyl) -NHCOR6, -NO2, -CN, -F, -Cl, -Br, -l, -O-C1...6-alkyl, -O-C6...14-alkyl, -OCO) R6, -S-C1...6-alkyl, -S-C6...14Aryl, -SOR6, -SO3H, -SO2R6, -OSO2C1...6 Heterocyclic alkyl, -OS2C6...14Aryl, -CSR6, -COOH, -R6, -CO14A, -SCSR6 -O6 are a single, tricyclic or tricyclic ring, or a ring, which may be one, three or more, or more, or a ring, which may be connected to a single, or a combination of them, and may be connected to a ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring, ring,-C2... 12-alkenyl, unsaturated, single or multiple, straight or branched chain, where appropriate, replaced by -OH, -SH, -NH2, -NHC1... 6-alkyl, -N(C1... 6-alkyl) 2, -NHC6... 14Aryl, -N(C6... 14Aryl) 2, -N(C1... 6Alkyl) -C6... 14Aryl), -N(C1... 6Alkyl) -NHCOR6, -NO2, -CN, -F, -Cl, -Br, -I, -O-C1... 6Alkyl, -O-C6... 14Aryl, -OCO) R6, -S-C1... 6Alkyl, -S-C6... 14Aryl, -SOR6, -SO3H, -SO2R6, -OSO2C1... 6 Heterocyclic heterocyclic heterocycles, -O2C6... 14Aryl, -CSR6 -COOH, -S14A, -CO6 -R6, -CO6 -R6 -R14 are a tricyclic or a heterocyclic ring, which may be one, two, three or more rings or a ring, and may be connected to one or more rings or rings, and may be unidireally or intrinsically connected to one or more rings or rings, and may be replaced by a ring of three or more heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic het- Mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3 ...14 ring members, whether or not repeatedly substituted with -OH, -SH, -NH2, -NHC1...6-alkyl, -N(C1...6-alkyl) 2, -NHC6...14Aryl, -N(C6...14Aryl) 2, -N(C1...6Alkyl) -C6...14Aryl), -N(C1...6Alkyl) -NHCOR6, -NO2, -CN, -F, -Cl, -Br -I, -O-C1...6-alkyl, -O-C6...14-alkyl, -OCO) R6, -S-C1...6-alkyl, -S-C6...14Aryl, -SOR6, -SO3H, -SO2R6, -OSO2C1...6 Heterocyclic alkyl, -OS2C6...14Aryl, -CSR6 -COOH, -R14A, -S6R6 -COOH, -R14A, -S14A, -S14A, -S14R6, -S14R6 -COOH, -S14R6 -COOH, -S14R6 -COOH, -S14R6 -COOH, -S14R6 -COOH, -S14R6 -COOH, -S14R6 -COOH, -S14R6 -COOH, -S14R6 -COOH, -S14R6 -SCOOH, -SCOOH, -SCOOH, -SCOOH -SCOOH, -SCOOH -SCOOH, -SCOOH -SCOOH, -SCOOH -SCOOH, -SCOOH -SCOOH, -SCOOH -SCOH, -SCOH -SCOH -SCOH, -SCOH -SCOH -SCOH, -SCOH -SCOH -SCOH, -SCOH -SCOH -SCOH, -SCOH -SCOH -SCOH, -SCOH -SCOH -SCOH -SCOH, -SCOH -SCOH -SCOH -SCOH -SCOH, -SCOH -SCOH -SCOH -SCO- Mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5 to 15 ring members and 1 to 6 heteroatoms, preferably N, O and S, where appropriate, replaced one or more times by -OH, -SH, -NH2, -NHC1...6-alkyl, -N(C1...6-alkyl) 2, -NHC6...14Aryl, -N(C6...14Aryl) 2, -N(C1...6Alkyl) ((C6...14Aryl), -N(C1...6Alkyl) -NHCOR6, -NO2, -CN, -F, -Cl, -Br, -I, -O-C1...6-alkyl, -O-C6...14-alkyl. -OCO) R6, -S-C1...6-alkyl, -S-C6...14Aryl, -SOR6, -SO3H, -SO2R6, -OSO2C1...6 Heterocyclic, -O2C6...14Aryl, -CSR6, -COOH, -SCSR6, -COOH, -O6...6, -C14 or -C15 are a tricyclic ring, or a tricyclic compound, containing one or more monocyclic or monocyclic compounds, or having three or more non-metals, and one or more monocyclic or monocyclic rings, or rings, or rings, which are not connected, or are not connected, and which have more than one or more non-metals, three or more non-metals, and which are connected, respectively, by means of a single or a common conductor, to a single or a common conductor, and which are connected by means of one or two or more conductors, or two or two or more electrical or electrical or electrical or electrical or electrical connections, electrical or electrical, electrical, electrical or electrical, electrical or electrical, electrical or electrical, electrical or electrical, electrical or electrical, electrical or electrical or electrical, or electrical, or electrical, or electrical, or other means, or other means, or other means, or other than electric, or other than electric, and electric, or electric, or other than electric, or electric, or any of any of any of any of any other energy;- carbocyclic or heterocyclic saturated or monocyclic unsaturated spirocycles with 3 to 10 ring members, whereby heterocyclic systems contain 1 to 6 heteroatoms, preferably N, O and S, whether or not repeatedly substituted with -OH, -SH, -NH2, -NHC1...6-alkyl, -N(C1...6-alkyl) 2, -NHC6...14Aryl, -N(C6...14Aryl) 2, -N(C1...6Alkyl) C6...14Aryl), -N(C1...6Alkyl) -NHCOR6, -NO2, -CN, -F, -Cl, -Br, -I, -O-C1...6-alkyl, -O-C6...14-alkyl, -OCO) R6, -S-C1...6-alkyl, -S-C6...14Aryl, -SOR6, -SO3H, -SO2R6, -OSO2C1...6Alkyl, -OS2C6...14Aryl, -CSR6, -COOH, -COR6, -COR6, -COR5, -COR6, -COR14 or -O-C1...6, tricyclic or monocyclic, or tricyclic, with unsaturated or unsaturated monocyclic or polycyclic rings, or with unsaturated or unsaturated monocyclic or polycyclic or polycyclic ...R15 is the ring member and 1 to 6 heteroatoms, preferably N, O and S, where the C6...14Aryl groups and the carbocyclic and heterocyclic substituents may be replaced by R4 one or more times, if necessary;R2 is R3 can be hydrogen or -OH, where at least one of the substituents must be -OH;R4 is -H, -OH, -SH, -NH2, -NHC1...6-alkyl, -N(C1...6-alkyl) 2, -NHC6...14Aryl, -NSOC6...14Aryl) 2, -NC1...6...6 (C6...14Aryl), -NNOC6...6 (C6...14Aryl), -NORHC2, -COOH, -CNOH, -COOH, -CNF6, -COOH, -C6...6 (C6...6), -C6...6 (C6...6), -C6...6 (C6...6), -C6...6 (C6...6), -C6...6 (C6...6), -C6 (C6...6), -C6 (C6...6 (C6), -C6 (C6...6), -C6 (C6...6), -C6 (C6...6), -C6 (C6...6), -C6 (C6 -C6 -C6 -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C, -C - Mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3 ...14 ring members, -F, -Cl, -Br, -I, -F, -Cl, -Br, -I, -F, -Cl, -Br, -I, -I, -F, -Cl, -Br, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, -I, whether or not substituted with -OH,SH, -NH2, -NHC1...6-alkyl, -N(C1...6-alkyl) 2, -NHC6...14-aryl, -N(C6...14-aryl) 2, -N(C1...6-alkyl) ((C6...14-aryl), -NHCOR6, -NO2, -CN, -O-C1...6 alkyl, -O-C6...14-aryl, -O(CO) R6, -S-C1...6-alkyl, -S-C6...14-aryl, -SOR6, -SO3H, -SO2R6, -OSO2C1...6-alkyl, -OSO2C6...14-aryl, -R6, -COOH, -CO) Heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic hetO and S are, -F, -Cl, -Br, -l, -F, -Cl, -Br, -l, -F, -Cl, -Br, -l, -F, -Cl, -Br, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l, -l -l -l -l -l -l -l -l -l -l -l -l -l -l -l -l -l -l -l -l -l -l -l -l -l -l -l -l -l -l -l -l -l - - - - - - where appropriate, replaced one or more times by -OH, -SH, -NH2, -NHC1...6-alkyl, -N(C1...6-alkyl) 2, -NHC6...14-aryl, -N(C6...14-aryl) 2, -N(C1...6-alkyl) -C6...14-aryl), -NHCOR6, -NO2, -CN, -O-C1...6-alkyl, -O-C6...14-aryl, -O(CO) R6, -S-C1...6-alkyl, -S-C6...14-aryl, -SOR6, -SO3H, -SO2R6, -OSO2C1...6-alkyl, -OSO2C6...6-alkyl, -CS(R6, -COOH, -COR6), wherein the heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocyclic heterocycR6 can -H, -NH2, -NHC1...6-alkyl, -N(C1...6-alky) 2, -NHC6...14Aryl, -N(C6...14Aryl) 2, -N(C1...6Alkyl) ((C6...14Aryl), -O-C1...6-alkyl, -O-C6...14-alkyl, -S-C1...6-alkyl, -S-C6...14Aryl, -C1...12-alkyl, whether or not with a straight or branched chain, - C2...12-alkenyl, unsaturated, single or multiple, straight or branched chain, - Mono-, bi- or tricyclic saturated or mono- or polyunsaturated Carbocycles with 3 ...14 ring members, - means mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles having 5...15 ring members and 1...6 heteroatoms, preferably N, O and S. - (CH2) m-, - (CH2) m- (CH=CH) n- (CH2) p-, - (CH) CHOZ-m-, - (C=O), - (C=S), - (C=N-Z), - (O), - (S), - (NZ), where m, p = 0 .. 3 and n = 0... 2 are andZfor -H, or - C1...12-alkyl, straight or branched chain, -C2...12-alkenyl, one or more unsaturated straight-chain or branched-chain mono-, bi- or tricyclic saturated or one or more unsaturated carbocycles with 3 ....14 ring members, -mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5...15 ring members and 1...6 heteroatoms, preferably N, O and S. where D can only be S or CH2 if B means carbon. - (CH2) m-, -O-, -S-, - (N-Z) -, where m and Z have the meanings already described.

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, malonic acid, maleic acid, fumaric acid, gerbic acid, sulfuric acid, sulfuric acid, algaline acid, benzoic acid, 2-algaline-acetylsalicylic acid, 2-algaline-acetylsalicylic acid, 2-alkylsalicylic acid, 2-alkylsalicylic acid, 2-algaline-acetylsalicylic acid, 2-alkylsalicylic acid, 2-alkylsalicylic acid, 2-alkylsalicylic acid, 2-alkylsalicylic acid, 2-alkylsalicylic acid, 2-alkylsalicylic acid, 2-alkylsalicylic acid, 2-alkylsalicylic acid, 2-alkylsalicylic acid, 2-alkylsalicylic acid, 2-alkylsalicylic acid, 2-alkylsalicylic acid, 2-alkylsalicylic acid, 2-alkylsalicylic acid, 2-alkylsalicylic acid, 2-alkylsalicylic acid, 2-alkylsalicylic acid, 2-alkylsalicylic acid, 2-alkylsalic acid, 2-alkylsalic acid, 2-alkylsalic acid, 2-alkylsalic acid, 2-alkylsalic acid, 2-alkylsalic acid, 2-alkylsalic acid, 2-alkylsalic acid, 2-alkylsalic acid, 2-alkylsalic acid, 2-alkylsalic acid, 2-alkylsalic acid, 2-alkylsalic acid, 2-alkylsalic acid, 2-alkylsalic acid, 2-alkylsalic acid, 2-alkylsalic acid, 2-alkylsalic acid, 2-alkylsalic acid, 2-alkylsalic acid, 2-alkylsalic acid, 2-alkylsalic acid, 2-alThe use of potassium ammonia and amine as organic bases is preferred, but tertiary amines such as trimethylamine, triethylamine, pyridine, N,N-dimethylaniline quinoline, isokinoline, α-picoline, β-picoline, γ-picoline, quinaldine or pyrimidine are preferred. Furthermore, physiologically compatible salts of the compounds of formula 1 can be obtained by converting derivatives containing tertiary amino groups into the corresponding quaternary ammonium salts by means of a quaternizing agent, which is known in itself. Furthermore, the invention relates to the compounds of formula 1 containing one asymmetric carbon atom, the D-form, the L-form and the D,L-mixtures and, in the case of several asymmetric carbon atoms, the diastereomeric forms.The 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. 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 purpose of this invention is therefore to ensure that the compounds of formula 1 and their salts and pharmaceutical preparations containing these compounds or their salts are not used in the manufacture of other drugs.In some cases, the use of TNFα inhibition may be beneficial in the treatment of diseases in which TNFα inhibition is useful. These include joint inflammation including arthritis and rheumatoid arthritis, as well as other arthritic conditions such as rheumatoid spondylitis and osteoarthritis. Other potential uses include the treatment of patients with 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 erythematosus, multiple sclerosis, glomerulonephritis and uveitis, insulin-dependent diabetes mellitus and demyelination. In addition, the compounds of the invention may also be used to treat infections such as viral and parasitic infections, for example, malaria, infection-related fever, infection-related muscle pain,The Commission has already taken a number of steps to ensure that the Community's

The compounds of the invention are inhibitors of phosphodiesterase 4. The purpose of this invention is therefore that the compounds of formula 1 and their salts and pharmaceutical preparations containing these compounds or their salts may 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, and therefore the compounds of the invention can 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, eosinophile-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 keratosis or psoriasis.

The present invention is based on the fact that the compounds of formula 1 and their salts can inhibit both the lipopolysaccharide (LPS) induced release of TNFα in human blood in vitro and the LPS induced pulmonary neutrophil infiltration in ferrets and domestic pigs in vivo.

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 bladder weakness and urinary stones-induced colic. 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 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 dispersed silica acids, silicone oil, higher molecular fatty acids (such as stearic acid), gelatine, agar 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), high molecular polymers such as liquid polyethylene oxide, microcrystalline cellulose carboxymethyl cellulose, polyvinylpyrrolidone, dextrane or gelatine, solid carriers such as starch, lactose, mannitol, methyl cellulose, talcum, high dispersion acids, higher molecular acids (stearic acid), gelatine, agar-agar, calcium, polyphosphate, magnesium, animal and plant solids such as polymethyl collagen.

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 atoms in the fatty acid chains, e.g. palmitin, laurine, tridecyl, margarine, stearin, arachin, myristin, benzoyl, pentadecyl, linol, elaidin, brassidin, eruca or olsacids, esterified with one to three C alcohols such as methanol, ethanol, dibutanol, propanoic acid, benzoyl, pentanoic acid or their isomers, glycosyl or glycerol. The use of the esters may be for example commercial vegetable oil, risopyrol, isopropyl or isopropyl esterol, isopropyl/ethanol, isopropyl ether, sesame oil, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic acid, polypropanoic, polypropanoic acid, polypropanoic, polypropanoic, polypropanoic, polypropanoic, polypropanoic, polypropanoic, polypropanoic, polypropanoic, polypropanoic, poly

The solvents, gelling agents and solvent intermediates are water or water-miscible solvents, for example 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, cellulose ester, morpholine, dioxane, dimethyl sulfoxide, dimethylform, tetrahydrofuran, cyclohexanamide, etc.

Cellulose ethers which dissolve or precipitate in water and in organic solvents, such as hydroxypropylmethylcellulose, methylcellulose, ethylcellulose or soluble starches, may be used as film-forming agents.

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

Other formulating aids may be used: glycerin, paraffin of different viscosity, triethanolamine, collagen, allantoin, novantisol acid. The use of surfactants, emulsifiers or net agents may also be necessary for the formulation, such as those of na-lauryl sulphate, fatty alcohol ether sulphates, di-na-n-lauryl-β-iminodipronate, polyoxyethylene oil or sorbitol monooleate, sorbitol monosterate, polysorbates (e.g. Tween), alcohol, lecithin, glycerethylene monosterate, polyoxyethylene, alkylphenol polyglycol, cetyltrimethyl chloride or risin/diethylmethylphosphate. Stabilizers such as Montmorillonite or colloidal silica to stabilize emulsions or to prevent the breakdown of active substances such as antioxidants such as tocopherol or butyl hydroxyanisol, or preservatives such as p-hydroxybenzoic acid esters may also be required to prepare the desired formulations, if appropriate.

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 before administration.

The preparations are 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. The compounds of the general formula 1, with the meanings of R1, R2, R3, R4, R5, A, B, D and E given above, are obtained according to the invention. by converting compounds according to formula 1, for which R2 or R3 or R2 and R3 = -O-R7 respectively, by splitting R7 into the compounds of the invention. R7 is used for substituents suitable as starting groups, such as alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl, acyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, N-substituted aminocarbonyl, silyl, sulfonyl groups and complexes, such as compounds of boric acid, phosphoric acid and covalently or coordinately bound metals such as zinc, aluminium or copper.Other A particularly preferred reaction for the separation of R7 in the manufacturing process of the invention is a leaching with suitable bases, such as baking soda, potash or sodium carbonate or potassium carbonate. These acidifications are preferably used for R7 = acyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, N-substituted aminocarbonyl, silyl, sulfonyl groups and complexes such as compounds of boric acid, phosphoric acid and coordinationally bound metals such as zinc, aluminium or copper. A particularly preferred reaction for the separation of R7 from compounds in which R7 is an alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl group, as defined in the manufacturing process of the invention, is ether separation, for example by hydrobromic acid, hydrochloric acid, hydrochloric acid iodide, and activating Lewis acids such as AlCl3, BF3, BBr3 or LiCl,in the absence or in the presence of additional activators, such as ethanol-1,2-dithyl or benzylmercaptan, and ether fissions by hydrogen, at elevated or normal pressure, in the presence of an appropriate catalyst, such as palladium or iridium catalysts.

According to the invention, the compounds of general formula 1, with the meanings of R1, R2, R3, R4, R5, A, B, D and E as previously described, are also obtained by conversion of the sub-structure: The product is not intended to be used in the manufacture of other products than those mentioned in the first subparagraph. Particularly preferred conversion reactions with compounds of the invention of formula 1 are, for example, for A = - A = - (CH-OH) or A = -CH2- by means of known reducing agents, such as sodium borohydride, or by hydration, which may be done stereoselectively. Other preferred conversion reactions are the transfer of compounds for which D and E mean oxygen into substances for which only D means oxygen, but E stands for -(N-Z), where Z has the already explained meaning.

Examples of implementation

Example manufacturing processes for compounds of formula 1 according to the invention from starting materials of the described type where R7 is an alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl group:

Example 1: N- ((3,5-Dichlorpyridine-4-yl)-2-[1-(4-Fluorbenzyl) -5-Hydroxy-Indol-3-yl]-2-Oxoacetamide (1) and its salts

g N-(3,5-dichlorpyridine-4-yl)-2-[1-(4-fluorobenzyl) -5-methoxy-indol-3-yl)-2-oxoacetamide (3 mmol) is dissolved in 100 ml of dichloromethane The solution is heated to a return flow and stirred with a solution of 14 mmol BBr3 in 15 ml of dichloromethane. The reaction mixture is boiled for 3 hours at the return flow. After cooling, the solution is stirred intensively with 200 ml of aqueous sodium hydrocarbonate solution at 20 °C for 3 hours. The product crystallizes. It is isolated, dried at 60 °C and decrystallized from 80 ml of ethanol. The yield is 1.1 g (80 % d. theory) The melting point is 213-214 °C

Example 2 N- ((3,5-Dichlorpyridine-4-yl)-2-[1-(4-Fluorbenzyl) -5-Hydroxy-Indol-3-yl]-2-Oxoacetamide (1) and its salts

5 g (38 mmol) anhydrous aluminium chloride is added to 50 ml of ethanol-1.2-dithyl. At 0 °C, a solution of 4.7 g N- ((3,5-dichlorpyridine-4-yl)-2-[1- ((4-fluorbenzyl) -5-methoxy-indol-3-yl) -2-oxoacetamide (10 mmol) is added to 50 ml of dichloromethane. The mixture is stirred for 4 hours at 0 °C. 50 ml of 10 per cent hydrochloric acid is added to tubes at 0-10 °C. The crystallizing product is isolated, washed with water and dried at 20 °C. A pure product is obtained by recrystallization of ethanol (180 ml). The yield is 3.1 g (67% of the theory). The melting point is 212 to 214 °C

An example of a manufacturing process for compounds of formula 1 according to the invention from starting materials of the described type where R7 is an acyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, N-substituted aminocarbonyl, silyl, sulphonyl group is:

Example 3: It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

5 g N-(3,5-dichlorpyridine-4-yl)-2-[5-acetoxy-1-(4-fluorbenzyl) indole-3-yl]-2-oxoacetamide (10 mmol) are stirred in 50 ml of dilute baking soda for 1 hour at 40 - 50 °C. The solution is neutralized and compressed until dry under refrigeration with ice with hydrochloric acid (10 %ig). The backing is dissolved in 80 ml of acetone. Insoluble components are separated. The clear solution is mixed with a solution of 0,4 g NaOH in 3 ml of water and stirred for 2 hours at 20 °C. The crystallized product is isolated. Washed with acetone and dried at 60 °C. The yield is 2.44 g (51% of the theory). The melting point is 265 °C.

Model manufacturing process for compounds of the invention of formula 1 from other compounds of the invention of formula 1.

Example 4 N- ((3,5-Dichlorpyridine-4-yl)-2-[1-(4-Fluorbenzyl) -5-Hydroxy-Indol-3-yl]-2-Hydroxy-Acetamide (3)

Suspend 1 g N-(3,5-dichloropyridine-4-yl)-2-[[1-(4-fluorobenzyl) -5-hydroxy-indol-3-yl]-2-oxoacetamide (1.2 mmol) in 75 ml of methanol. After adding a solution of 0,2 g sodium borohydride to 3 ml of dilute baking soda, stir the reaction mixture for 6 hours at 20 °C. After distillation of the solvent, the residue is recrystallized from 40 ml of ethanol. The yield is 0.5 g (50% of the theory) The following shall be added to the list of active substances:

The following are examples of many other compounds of formula 1 which can be produced using the exemplary variants given: Other

The compounds of the invention are potent inhibitors of phosphodiesterase 4 and TNFα release and their therapeutic potential is demonstrated in vivo, for example by inhibition of the late asthmatic phase response (eosinophilia) in guinea pigs and by influence of allergen-induced vascular permeability in actively sensitized 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 over 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 4 g/ m3 for the PMNL. The PDE4 is inserted into the PDE4 at 10 °C. The following two steps are followed by a second step of induction of the PDE4 at pH 67,4 g/ m3 and the resulting PDE4 is inserted into the PDE4 at pH 67,4 g/ m3 for the PMNL. The resulting PDE4 is inserted into the PDE4 at 10 °C. The resulting PDE4 is inserted into the PDE4 at pH 67,4 and the resulting PDE4 is inserted into the PDE4 at a second step of the PDE4 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 Adv. Cycl. Nucl. Res 1979. 10, 69-92). The reaction mixtures contain 50 mM Tris-HCl (pH 7.4), 5 mM MgCl2, the inhibitors in variable concentration, the corresponding enzyme preparation and the additional components necessary to detect the individual isoenzymes (see below). The reaction is initiated by the addition of the substrate 0,5 μM [3H]-cAMP or [3H]-cGMP (approximately 6000 CPM/test). The final volume is 100 ml. Test substances are prepared as stock solutions in DMSO.The DMSO concentration in the reaction mixture is 1% v/v. At this DMSO concentration, PDE activity is not affected. After starting the reaction by adding a substrate, the samples are incubated at 37°C for 30 minutes by heating the test tubes to 110 °C for 2 minutes. The reaction is stopped. The samples are left in ice for another 10 minutes. After adding 30 μl 5'-nucleotidase (1 mg/ml from a suspension of Crotalus adamanteus venom), incubation is carried out for 10 minutes at 37°C. The samples are placed on ice, 400 μl of a mixture of Dox+11+ water ethanol (111+) added, and then incubated for 15 minutes.The test vessels are centrifuged for 20 minutes at 3000 g x 200 μl Aliquots of the residue are transferred directly into scintillation vessels.

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 for inhibition of phosphodiesterase 4 were determined in the range 10-9 to 10-5 M. Selectivity to PDE types 2, 3 and 5 was a factor of 100 to 10 000.

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 tissue is washed with RPMI 1640 and then exposed to protease (2.0 mg/ml, collagenase (1.5 mg/ml), hyaluronidase (0.75 mg/ml) and DNAse (0.05 mg/ml) for 2 hours at 37 °C (1 g of tissue per 4 ml of RPMI 1640 with enzymes). The resulting cells, a mixture of epithelial cells, monocytes, macrophages, lymphocytes, fibroblasts and granulocytes, are filtered and washed by repeated centrifugation in nutrient solution,The cells are incubated with the test substances at different end concentrations for 30 minutes and then stimulated to release TNFα by the addition of anti-IgE (7,2 μg/ml). The maximum release into the medium occurs after approximately 18 hours. During this period the cells are incubated at 37 °C and 52% of the mean. The medium is obtained by incubation (incubation) up to 4000 °C (570 °C) and stored at - 4000 °C.The determination of TNFα in the head is carried out by so-called sandwich ELISAs (basic pharmacological material) which can detect cytokine concentrations in the range of 30-1000 pg/ml. 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.

Inhibition of late-stage eosinophilia 24 h after inhaled ovalbumin challenge in actively sensitised guinea pigs

Inhibition of pulmonary eosinophil infiltration by the substances is assessed in an in vivo test in active ovalbumin (OVA) sensitized male Dunkin-Hartley guinea pigs (200-250 g). Sensitization is achieved by two intraperitoneal injections of a suspension of 20 μg OVA with 20 mg aluminium hydroxide as adjuvant in 0.5 ml saline per animal on two consecutive days. 14 days after the second injection, the animals are treated with mepiramate maleate (10 mg/ kg i.p.) to prevent anaphylactic death. 30 minutes later the animals are exposed to an OVA aerosol box in a plastic for 30 sec (0.5 mg/ ml) by air pressure (19.24 hours after the challenge, the animals are anesthetized with an overdose of ethylurethane (1.5 g/kg body weight i.p.) and a bronchoalveolar lavage (BAL) with 2 x 5 ml of physiological saline is performed. The BAL liquid is collected, centrifuged at 300 rpm for 10 min and then the cell pellet is resalved in 1 ml of physiological saline. The eosinophils in the BAL are administered with an automatic cell differentiation test (BAL) (Biocontics H1). $\text{\% Hemmung = 100 -}\frac{\text{100 · (B - C)}}{\text{(A - C)}}$ A = Eosinophil in the control group with OVA challenge and VehicelB = Eosinophil in the substance-treated group with OVA challengeC = Eosinophil in the control group with 0.9% NaCl challenge and Vehicel

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

The compounds of the invention inhibit late-stage eosinophilia by 30% to 80% after intraperitoneal administration of 10 mg/kg and by 40% to 70% 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.

Effects on allergen-induced vascular permeability in actively sensitised Brown-Norway rats

Male Brown-Norway rats weighing 280-300 g were actively sensitised by intraperitoneal injection of a suspension of 1 mg ovalbumin in combination with 100 mg aluminium hydroxide in 1 ml/animal over 2 consecutive days. Three weeks after sensitisation, the rats were sedated with sodium thiopental and fixed in a supine position. For perfusion of the nasal cavity, a polyethylene catheter was pushed into the trachea retrograde to the inner opening of the choan so that the solution could drip out through the nostrils. A short tracheal catheter was orthographed into the trachea to allow for breathing. For perfusion, a phosphate-based cofactor pump (PBS) was continuously pumped through the nasal cavity with a roller (0,0 mm) to allow the solution to drain out.Evans Blue was used as a plasma anaesthetic and injected intravenously (1 ml/ animal of a 1% solution in PBS) through a catheter in the jugular vein. The substance was applied topically. In this application, the test substance was added to the perfusion medium (PBS). The nasal mucosa was perfused with a PDE4 inhibitor solution for 30 min. Evans blue was then injected with ovalbumin solution (Challenge) immediately before the start of the perfusion. After the start of the ovalbumin challenge (10 mg/ml ovalbumin dissolved in PBS), all 15 min fractions were collected in the fraction collectors over a period of 60 min. The Evans blue concentration in the perfusates was measured by photometer digiscan at a wavelength of 620 nm.The 60 min duration of action was calculated using an AUC programme, and the product group's action was calculated as a % of vehicle controls.

For the compounds of the invention, IC50 values were determined in the range 10-8 to 10-5 M.

The applicability of the compounds of the invention measured in formula 1 for the treatment of chronic obstructive pulmonary disease is demonstrated by the inhibition of LPS-induced TNFα release in human blood and by the inhibition of LPS-induced pulmonary neutrophil infiltrator in ferrets and domestic pigs.

One of the most important stimulus mechanisms for the study of TNFα release is lipopolysaccharides (LPS). LPS is part of the bacterial cell wall and is released by killing the bacteria (antibiotics or immune system). LPS particularly stimulates the activity of phagocytic leukocytes (tissue macrophages, granulocytes, monocytes) and causes leukocytes to migrate from the bloodstream into the affected tissue. One of the key cytokines for these mechanisms is TNFα, which is released from the affected cell source (mainly the initiators are the monocytes and macrophages) in large quantities and is stored in large quantities and preserved in the environment.

LPS-induced release of TNFα in 1:5 human blood

For the TNFα release study, blood was collected from different donors (cytate inhibition) and diluted with cell culture medium RPMI 1640 1:5. The test substances were added to the samples at different concentrations before the LPS challenge. Leukocyte stimulation was performed 30 min later with Salmonella abortus equi lipopolysaccharide (LPS) at a final concentration of 10 μg/ ml. After incubation of the test pieces for 24 hours at 37°C and 5% CO2 in the incubator, the diluted blood was centrifuged and the TNFα concentration was measured in the free surplus by ELISA. For the compounds of the invention, IC50 values in the range 10-7 to 10-5 M were determined. For example, for the compound in Example 1, an IC50 value of 0.8 μmol/l was determined. By comparison, the reference standard SB 207499 determined an IC50 value of 7.0 μmol/l.

Inhibition of lipopolysaccharide (LPS) induced neutrophils in ferrets

The inhibition of pulmonary neutrophil infiltration by the substances is tested in an in vivo test on male ferrets (0.6-2 kg). The animals are anesthetized with sodium pentobarbital (40 mg/kg i.p.), placed individually in a closed 5 l chamber misting box and exposed for 10 minutes to an ultrasonically evaporated aerosol of 0.01% LPS (lipopolysaccharide) solution (plus 0.1% hydroxylamine in PBS). The aerosol is produced by a nebulizer driven by a pressurised air (0.2 Mpa) and the animals are treated with a physiological aerosol solution. During the whole procedure, the animals are observed and treated with a physiological control to remove the nebulizer immediately after the LPS is removed from the breathing space.In order to measure the number of neutrophils that have been introduced, the animals are sedated with an overdose of ethylurethane (1,5 g/kg body weight i.p.) 6 hours after the LPS provocation and a bronchioalveolar lavage (pulmonary lavage, BAL) is performed with 2 x 10 ml of saline. The number of cells in the pooled original BAL liquid (100 μ) is measured by the H1C-contactor (Firma Bayer Technique) and the different coccycles are determined. The number of cells is differentiated by 2 groups (LPS) or by a separate physiological test with no LPS.Anti-inflammatory agents, especially those that affect TNFα release or neutrophil granulocyte function, inhibit the migration of leukocytes.

For the compounds of the invention, ID50 values in the range of 1 to 20 mg/kg i.p. were determined. For example, the compound in Example 1 was administered at doses of 1, 3 and 10 mg/kg i.p. to up to 3 animals at 2 hours prior to LPS provocation. Neutrophilia in the BAL was dose-dependently inhibited (18%, 64% and 78%). The ID50 is 2.4 mg/kg i.p. The use of the selective PDE4 inhibitor RPR-73401 (reference substance) at a dose of 1 mg/ kg i. p. produced a 49% inhibition of neutrophils.

For intrapulmonary application, the animals are anaesthetised (40 mg/kg i.p. Pentobarbital sodium, 3%ig, 1.3 ml/kg) with the trachea opened, a 7 cm PVC catheter attached and the test substances in powder form (mixed with lactose at 20 mg/kg) administered by injection intrapulmonary 2 hours before LPS provocation. Intrapulmonary administration of the compound in Example 1 at doses of 1, 3 and 10 mg/ kg inhibits dose-dependent LPS-induced neutrophils (43%, 65% and 100%).

LPS-induced neutrophils in domestic pigs

A pulmonary neutrophil may be induced in domestic pigs similar to ferrets The animals are anesthetized (pentobarbital 10 mg/kg intravenously) and intubated. A bronchoscope is used to perform a partial bronchoalveolar lavage to measure the proportion of neutrophil granulocytes under physiological conditions. The test substance is then applied and the animals are inhaled via the tracheal tube with an ultrasonic nebulised aerosol of 0.03% LPS (lipopolysaccharide) solution (plus 0.1% hydroxylamine in PBS) for 20 minutes. The inhaled LPS causes reactive inflammation of the atrophy and moves it to the granulocyte mass.

The pig is particularly suitable for these studies because of its great anatomical and physiological similarities to humans. For the compounds of the invention, inhibitions of LPS-induced neutrophils of 20% to 65% were determined at 10 mg/ animal intrapulmonary administration. The intrapulmonary administration of the compound in Example 1 at the 10 mg/ animal dose (approximately 0.75 mg/ kg) inhibited LPS-induced pulmonary neutrophils by 51%.

Claims (14)

1. Hydroxyindoles of the formula 1 in which

   R ¹    is

   - C_1...12-alkyl, straight-chain or branched-chain,    optionally mono- or polysubstituted by -OH, -SH, -NH₂, -NHC_1...6-alkyl, -N(C_1...6-alkyl)₂, -NHC_6...14-aryl, -N(C_{6 ... 14}-aryl)₂, -N(C_1...6-alkyl) (C_6...14-aryl), -NHCOR⁶, -NO₂, -CN, -F, -Cl, -Br, -I, -O-C-_1...6-alkyl, -O-C_6...14-aryl, -O(CO)R⁶, -S-C_1...6-alkyl, -S-C_{6 ...14}-aryl, -SOR⁶, -SO₃H, -SO₂R⁶, -OSO₂C_1...6-alkyl, -OSO₂C_6...14-aryl,-(CS)R⁶, -COOH, -(CO)R⁶, mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles having 3...14 ring members, 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 included carbocyclic and heterocyclic substituents for their part can optionally be mono- or polysubstituted by R⁴,

   - C_1...12-alkenyl, mono- or polyunsaturated, straight-chain or branched-chain,    optionally mono- or polysubstituted by -OH, -SH, -NH₂, -NHC_1...6-alkyl, -N(C_1...6-alkyl)₂, -NHC_6...14-aryl, -N(C_{6... 14}-aryl)₂, -N(C_1...6-alkyl)(C_6...14-aryl), -NHCOR⁶, -NO₂, -CN, -F, -Cl, -Br, -I, -O-C-_1...6-alkyl, -O-C_6...14-aryl, -O(CO)R⁶, -S-C_1...6-alkyl, -S-C_6...14-aryl, -SOR⁶, -SO₃H, -SO₂R⁶, -OSO₂C_1...6-alkyl, -OSO₂C_6...14-aryl, -(CS)R⁶, -COOH, -(CO)R⁶, mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles having 3...14 ring members, 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 included carbocyclic and heterocyclic substituents for their part can optionally be mono- or polysubstituted by R⁴,

   - mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles having 3...14 ring members,    optionally mono- or polysubstituted by -OH, -SH, -NH₂, -NHC_1...6-alkyl, -N(C_1...6-alkyl)₂, -NHC_6...14-aryl, -N(C_6...14-aryl)₂, -N(C_1...6-alkyl) (C_6...14-aryl), -NHCOR⁶, -NO₂, -CN, -F, -Cl, -Br, -I, -O-C-_1...6-alkyl, -O-C_6...14-aryl, -O(CO)R⁶, -S-C_1...6-alkyl, -S-C_6...14-aryl, -SOR⁶, -SO₃H, -SO₂R⁶, -OSO₂C_1...6-alkyl, -OSO₂C_6...14-aryl, -(CS)R⁶, -COOH, -(CO)R⁶, mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles having 3...14 ring members, 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 included carbocyclic and heterocyclic substituents for their part can optionally be mono- or polysubstituted by R⁴,

   - 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,    optionally mono- or polysubstituted by -OH, -SH, -NH₂, -NHC_1...6-alkyl, -N(C_1...6-alkyl)₂, -NHC_6...14-aryl, -N(C_6...14-aryl)₂, -N(C_1...6-alkyl) (C_6...14-aryl), -NHCOR⁶, -NO₂, -CN, -F, -Cl, -Br, -I, -O-C-_1...6-alkyl, -O-C_6...14-aryl, -O(CO)R⁶, -S-C_1...6-alkyl, -S-C_6...14-aryl, -SOR⁶, -SO₃H, -SO₂R⁶, -OSO₂C_1...6-alkyl, -OSO₂C_6...14-aryl, -(CS)R⁶, -COOH, -(CO)R⁶, mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles having 3...14 ring members, 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 included carbocyclic and heterocyclic substituents for their part can optionally be mono- or polysubstituted by R⁴,

   - carbo- or heterocyclic saturated or mono- or polyunsaturated spirocycles having 3...10 ring members, where heterocyclic systems contain 1...6 heteroatoms, which are preferably N, O and S,    optionally mono- or polysubstituted by -OH, -SH, -NH₂, -NHC_1...6-alkyl, -N(C_1...6-alkyl)₂, -NHC_6...14-aryl, -N(C_6...14-aryl)₂, -N(C_1...6-alkyl) (C_6...14-aryl), -NHCOR⁶, -NO₂, -CN, -F, -Cl, -Br, -I, -O-C-_1...6-alkyl, -O-C_6...14-aryl, -O(CO)R⁶, -S-C_1...6-alkyl, -S-C_6...14aryl, -SOR⁶, -SO₃H, -SO₂R⁶, -OSO₂C_1...6-alkyl, -OSO₂C_6...14-aryl, -(CS)R⁶, -COOH, -(CO)R⁶, mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles having 3...14 ring members, 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 included carbocyclic and heterocyclic substituents for their part can optionally be mono- or polysubstituted by R⁴,

   R ² , R ³    can be hydrogen or -OH, where at least one of the two substituents must be -OH;

   R ⁴    is -H, -OH, -SH, -NH₂, -NHC_1...6-alkyl, -N(C_1...6-alkyl)₂, -NHC_6...14-aryl, -N(C_6...14-aryl)₂, -N(C_1...6-alkyl) (C_6...14-aryl), -NHCOR⁶, -NO₂, -CN, -COOH, -(CO)R⁶, -(CS)R⁶, -F, -Cl, -Br, -I, -O-C_1...6-alkyl, -O-C_6...14-aryl, -O(CO)R⁶, -S-C_1...6-alkyl, -S-C_6...14-aryl, -SOR⁶, -SO₂R⁶.

   R ⁵    is

   - mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles having 3...14 ring members,    mono- or polysubstituted by -F, -Cl, -Br, -I,    optionally mono- or polysubstituted by -OH, -SH, -NH₂, -NHC_1...6-alkyl, -N(C_1...6-alkyl)₂, -NHC_6...14-aryl, -N(C_6...14-aryl)₂, -N(C_1...6-alkyl)(C_6...14-aryl), -NHCOR⁶, -NO₂, -CN, -O-C_1...6-alkyl, -O-C_6...14-aryl, -O(CO)R⁶, -S-C_1...6-alkyl, -S-C_6...14-aryl, -SOR⁶, -SO₃H, -SO₂R⁶, -OSO₂C_1...6-alkyl, -OSO₂C_6...14-aryl, -(CS)R⁶, -COOH, -(CO)R⁶, mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles having 3...14 ring members, 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 included carbocyclic and heterocyclic substituents for their part can optionally be mono- or polysubstituted by R⁴,

   - 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,    mono- or polysubstituted by -F, -Cl, -Br, -I,    optionally mono- or polysubstituted by -OH, -SH, -NH₂, -NHC_1...6-alkyl, -N(C_1...6-alkyl)₂, -NHC_6...14-aryl, -N(C_6...14-aryl)₂, -N(C_1...6-alkyl) (C_6...14-aryl), -NHCOR⁶, -NO₂, -CN, -O-C_1...6-alkyl, -O-C_6...14-aryl, -O(CO)R⁶, -S-C_1...6-alkyl, -S-C_6...14-aryl, -SOR⁶, -SO₃H, -SO₂R⁶, -OSO₂C_1...6-alkyl, -OSO₂C_6...14-aryl, -(CS)R⁶, -COOH, -(CO)R⁶, mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles having 3...14 ring members, 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 included carbocyclic and heterocyclic substituents for their part can optionally be mono- or polysubstituted by R⁴,

   R ⁶    can be

   -H, -NH₂, -NHC_1...6-alkyl, -N(C_1...6-alkyl)₂, -NHC_6...14-aryl, -N(C_6...14-aryl)₂, -N(C_1...6-alkyl) (C_6...14-aryl), -O-C_1...6-alkyl, -O-C_6...14-aryl, -S-C_1...6-alkyl, -S-C_6...14-aryl, -C_1...12-alkyl, straight-chain or branched-chain, -C_1...12-alkenyl, mono- or polyunsaturated, straight-chain or branched-chain, -mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles having 3...14 ring members -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;

   A   is either a bond, or

   -CH₂)_m-, -(CH₂)_m-(CH=CH)_n-(CH₂)_p-, -(CHOZ)_m-, -(C=O)-, -(C=S)-, -(C=N-Z)-, -O-, -S-, -NZ-,

   where m, p = 0...3 and n = 0...2 and

   z   is

   -H, or where m, p = 0...3 and n = 0...2 and -C_1..12-alkyl, straight-chain or branched-chain, -C_1...12-alkenyl, mono- or polyunsaturated, straight-chain or branched-chain, -mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles having 3...14 ring members, -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;

   B   can either be carbon or sulphur, or -(S=O)-;

   D   can be oxygen, sulphur, CH₂ or N-Z, where D can only be S or CH₂ if B is carbon; and

   E   can be a bond, or else

   -(CH₂)_m-, -O-, -S-, -(N-Z)-, where m and Z have the meaning already described beforehand.
2. Physiologically tolerable salts of the compounds as shown in formula 1 according to Claim 1, characterized by neutralization of the bases with inorganic or organic acids or by neutralization of the acids with inorganic or organic bases or by quaternization of tertiary amines to give quaternary ammonium salts.
3. Compounds as shown in formula 1 according to Claim 1 or 2 having an asymmetric carbon atom in the D form, the L form and D,L mixtures, and, in the case of a number of asymmetric carbon atoms, the diastereomeric forms.
4. Compounds as shown in formula 1 according to one of Claims 1 to 3, selected from:

   N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide; and physiologically tolerable salts thereof.
5. Compounds as shown in formula 1 according to one of Claims 1 to 3 selected from one of the following compounds and physiologically tolerable salts thereof:

   N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-hydroxyacetamide;

   N-(3,5-dichloropyridin-4-yl)-2-[1-(2,6-difluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;

   N-(3,5-dichloropyridin-4-yl)-2-[1-(3-nitrobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide Na salt;

   N-(3,5-dichloropyridin-4-yl)-2-(1-propyl-5-hydroxy-indol-3-yl)-2-oxoacetamide;

   N-(3,5-dichloropyridin-4-yl)-2-(1-isopropyl-5-hydroxyindol-3-yl)-2-oxoacetamide;

   N-(3,5-dichloropyridin-4-yl)-2-(1-cyclopentylmethyl-5-hydroxyindol-3-yl)-2-oxoacetamide;

   N-(2,6-dichlorophenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;

   N-(2,6-dichloro-4-trifluoromethylphenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;

   N-(2,6-dichloro-4-trifluoromethoxyphenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;

   N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-6-hydroxyindol-3-yl]-2-oxoacetamide;

   N-(3,5-dichloropyridin-4-yl)-5-hydroxy-1-(4-methoxybenzyl)indole-3-carboxamide.
6. Process for the preparation of compounds as shown in formula 1 according to one of Claims 1 to 5, characterized in that compounds as shown in formula 1, for which R² or R³ or R² and R³ = -O-R⁷, are converted into the compounds according to the invention by removal of R⁷, where R⁷ in this case is a substituent suitable as a leaving group.
7. Process according to Claim 6, in which R⁷ is alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl, acyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, N-substituted aminocarbonyl, silyl or sulphonyl groups, and complexing agents, such as, for example, compounds of boric acid, phosphoric acid and covalently or coordinatively bonded metals, such as zinc, aluminium or copper.
8. Process for the preparation of compounds as shown in formula 1 according to one of Claims 1 to 5, characterized in that compounds of the general formula 1 are converted by means of conversions of the sub-structure: into other compounds of the formula 1 according to the invention.
9. Use of the compounds as shown in formula 1 according to one of Claims 1 to 5 as therapeutic active compounds for the production of medicaments for the treatment of disorders in which the inhibition of TNFα is therapeutically beneficial.
10. Use of the compounds as shown in formula 1 according to one of Claims 1 to 5 as therapeutic active compounds for the production of medicaments for the treatment of disorders in which the inhibition of phosphodiesterase 4 is therapeutically beneficial.
11. Use of the compounds as shown in formula 1 according to one of Claims 1 to 5 as therapeutic active compounds for the production of medicaments for the treatment of disorders which are connected with the action of eosinophils.
12. Use of the compounds as shown in formula 1 according to one of Claims 1 to 5 as therapeutic active compounds for the production of medicaments for the treatment of chronic obstructive pulmonary diseases (COPD).
13. Medicaments comprising one or more compounds according to one of Claims 1 to 5 in addition to customary physiologically tolerable carriers and/or diluents or auxiliaries.
14. Process for the production of a medicament according to Claim 13, characterized in that one or more compounds according to Claims 1 to 5 are processed to give pharmaceutical preparations or brought into a therapeutically administrable form using customary pharmaceutical carriers and/or diluents or other auxiliaries.