GB2350110A

GB2350110A - Pharmaceutically active benzofurans

Info

Publication number: GB2350110A
Application number: GB9911453A
Authority: GB
Inventors: Gabriele Braeunlich; Mazen Es-Sayed; Ruediger Fischer; Burkhard Fugmann; Rolf Henning; Stephen Schneider; Michael Sperzel; Karl-Heinz Schlemmer; Graham Sturton; Mary Fitzgerald; Barbara Briggs; Arnel Concepcion; William Bullock
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1999-05-17
Filing date: 1999-05-17
Publication date: 2000-11-22
Also published as: GB9911453D0; WO2000069841A3; AU4561600A; WO2000069841A2

Abstract

Benzofurans of the general formula (I) <EMI ID=1.1 HE=28 WI=108 LX=528 LY=840 TI=CF> <PC>and salts thereof,<BR> wherein the various symbols are as defined in the specification, are useful in medicaments, especially for the treatment of inflammatory conditions.

Description

Le A 32 885 Ho/ngb/NTN12.04.1999 2350110 Benzofuranylaminoalcohols The

invention relates to Benzofuranylaminoalcohols, processes for their preparation and their use in medicaments.

It is known that the NADPH oxidase of phagocytes is the physiological source to the superoxide radical anion and reactive oxygen species derived therefrom which are important in the defence against pathogens. Moreover, both inflammatory (e.g. TNFa, IL-1 or IL-6) and anti- inflammatory cytokines (e.g. IL-10) play a pivotal role in host defence mechanism. Uncontrolled production of inflammatory mediators can lead to acute or chronic inflammation, auto immune diseases, tissue damage, multi- organ failure and to death. It is additionally known that elevation of phagocyte cyclic AMP leads to inhibition of oxygen radical production and that this cell function is more sensitive than others such as aggregation or enzyme release.

Benzofaran derivatives having phosphodiesterase IV (PDE IV)-inhibiting action are described in EP 731099. The reference describes only single-hydroxyl substituted derivatives, however. Benzofuranylaminoalcohols without 3-Ureido moiety are disclosed for the treatment of diseases in the circulatory system in US 4, 056,626. In order to provide alternative compounds with similar or improve d PDE IVinhibitory activity, the present invention relates to Benzofiirmylaminoalcohols of the general formula (1) L A 11 2k3 NRI C NR R5R 6 0 0:1 4 (1) 0 CO-R in which A represents hydrogen, straight-chain or branched acyl or alkoxycarbonyl, each having I to 6 carbon atoms, halogen, carboxyl, cyano, nitro, hydroxyl, Le A 32 885 trifluoromethyl or trifluoromethoxy, or straight-chain or branched alkyl having I to 6 carbon atoms, which is optionally substituted by carboxyl, alkoxy or alkoxycarbonyl each having I to 4 carbon atoms, phenoxy or benzoyl, R' represents hydrogen, straight-chain or branched alkyl having I to 4 carbon atoms, an aminoprotecting group or a group of the formula -CO-R7 in which R7 denotes straight chain or branched alkoxy having I to 4 carbon atoms, R' and R' are identical or different and represent hydrogen, cycloalkyl having 3, 4, 5 or 6 carbon atoms, straight chain or branched alkyl, alkoxycarbonyl or alkenyl each having I to 8 carbon atoms, 15 or and R? together with the nitrogen atom form a 5-, 6- or 7-membered saturated heterocycle optionally having a further oxygen atom, 20 R' represents aryl having 6, 7, 8, 9 or 10 carbon atoms or represents a 5, 6 or 7 membered, aromatic saturated or unsaturated heterocycle, which can contain I to 3 oxygen, sulphur, nitrogen atoms as heteroatoms or a residue of a formula -NR!, 25 wherein R' denotes hydrogen or straight-chain or branched alkyl or alkoxycarbonyl. each having I to 6 carbon atoms, 30 Le A 32 885 and to which finther a benzene ring can be fused and wherein aryl and/or the heterocycle are optionally monosubstituted to trisubstituted by identical or different substituents from the series comprising hydroxyl, halogen, nitro, IH tetrazolyl, pyridyl, trifluoromethyl, tfifluoromethoxy, difluoromethyl, difluoro methoxy, cyano, carboxy, straight-chain or branched alkoxy, alkoxycarbonyl or acyl each having I to 6 carbon atoms or by straight-chain or branched alkyl having I to 5 carbon atoms, which is optionally substituted by carboxyl or straight-chain or branched alkoxycarbonyl having I to 4 carbon atoms or by a group of formula -NR!R", -SR", -(NH)a-S02R 12 or _O_SO2R", in which R! and R" are identical or different and denote hydrogen or a straight- chain or branched alkyl having I to 4 carbon atoms, or R!denotes hydrogen and R'O denotes straight-chain or branched acyl having I to 6 carbon atoms, R" denotes hydrogen or straight-chain or branched alkyl having I to 4 carbon atoms, a denotes a number 0 or 1, R 12 and R 13 are identical or different and represent straight-chain or branched alkyl having I to 6 carbon atoms, benzyl or phenyl, which are optionally Le A 32 885 substituted by trifluoromethyl, halogen or straight-chain or branched alkyl having I to 4 carbon atoms, L represents an oxygen or sulfur atom 5 R' and W represents hydrogen or straight-chain or branched alkyl having I to 6 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms or by a 5 to 7 membered aromatic, saturated or unsaturated heterocycle having I to 3 heteroatoms from the series comprising N, S, 0 and/or a residue of a formula -NR 14 wherein R 14 denotes hydrogen or straight-chain or branched alkyl or alkoxycarbonyl each having I to 6 carbon atoms and to which a phenyl ring can be fused and which are optionally monosub stituted to disubstituted by identical or different substituents from the series comprising halogen, cyano or by a straight-chain or branched alkyl or alkoxy carbonyl each having I to 6 carbon atoms, or R' and W together with the nitrogen atom form a 5 to 6 membered saturated or unsaturated heterocycle having I to 3 heteroatoms from the series comprising N, S, 0 and/or a residue of a formula -NR 14' wherein R"' have the abovementioned meaning of R 14 and is identical or different to the latter Le A 32 885 1 and to which a phenyl ring can be fused and which is optionally monosub stituted to disubstituted by identical or different substituents from the series comprising halogen, cyano or by a straight-chain or branched alkyl or alkoxycarbonyl each having 1 to 6 carbon atoms, and salts thereof The benzofuranylaminoalcohols according to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.

Physiologically acceptable salts are preferred in the context of the present invention.

Physiologically acceptable salts of the benzofuranylaminoalcohols can be metal or ammonium salts of the substances according to the invention, which contain a free carboxylic group. Those which are particularly preferred are, for example, sodium, potassium, magnesium or calcium salts, and also ammonium salts which are derived from arnmonia, or organic amines, such as, for example, ethylamine, di- or triethyl amine, di- or triethanolarnine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.

Physiologically acceptable salts can also be salts of the compounds according to the invention with inorganic or organic acids. Preferred salts here are those with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or salts with organic carboxylic or sulphonic acids such as, for example, acetic acid, maleic acid, famaric acid, malic acid, citric acid, tartaric acid, ethane sulphonic acid, benzenesulphonic acid, toluenesulphonic acid or naphthalenedi sulphonic acid.

The compounds according to the invention can exist in stereoisomeric forms which either behave as image and mirror image (enantiomers), or which do not behave as Le A 32 885 image and mirror image (diastereorners). The invention relates both to the antipodes and to the racemate forms, as well as to individual diastereomers. and to the diastereomer mixtures. The racemate forms, like the diastereomers, can be separated into the stereoisomerically uniform constituents in a known manner.

Heterocycle in general represents a 5- to 7-membered aromatic, saturated or unsaturated, preferably 5- to 6- membered, aromatic or saturated ring, which can contain up to 3 oxygen, sulphur, nitrogen atoms or a residue of a formula -NW as heteroatoms and to which ftu-ther aromatic rings can be fused.

The following are mentioned as preferred: thienyl, ftiryl, pyrrolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxazolyl, thiazolyl, dihydrothiazolyl, benzothiaazolyl, isothiazolyl, benzisothiazolyl, oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl, benzimidazolyl, indolyl, morpholinyl, pyrrolidinyl, piperidyl, piperazinyl, oxazolinyl or triazolyl.

Preferred compounds of the general formula (I) are those in which A represents hydrogen, halogen, carboxyl, cyano, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy or alkoxy having up to 4 carbon atoms R' represents hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a group of the formula -CO-W in whdch R 7 denotes straight chain or branched alkoxy having up to 4 carbon atoms, 30 Le A 32 885 R' and R3 are identical or different and represent hydrogen, cyclobutyl, cyclopentyl, cyclohexyl or straight-chain or branched alkyl, alkoxycarbonyl or alkenyl each having up to 4 carbon atoms, or or R2 and R' together with the nitrogen atom form a pyrrolidinyl-, piperidinyl- or morpholinyl-ring, and.

W represents phenyl, pyridyl or thienyl, wherein both rings are optionally mono substituted to trisubstituted by identical or different substituents from the series comprising hydroxyl, fluorine, chlorine, bromine, nitro, carboxy, straigbt-chain or branched alkoxy, alkoxycarbonyl or acyl each having up to 3 carbon atoms, or by straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by carboxyl or straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms L represents an oxygen or sulfur atom, and R' represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl, pyridyl, imidazolyl, pyrryl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl and/or a residue of a formula -NR 14 wherein R 14 denotes hydrogen or straight-chain or branched alkyl or alkoxycarbonyl each having up to 4 carbon atoms, Le A 32 885 and wherein the ring systems are optionally monosubstituted by straight- chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms, or 5 and W together with the nitrogen atom form a pyrazolyl-, triazolyl-, tetrazolyl-, imidazolyl-, pyrryl-, morpholinyl-, piperidinyl-, pyrTolidinyl-, piperaziny1ring and/or a residue of a formula -NR 14' wherein R 14' have the abovementioned. meaning of R 14 and is identical or different to the latter, and wherein the ringsystern is optionally monosubstituted to trisubstituted by identical or different substituents from the series comprising halogen, cyano or by a straight-chain or branched alkyl having up to 6 carbon atoms, and salts thereof 20 Particularly preferred compounds of the general formula (1) are those in which A represents hydrogen, R' represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms or a group of the formula -CO-R', in which Le A 32 885 denotes straight chain or branched alkoxy having up to 3 carbon atoms, and represent hydrogen, represents phenyl or pyridyl, which are optionally up to difold substituted by identical or different substituents from the series fluorine, chlorine, methyl or methoxy, L represents an oxygen atom, R' and R' represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl, pyridyl, imidazolyl, pynyl, piperidinyl and/or a residue of a formula -NR", wherein R 14 denotes hydrogen or straight-chain or branched alkyl or alkoxycarbonyl each having up to 3 carbon atoms, and wherein the ring systems are optionally monosubstituted by straight- chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms, or R' and R' together with the nitrogen atom form a imidazolyl, pyrryl-, morpholinyl-, piperidinyl-, pyrrolidinyl-, piperazinylring and/or a residue of a formula -NC', wherein C' have the abovementioned meaning of R and is identical or different to the latter, Le A 32 885 and wherein the ringsystem are optionally monosubstituted to trisubstituted by identical or different substituents from the series comprising by a straight-chain or branched alkyl or alkoxycarbonyl each having up to 3 carbon atoms, 5 and salts thereof Very particular preferred compounds of the general formula (I) are those shown in table A: 10 Structure 0 Y NH2 NH N'N 0 JO 0 0 - --y^ j OH 1 c 1 0 Y NH 2 NH rN"'O 0 0 0 H c 1 __, N j 1 1 Le A 32 885 Structure OyNH 2 1 0 0 0 OH cl 1 cl 0 y NH 2 NH 0 oú 0 0 n"' 1 OH cl N 1 1 cl 0 y NH 2 NH oN 0 N """o 0 H OH cl 1 cl Le A 32 885 Structure NH 2 0- NH "0 0 1 cl N 1-o 0 OH cl NH2 0-- NH 1, 0 \ 1 cl 0 oi OH \ A cl 0 y NH 2 0 0 H OH cl N 1 cl 0 y NH 2 rN -1o 0 NJ OH 1 cl cl - Le A 32 885 A process for the preparation of the compounds of the general formula (1) has additionally been found, characterized in that compounds of the general formula (II) 5 L 11 - 2 3 A NRi-C NR R 717-o 0 c 0 14 R in which A, R', W, W, W and L have the abovementioned meaning, 10 are reacted with amines of the general formula (Ill) W-NH (111) in which W and R' have the abovementioned meaning, in the presence of an inert solvent. 20 The process according to the invention can be illustrated by way of example by the following equations:

Le A 32 885 0 11 NH-C-NH 2 77--O 0 C ".0 + NH 2 0 C1 ( Nr" 0 11.

,,NH-C-NH2 0 rNH 0 0 C N CrH H C1 Suitable solvents are generally customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane or tetrahydrofurane, acetone, dimethylsulfoxide, dimethylforinamide or alcohols such as methanol, ethanol, propanol or halogenohydrocarbons such as dichloromethane, tricWoromethane or tetrachloromethane and mixtures of two or three of the abovementioned solvents. A mixture of methanol and tetrahydrofurane is preferred.

The process is in general carried out in a temperature range from -30'C to +100'C, preferably from O'C to 50'C.

The process is generally carried out at normal pressure. However, it is also possible to carry out it at elevated or reduced pressure (for example in a range from 0.5 to 5 bar).

The compounds of the general formula (11) are new and can be prepared by reacting compounds of the general formula (IV) Le A 32 885 L 11 2 NRL-C NR R 3 HO 0 C (IV) 14 R in which, L, R, W, W and W have the abovernentioned meaning, 5 and glycidol of the formula (V) LC OH in the presence of triphenylphosphin and diethylazodicarboxylate in an inert solvent.

It is -possible to use the glycidol of formula (V) in nacemic or in pure enantiomeric form.

Suitable solvents are generally customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane or tetrahydroffirane, acetone, dimethylsulfoxide, dimethylformamide or alcohols such as methanol, ethanol, propanol or halogenohydrocarbons such as dichloromethane, trichloromethane or tetrachloromethane. Tetrahydrofurane is preferred. 20 The process is in general carried out in a temperature range from -30'C to +100'C, preferably from O'C to room temperature. The process is generally carried out at normal pressure. However, it is also possible to 25 carry out it at elevated or reduced pressure (for example in a range from 0.5 to 5 bar).

Le A 32 885 The compounds of the general formula (III) and (V) are known or can be prepared by customary methods.

The compounds of the general formula (IV) are known or as species new and can be prepared characterized in that [A] first compounds of the general formula (VI) A CN C6 H 1 0 0 0 (VI) R 4 in which A and W have the abovementioned meaning, are reacted with a catalytic amount of alkali alcoholates, preferred sodium ethanolate to compounds of the general formula (VII) A NH2 I:Z 0- R 4 (VII) C6H -""O in which A and W have the abovementioned meaning, followed by reaction with compounds of the general formula (Vill) R'-N=C=L (Vill) in which Le A 32 885 and L have the abovementioned meaning, in inert solvents, if appropriate in the presence of a base and/or in the presence of an auxiliary to compounds of a general formula (IX) 5 L 11 2 A NH-C-NR H 0 CO-R 4 (IX) CH I""'0 6 5 in which A, L, W und W have the abovementioned meaning, 10 and in a last step the benzyl group is eliminated by hydrogenation, or [B] compounds of the general formula (X) A NH-R 1 CO-R' 00- (X) HO in which A, R' and W have the abovementioned meaning are reacted with compounds of the general formula (VIII) W-N=C=L (V111) Le A 32 885 in which L and W have the abovementioned meaning, 5 in inert solvents, if appropriate in the presence of a base, and in the case of WIR'= H and L = 0, compounds of the general formulae (VII) or (X) are reacted with compounds of the general formula (XI) E-SO,-N=C=O(XI) in which E denotes halogen, preferably chlorine, and in the case of R/R= H and L= S, compounds of the general formula (X) are reacted with NH4SCN, and in case of R', W and/or W:A H the amino groups are derivated optionally by common methods.

Suitable solvents for the first step of the procedure [A] (VI-VII) are generally alcohols such as methanol, ethanol or propanot. Ethanol is preferred. Suitable bases for the first step are generally alkali alcoholates such as sodium methanolate, sodium ethanolate or sodium propanolate. Sodium ethanolate ist 30 preferred.

Le A 32 885 The base is employed in catalytic amounts.

The process is in general carried out in a temperature range from O'C to 60'C, preferably at room temperature.

Suitable solvents for the second step of the procedure [A] (VII -> IX) are generally customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane or tetrahydrofurane, dimethylsulfoxide, dimethylformamide or halogenohydrocarbons such as dichloromethane, trichloro methane or tetrachloromethane. Dichloromethane is preferred.

The process is in general carried out in a temperature range from -30'C to +400C, preferably from -I OC to room temperature.

The hydroxyl-protective group is in general removed with hydrogen in ethyl acetate, diethyl ether or tet-ahydrofurane. Suitable catalysts are the abovementioned catalysts, preferably palladium and palladium on charcoal.

Suitable solvents for the procedure [B] are generally customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane or tetrahydrofurane, dimethylsulfoxide, dimethylformarnide or halogeno hydrocarbons such as dichloromethane, trichloromethane or tetrachloromethane.

Dichloromethane is preferred.

Le A 32 885 Suitable bases of the procedure [B], if appropriate, are generally inorganic or organic bases. These preferably include alkali metal hydroxies; such as, for example, sodium hydroxide, sodium hydrogencarbonate or potassium hydroxide, alkaline earth metal hydroxides such as, for example, barium hydroxide, alkali metal carbonates such as calcium carbonate, or alkaline metal or organic arnines (trialkyl(C,C6)arnines) such as triethylamine, or heterocycles such as 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8 diazabicyclo[5.4.0]undec-7-ene (DBU), or amides such as sodium amides, lithium butyl amide or butyllithium, pyridine or methylpiperidine. It is also possible to employ alkali metals, such as sodium or ist hydrides such as sodium hydride, as bases.

Potassium carbonate, triethylarnine, sodium hydrogencarbonate and sodium hydroxide are preferred.

The base is employed in an amount from I mol to 10 mol, preferably from 1. 0 mol to 4 mol, relative to I mol of the compounds of the general formulae (VIII).

The process is in general carried out in a temperature range from -30'C to +100'C, preferably from -I O'C to +50'C.

The compounds of the general formula (VI) are as species new and can be prepared by reaction of compounds of the general formula (XII) A CHO I (XII) C6H-"'O XOH 5 in which A has the abovementioned meaning, Le A 32 885 with hydroxylamine hydrochloride in a presence of sodium formiate to compounds of the general formula (XIII) A CN I UOH (XIII) C Hl-O 6 5 in which A has the abovementioned meaning, followed by reaction with compounds of the general formula (XIV) W-CO-CH2-T (XIV) in which 15 W has the abovementioned meaning, and T represents halogen, preferably bromine, in inert solvents and in the presence of a base.

Suitable solvents are generally customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane or tetrahydrofiwme, acetone, dimethylsulfoxide, dimethylfonnamide or alcohols such as methanol, ethanol, propanol or halogenohydrocarbons such as dichloromethane, tri chloromethane or tetrachloromethane. Acetone and dimethylformamide are preferred.

Le A 32 885 Suitable bases for the procedure are generally inorganic or organic bases. These preferably include alkali metal hydroxides such as, for example, sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as, for example, barium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate, alkaline earth metal carbonates such as calcium carbonate. Potassium carbonate (powdered) is preferred.

The base is employed in an amount from 1 mol to 10 mol, preferably from 1. 0 mol to 4 mol, relative to 1 mol of the compounds of the general formulae (M).

The process is in general carried out in a temperature range from -30'C to +1OWC, preferably from - 1 O'C to +60'C.

The process is generally carried out at normal pressure. However, it is also possible to carry out it at elevated pressure or at reduced pressure (for example in a range from 0.5 to 5 bar). The compounds of the general formula (XII) are know as species new and can be 20 prepared by reaction of 2,4-dihydroxy-benzaldehydes with benzylbromide in one of the abovernentioned solvents and bases, preferably in acetone with potassium carbonate at room temperature. The compounds of the general formula (XIII) are new and can be prepared like 25 described above.

The compounds of the general formula (XIV) are known or as species new and can be prepared by customary methods.

The compounds of the general formulae (Ill), (V), (VIII), (IX) and (X) are known or as species new and can be prepared by customary methods.

Le A 32 885 The compounds of the general formula (VII) can be prepared like described above or in a single step procedure by reacting compounds of the general formula (XIII) with compounds of the general formula (XIV) in the presence of a surplus of sodium ethylate under reflux Surprisingly it was found that compounds given by the general formula (I) inhibited oxygen radical formation as well as TNFa (tumor necrosis factor) production, but potentiated the release of IL-10. These compounds elevated cellular cyclic AMP probably by inhibition of phagocyte phosphodiesterase activity.

The compounds according to the invention specifically inhibit the production of super oxide by polymorphonuclear leukocytes (PMN). Furthermore, these compounds inhibit TNFoc release and potentiate IL-10 production in human monocytes in response to a variety of stimuli including bacterial lipopolysaccharide (LPS), complement-opsonized zymosan (ZymC3b) and IL-lB.

The described effects are probably mediated by the elevation of cellular cAMP probably due to inhibition of the type IV phosphodiesterase responsible for its degradation.

They can therefore be employed in medicaments for the treatment of acute and chronic inflammatory processes.

The compounds according to the invention are preferably suitable for the treatment and prevention of acute and chronic inflammation and auto immune diseases, such as emphysema, alveolitis, shock lung, all kinds of asthma, COPD, ARDS, bronchitis, arteriosclerosis, arthrosis, inflammations of the gastro-intestinal tract, rheumatoid arthritis, myocarditis, sepsis and septic shock, arthritis, rheumatoid spondylitis and 30 osteoarthritis, grain negative sepsis, toxic shock syndrome, acute respiratory distress syndrome, bone resorption diseases, reperfasion injury, graft vs host reaction, allograft Le A 32 885 -24 rejection, malaria, myalgias, HIV, AIDS, cachexia, Cronh's disease, ulcerative colitis, pyresis, system lupus erythematosus, multiple sclerosis, type I diabetes mellitus, psoriasis, Bechet's disease, anaphylactoid purpura nephritis, chronic glomerulo nephtritis, inflammatory bowel disease and leukemia. The compounds according to the invention are additionally suitable for reducing the damage to infaret tissue after reoxygenation. In this case the simultaneous administration of allopurinol to inhibit xanthine oxidase is of advantage. Combination therapy with superoxide dismutase is also of use.

Test description

I. Preparation of human PMN Blood was taken from healthy subjects by venous puncture and neutrophils were purified by dextran sedimentation and resuspended in the buffered 15 medium. 2. Inhibition of FMLP- stimulated production of superoxide racidal anions. Neutrophils (2.5 x 10'mt-') were mixed with cytochrome C (1.2 mg/ml) in the wells of a microtitre plate. Compounds according to the invention were added 20 in dimethyl sulphoxide (DMSO). Compound concentration ranged from 2.5 nM to 10 iM, the DMSO concentration was 0. 1% v/v in all wells. After addition of cytochalasin b (5 ig x ml-') the plate was incubated for 5 min at 37'C. Neutrophils were then stimulated by addition of 4 x 10-'M FMLP and superoxide generation measured as superoxide dismutase inhibitable reduction 25 of cytochrome C by monitoring the OD550 in a microtitre plate spectrophotometer, such as a Thermomax microtitre plate spectrometer. Initial rates were calculated using a kinetic calculation program, e.g. a softmax programme. Blank wells contained 200 units of superoxide dismutase. 30 The inhibition of superoxide production was calculated as follows:

Le A 32 885 1 [1-((Rx-Rb))]. 100 = % inhibition ((Ro, - Rb)) Rx = Rate of the well containing the compound according to the invenfion.

Ro = Rate in the control well.

Rb = Rate in the superoxide dismutase containing blank well.

Compounds according to the invention have IC50 values in the range 0,00 1 RM- I RM. Example 6 exhibits a IC50(02-)-value of 0.08 PM.

3. Measurement of PMN cyclic AMP concentration The compounds according to the invention were incubated with 3.7 x 106 PMN for 5 min at 37'C before addition of 4 x 10-8 M FMLP. After 6 min protein was precipitated by the addition of 1% v/v conc. HCl in 96% v/v ethanol containing 0. 1 mM EDTA. After centrifugation the ethanolic extracts were evaporated to dryness under N2and resuspended in 50 mM Tris/HCl pH 7.4 containing 4 mM EDTA. The cyclic AMP concentration in the extracts was determined using a cyclic AMP binding protein assay supplied by Amersham International p1c.

Cyclic AMP concentrations were expressed as percentage of vehicle containing control incubations.

Compounds elavate the cAMP-level at I jiM compound 0400% of control values.

4. Assay of PMN phosphodiesterase This was performed as a particulate fraction from human PMN essentially as described by Souness and Scott (Biochem. J. 291, 389-395, 1993). Particulate fractions were treated with sodium vanadate / glutathione as described by the authors to express the descrete stereospecific site on the phosphodiesterase enzyme. Compounds according to the invention had IC,, values ranging from 0.00 1 [LM to 10 jiM. Example 6 exhibits a IC50(PDE IV) of 0. 17 tM.

Le A 32 885 5. Assay of human platelet phosphodiesterase This was performed essentially as described by Schmidt et al. (Biochem.

Pharmacol. 42, 153-162, 1991) except that the homogenate was treated with vanadate glutathione as above. Compounds according to the invention had'C50 values greater than 100 LM.

6. Assay of binding to the rolipram binding site in rat brain membranes This was performed essentially as described by Schneider et al. (Eur. J.

Pharmacol. 127, 105-115, 1986). Compounds according to the invention had IC50 values in the range 0,0 1 to 10 pM. 7. Preparation of human monocytes Blood was taken from normal donors.

Monocytes were isolated from peripheral blood by density centrifugation, followed by centrifugal elutriation.

8. Endotoxin induced TNF release Monocytes (I x 10' mr) were stimulated with LPS (2 [tg ml-') and coincubated with the compounds at different concentrations (10' to 10 tg ml-'). Compounds were dissolved in DMSO/mediurn (2% v/v). The cells were incubated in RPMI 1640 medium glutamine/FCS supplemented and at 37'C in a humidified atmosphere with 5%CO2. After 18 to 24 hours TNF was determined in the supernatants by an human TNF specific ELISA (medgenix). Controls were nonstimulated and LPS stimulated monocytes without compounds.

9. Endotoxin induced shock lethality in mice B6132F I mice (n= 10) were sensitized with galactosamine (600 mg/kg), and shock and lethality were triggered by LPS (0.01 tg/mouse). The compounds were administered intravenously I hour prior LPS. Controls were LPS challenged mice without compound. Mice were dying 8 to 24 hours post LPS challenge.

Le A 32 885 The galactosamine / LPS mediated mortality was reduced.

10. Stimulation of human monocytes and determination of cytokine levels 5 Human monocytes (2x1 0' in I ml) were stimulated with 100 ng/ml LPS, 0.8 mg/ml zymC3b or 10 ng/ml IL-lB in the presence of test compounds. The final DMSO concentration was maintained at 0. 1 % v/v. Cells were incubated overnight in a humidified atmosphere of 5%C02 at 370C. Supernatants were harvested and stored at -70'C. The TNF(x concentration was measured by ELISA using the A6 anti-TNF monoclonal antibody (Miles) as the primary antibody. The secondary antibody was the polyclonal anti-TNFa antibody IP300 (Genzyme) and the detection antibody was a polyclonal anti-rabbit IgG alkaline phosphatase conjugate (Sigma). IL-10 was determined by ELISA (Biosource).

The new active compounds can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using iner nontoxic, pharmaceutically suitable excipients; or solvents. In this connection, the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts which are sufficient in order to achieve the dosage range indicated.

The formulations are prepared, for example, by extending the active compounds with solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, where, for example, in the case of the use of water as a diluent, organic solvents can be used as auxiliary solvents if appropriate.

Administration is carried out in a customary manner, preferably orally or parenterally.

In the case of parenteral administration, solutions of the active compound can be employed using suitable liquid vehicles.

Le A 32 885 In general, it has proved advantageous on intravenous administration to administer amounts from about 0.001 to 10 mg/kg, preferably about 0.01 to 5 mg/kg of body weight to achieve effective results, and on oral administration the dosage is about 0.01 to 25 mg/kg, preferably 0. 1 to 10 mg/kg of body weight.

In spite of this, it may be necessary to depart from the amounts mentioned, in particular depending on the body weight or the type of application route, on individual behaviour towards the medicament, the manner of its formulation and the time or interval at which administration takes place. Thus, in some cases it may be sufficient to manage with less than the abovementioned minimum amount, while in other cases the upper limit mentioned must be exceeded. In the case of administration of relatively large amounts, it is advisable to divide these into several individual doses over the course of the day.

Solvents a dichloromethane/methanol 15: 1 (v/v) b dichloromethane/methanol 20:1 c dichloromethane/methanol 50:1 d dichloromethane/methanol 40:1 e ethylacetate/cyclohexane 5:1 f chlorofomi/methanol 10:1 9 dichloromethane/methanol 10:1 h dichloromethane/methanol 30:1 i chlorofonn/methanol 30:1 j chloroform/methanol/water/acetic acid 70:30:5:5 k dichloromethane/methanol/formic acid M:0A 1 dichloromethane/methanol/NH3 M:0A m dichloromethane/methanot 5:1 n dichloromethane/methanol 7:1 0 dichloromethane/methanol/NH3 12:1:0.1 Le A 32 885 Starting compounds:

Example 1

4-Benzyloxy-2-hydroxybenzaldehyde -"0i::: CHO c 6 H " OH 13.8 g (0.1 mol) 2,4-dihydroxybenzaldehyde are dissolved in 150 mI acetone, 17.1 g (0. 1 mol) benzyIbromide and 13.8 g (0. 1 mol) potassium carbonate are added, and the mixture is stirred at room temperature for 3 d. After filtration, the solvent is removed in vacuo and the residual crude product flirther purified by column chromatography on silica gel using dichloromethane as eluent.

Yield: 9.2 g (40%) m.p.: 81-82'C H-NNIR (C13C13, 400 MHz): 8 = 5.11 (s, 2H; CH2): 6.5 1 (d, 1 H, Ar-H); 6. 61 (dd, 1 H, Ar-I1); 7.32 - 7.45 (m, 6H, Ar-H); 9.82 (s, 1H, CHO); 11.60 (s, 1H, OH) ppm.

Example 11

4-Benzyloxy-2-hydroxybenzonitrile 0,,aCN e6H," OH 25 25.0 g (0. 11 mol) of the example 1, 8.67 g (0. 13 mol) hydroxylamine hydrochloride and 15.0 g (0.22 mol) sodium fonnate are dissolved in 170 mi formic acid, and the solution Le A 32 885 stirred under reflux for 1-3 h. The reaction mixture is cooled to room temperature, poured into ice/water and extracted with dichloromethane. The organic layer is dried (Na2S04), the solvent removed in vacuo and the residue trituated with dichloromethane.

Alternatively, the precipitate which is formed after dilution with ice/water is filtered off and dried in a desiccator in the presence of phosphorus pentoxide. The crude product is crystallized from dichloromethane/cyclohexane.

Yield: 15.0 g (61 %) m.p.: 135-136'C S-NMR (400 MHz, DMSO-dj: 3 = 5.13 (s, 2H, CH2); 6.58 (d, I H, Ar-H); 6.60 (dd, IFI, Ar-H); 7.32 - 7.46 (m, 5H, Ar-H); 7.50 (d, 1H, Ar-11); 11. 10 (br.s, 1H, OH) ppm.

Example Ill (o-Bromo-2,4-dichloroacetophenone 0 Br cl To a solution of 155.2 g (788 mmol) 2,4-dichloroacetophenone in 450 ml glacial acetic acid are added 40.4 mI (788 mmol) bromine at 5WC. After 1 h at 5WC, further 4 mi (78.8 mmol) bromine are added and the mixture is stirred for an additional hour. The solution is cooled to room temperature, concentrated to half of its volume and diluted with 800 mI water. The mixture is neutralized with solid sodium carbonate and extracted three times with ethyl acetate. The organic layer is dried (Na2S04), the solvent removed in vacuo, finally under high vacuum. The crude product is used directly without further purification for the following reaction and stored in the meantime at -20'C.

Yield: 211.4 g (quant); yellow oil Le A 32 885 Example IV

3-Amino-2-(2,4-dichlorobenzoyl)-6-benzyloxy-benzofuran 5 I C1 C6 5 -'O H," "'0 0 - C1 a) Single step procedure:

10.0 g (44.0 mmol) of example II are dissolved in 200 ml ethanol, and 5. 98 g (88.0 mmol) sodium ethylate and 15.4 g (48.0 mmol) of example III are added.

The mixture is stirred under reflux for 4 d. During this time further 12. 0 g sodium ethylate and 7.7 g of example III are added. The solvent is removed in vacuo and the residue is purified by column chromatography on silica gel (eluent: 1. dichloromethane, 2. dichloromethane/methanol 98.2).

Yield: 8.1 g (44%) m.p.: 158'C NMR-data see below.

Example V 20

Two step procedure:

a) co-[(5-Benzyloxy-2-cyan)-phenoxy]-2,4-dichloroacetophenone:

Le A 32 885 CN C H----'Oj::::0 O%-j 6 5 C1 To a mixture of 26.6 g (118 mmol) of example II and 48.85 g (354 mmol) powdered potassium carbonate in 800 ml acetone are added 34.8 g (130 ml) of example III under reflux. After a further 1-2 h unter reflux, the mixture is filtered, the solvent evaporated in vacuo and the residue triturated using dichloromethane (Ist crop of product) and dichloromethane/cyclohexane (4:1) (2nd crop of product).

Yield: 26.2 g (54%) b) Two step procedure:

To a solution of 37.5 g (91 nimol) of the compound of example Va in 550 ml ethanol, three pellets of sodium hydroxide are added and the mixture is stirred at 50'C for 30 min. After cooling to room temperature, the mixture is filtered off (Ist crop of product) and the filtrate is diluted with 300 ml of water. Most of the ethanol is removed in vacuo and the formed precipitate is filtered (2nd crop of product).

Yield: 36.7 g (98%) H-NMR (DMSO-d6, 400 MHz): 8 = 5.14 (s, 2H, CH2): 6.97 (dd, I H, Ar-H); 7.10 (d, lH, Ar-H); 7.31 - 7.47 (m, 5H, Ar-H); 7,53 (br.s, 2H, NH2); 7.57 (s, 2H, Ar-H); 7.75 (s, I H, Ar-H); 7.93 (d, I H, Ar-H); ppm.

Ms (El): 411 (M') Le A 32 885 Example V1

N-[2-(2,4-Dichlorobenzoyl)-6-benzyloxy-benzofuran-3-yl] urea 2 o.:_H N-H 0 1 cl C H'O ",0 0 6 5 cl 30.9 g (75 mmol) of example IV are dissolved in 750 ml dichloromethane and cooled to WC. 11.6 g (82 mmol) chlorosulfonyl isocyanate in dichloromethane are added and the mixture is stirred at O'C for 30 min and at room temperature for 3 h. The solvent is removed in vacuo, the residue suspended in water and stirred vigorously for 3 h at 60T. After cooling to r.t. the suspension is filtered, the crude product dried in a desiccator in the presence of phosphorus pentoxide and triturated with diisopropylether at 40T.

Yield: 33.7 g (98%) m.p.: 192-193'C S-NMR (DMSO-d6,400 MHz): 8 = 5.18 (s, 2H, CH2); 7.00 (dd, 111, Ar-1l): 7. 05 (br.s, 2H, NI-12): 7.20 (d, I H, Ar-H); 7.30 - 7.47 (ni, 5H, Ar-H); 7.61 (dd, I H, Ar-11); 7.68 (d, 1 H, Ar-H); 7.82 (d, 1 H, Ar-1-1); 8.3 7 (d, 1 H, Ar-H); 9.71 (s, 1 H, N14) ppm.

MS (FAB): 455 (M+H)' Le A 32 885 Example V11

N-[2-(2,4-Dichlorobenzoyi)-6-hydroxy-benzoft=-3-yl]urea NH N-H 0 1 cl "o 0 - cl To a solution of 5.0 g of example VI in 100 m]. THF are added 250 mg 10% palladium on activated charcoal, and the mixture is hydrogenated at atmospheric pressure and room temperature for 1-3 d. If neccessary, fluther 125 mg 10% Pd/C are added and the hydrogenation is continued for 24 h. The mixtures is filtered through celite and the solvent is removed in vacuo to about 1/3 of the original volume. Dichloromethane is added, the mixture is stirred at O'C and the formed precipitate is filtered off. Yield: 4.0 g (quant.) m.p.: 230-23 PC 'I-I-NMR (DMSO-d6, 400 MHz): 8 = 6.73 (d, 1 H, Ar-H); 6.80 (dd, 1 H, Ar-H); 7.03 (br.s, 2H, NI-12): 7.60 (dd, 111, Ar-H); 7.65 (d, 111, Ar-11); 7.80 (s, 1H, Ar-H); 8.30 (d, I H, Ar-H); 9.72 (s, I H, N11); 10.40 (br.s, I H, OH) ppm. MS (EI): 364 (M).

In analogy to this procedure the following examples shown in table B are prepared:

Le A 32 885 Table B:

0 y N112 NH HO 0 R 14 R 17 R 15 R 16 Ex.-No. R 14 R's R 16 R 17 Yield(% of th.) Pf VIII F H F H 90 0,76 j) IX H H cl H 40 0,38 a) X OCH3 H OCH3 H 88 0,3P) XI cl H H H 91 0,36') XII 1 H H cl 91 0,31) XIII CH3 H CH3 H 58 0,26 bT- Example XVI

OYNII 2 1 0 77--o 0 0 cl 1 g (41.1 nunol) 6-hydroxybenzofurane, 2,82 mI (41,1 nimol) R-glycidol, and 10.8 g (4 1.1 mmol) triphenylphosphin are dissolved in 200 ml dry THR At O'C 6. 43 mI (41.1 mmol) diethyl azodicarboxylate (DEAD) are added dropwise, and the reaction mixture is stirred at room temperature for a total of 4 days. During this time, three Le A 32 885 additional portions of glycidol (0.94 ml, 13.7 mmol each), triphenylphosphin (3.6 g, 13.7 mmol each), and DEAD (2.1 ml, 13.7 mmol each) are added to the reaction mixture. The mixture is filtered (first crop of product), the filtrate concentrated to half of its original volume and filtered again (second crop of product). The filtrate is diluted with dichloromethane, washed with water twice, dried over sodium sulfate, and concentrated to a volume of about 200 ml. An equal volume of diethylether is added, the mixture stiffed for 15 min, and filtered again to yield a third crop of product.

Combined yield: 15.89 g (91.8% of th.) Rf = 0.57 (chlorofomi/methanol (15:1)) Preparation examples:

General procedure for the synthesis of benzofuranylamino alcohols:

The benzofuranyl epoxide is dissolved in 1:1 dry tetrahydrofurane/methanol, 2 molequivalent of the amine component are added, and the reaction mixture is stirred at 40 50'C for 1-7 days. After concentration, the residue is taken up in dichloromethane or chloroform, and washed with water several times. The organic layer is dried over sodium sulfate, concentrated, and the crude product purified by column chromato20 graphy over silica gel.

Le A 32 885 The following examples were prepared in analogy to the general procedure:

Ex, Structure Yield (% Rf No. oftheory) 1 0 y NH 2 17.1 0. 15 (g) NH N //^" N -"-o 1 0 1 0 U-- 0 H cl 2 0 y NH2 52.1 0.29(1) rN -"^o 0 0 H3C,N OH 1 cl 1 3 0 y NH 2 22.1 0. 3 1 (m) NH 0 1 0 1 0 OH cl 1 1 4 0 y NH2 21.8 0.46 (m) N Hf -" 0 0 0 M, C 0 H cl N 1 cl Le A 32 885 Ex.- Structure Yield (% Rf No. oftheory) 0 y NH2 46.5 0.28 (n) NH CM00C, NCL NHf-"1"^,o 0 1 0 OH cl 6 NH2 31.5 0.40(g) 0 --::: ( NH 0 1 cl rN -"-o ' 0 - 0i OH cl 7 NH2 61.2 0.40(g) 0 -- N H 0 ",0 1 cl 0 N 0 0 j 6 H \ A cl 8 0 y NH2 14.3 0.3P NH N"'O 0 0 M::'J H 1.1 OH cl N 1 cl 9 OyNH 2 31.0 0.25) 0 0 IIIINJ OH cl cl Le A 32 885

Claims

We claim:

I Benzofuranylaminoalcohohols of the general formula (1) L A 11 -
2
3 NR1-C NR R R5R6N 0 'CO
4 _00) -R H in which A represents hydrogen, straight-chain or branched acyl or alkoxycarbonyl, each having up to 6 carbon atoms, halogen, carboxyl, cyano, nitro, hydroxyl, trifluoromethyl or trifluoromethoxy, or straight-chain or branched alkyl having I to 6 carbon atoms, which is optionally substituted by carboxyl, alkoxy or alkoxycarbonyl. each having I to 4 carbon atoms, phenoxy or benzoyl, R' represents hydrogen, straight-chain or branched alkyl having I to 4 carbon atoms, an aminoprotecting group or a group of the formula -CO-R7 in which R7 denotes straight chain or branched alkoxy having I to 4 carbon atoms, R' and W are identical or different and represent hydrogen, cycloalkyl having I to 6 carbon atoms, straight chain or branched alkyl, alkoxycarbonyl or alkenyl each having I to 8 carbon atoms, Le A 32 885 or R2 and R' together with the nitrogen atom form a 5- to 7-membered saturated heterocycle optionally having a finiher oxygen atom, represents aryl having 16 to 10 carbon atoms or represents a
5 to 7 membered, aromatic saturated or unsaturated heterocycle, which can contain I to 3 oxygen, sulphur, nitrogen atoms as heteroatoms or a residue of a formula -NW, wherein R' denotes hydrogen or straight-chain or branched alkyl or alkoxy carbonyl each having I to
6 carbon atoms, and to which further a benzene ring can be fused and wherein aryl and/or the heterocycle are optionally monosubstituted to trisubstituted by identical or different substituents from the series comprising hydrox yl, halogen, nitro, 1H-tetrazolyl, pyridyl, trifluoromethyl, trifluo romethoxy, difluoromethyl, difluoromethoxy, cyano, carboxy, straight chain or branched alkoxy, alkoxycarbonyl or acyl each having I to 6 carbon atoms or by straight-chain or branched alkyl having I to 5 carbon atoms, which is optionally substituted by carboxyl or straight chain or branched alkoxycarbonyl having 1 to 4 carbon atoms or by a group of formula -NR!R'O, -SR", -(NH),-So2R 12 or _O_SO2R 13 in which R' and R" are identical or different and denote hydrogen or a straight chain or branched alkyl having I to 4 carbon atoms, Le A 32 885 or R?denotes hydrogen and R'O denotes straight-chain or branched acyl having I to 6 carbon atoms, R" denotes hydrogen or straight-chain or branched alkyl having I to 4 carbon atoms, a denotes a number 0 or 1, R 12 and R" are identical or different and represent straight-chain or branched alkyl having I to 6 carbon atoms, benzyl or phenyl, which are optionally substituted by trifluoromethyl, halogen or straight-chain or branched alkyl having I to 4 carbon atoms, L represents an oxygen or sulfur atom R' and W represents hydrogen or straight-chain or branched alkyl having I to 6 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms or by a 5 to 7 membered aromatic, saturated or unsaturated heterocycle having I to 3 heteroatoms from the series comprising N, S, 0 and/or a residue of a formula -NR" wherein R 14 denotes hydrogen or straight-chain or branched alkyl or alkoxy carbonyl each having I to 6 carbon atoms Le A 32 885 and to which a phenyl ring can be fused and which are optionally monosubstitated to disubstituted. by identical or different substituents from the series -comprising halogen, cyano or by a straight-chain or branched alkyl or alkoxycarbonyl each having I to 6 carbon atoms, or W and R' together with the nitrogen atom form a 5 to 6 membered saturated or unsaturated heterocycle having I to 3 heteroatoms from the series comprising N, S, 0 and/or a residue of a formula -NR"', wherein R 14' have the abovementioned meaning of R 14 and is identical or different to the latter and to which a phenyl ring can be fused and which is optionally monosubstituted to disubstituted by identical or different substituents from the series comprising halogen, cyano or by a straight-chain or branched alkyl or alkoxycarbonyl. each having I to 6 carbon atoms, and salts thereof 2. Compounds according to claim 1, in which A represents hydrogen, halogen, carboxyl, cyano, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy or alkoxy having I to 4 carbon atoms R' represents hydrogen, straight-chain or branched alkyl having I to 4 carbon atoms or a group of the formula -CO-W Le A 32 885 in which R' denotes straight chain or branched alkoxy having 1 to 4 carbon atoms, and W are identical or different and represent hydrogen, cyclobutyl, cyclopentyl, cyclohexyl or straight-chain or branched alkyl, alkoxycarbonyl or alkenyl each having 1 to 4 carbon atoms, or and together with the nitrogen atom form a pyrrolidinyl-, piperidinyl- or morpholinyl-ring, and W represents phenyl, pyridyl or thienyl, wherein both rings are optionally monosubstituted to trisubstituted by identical or different substituents 20 from the series comprising hydroxyl, fluorine, chlorine, bromine, nitro, carboxy, straight-chain or branched alkoxy, alkoxycarbonyl or acyl each having 1 to 3 carbon atoms, or by methyl, ethyl, n-propyl or isopropyl which is optionally substituted by carboxyl or straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms 25 L represents an oxygen or sulfur atom, R' and W represents hydrogen or straight-chain or branched alkyl having 1 to 4 carbon atoms, which is optionally substituted by phenyl, pyridyl, in-ddazolyl, pyrryl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl and/or a residue of a formula -NR 14, Le A 32 885 wherein R 14 denotes hydrogen or straight-chain or branched alkyl or alkoxy carbonyl each having 1 to 4 carbon atoms, and wherein the ring systems are optionally monosubstituted by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having 1 to 3 carbon atoms, or R' and R' together with the nitrogen atom form a pyrazolyl-, triazolyl-, tetra zolyl-, imidazolyl-, pyn-yP, morpholinyl-, piperidinyl-, pyrrolidinyl-, piperazinylring and/or a residue of a formula -NR"', wherein C' has the abovementioned meaning of W' and is identical or different to the latter, and wherein the ringsystern is optionally monosubstituted to trisubsti tuted by identical or different substituents from the series comprising halogen, cyano or by a straight-chain or branched alkyl having 1 to 6 carbon atoms, and salts thereof 3. Compounds according to claim 1 or 2, in which A represents hydrogen, Le A 32 885 represents hydrogen, methyl, ethyl, n-propyl or isopropyl or a group of the formula -CO-R, in which W denotes methoxy, ethoxy, n-propoxy or isopropoxy, and W represent hydrogen, W represents phenyl or pyridyl, which are optionally up to difold substituted by identical or different substituents from the series fluorine, chlorine, methyl or methoxy, L represents an oxygen atom, R' and W represents hydrogen or straight-chain or branched alkyl having 1 to 4 carbon atoms, which is optionally substituted by phenyl, pyridyl, imidazolyl, pyrryl, piperidinyl and/or a residue of a formula -NR", 20 wherein C denotes hydrogen or straight-chain or branched alkyl or alkoxycarbonyl each having 1 to 3 carbon atoms, 25 and wherein the ring systems are optionally monosubstituted by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having 1 to 3 carbon atoms, or Le A 32 885 M R' and R6 together with the nitrogen atom form a imidazolyl-, pyrryl-, morpholinyl-, piperidiny1-, pyrrolidinyl-, piperazinylring and/or a residue of a formula -NR 14' wherein R 14' have the abovementioned meaning of R and is identical or different to the latter, and wherein the ringsystern are optionally monosubstituted to trisubsti tuted by identical or different substituents from the series comprising by a straight-chain or branched alkyl or alkoxycarbonyl each having 1 to 3 carbon atoms, and salts thereof 4. Compounds according to any one of claims 1 to 3, selected from the group consisting of..

OYNH 2 NN 0 0 0 -1 OH cl 1 1 Le A 32 885 1 0 NH 2 rN -'o 1 0 1 0 1-1 NJ OH 1 cl 1 0 y NH 2 1 1 0 C----no 0 OH cl 1 cl 0 y NH 2 NH oi 11-1 1 0 N " Z 0' H OH cl N 1 cl Le A 32 885 1 0 y NH 2 NH H OH cl 1 G1 NH 0-z NH 0 cl 0 oi OH cl NH 0 NH 0 cl 0 0-j OH cl OyNH 2 N"""'O 0 0 OH cl N cl Le A 32 885 0 y NH 2 NH 0 0 NJ OH cl cl 5. A process for the preparation of compounds according to claim 1, characterized in that compounds of the general formula 11 L 11 - 2 3 A NRI-C NR R 0070:c:-o10 0 14 R in which A, W, R2, R, R' and L have the abovementioned meaning, 10 are reacted with amines of the general formula (III) WR 6 -NH (111) in which R' and R 6 have the abovementioned meaning, in the presence of an inert solvent. 20 Le A 32 885 6. Benzofuranylaminoalcohols according to any one of claims I to 4 for therapeutic use.
7. The composition containing at least one Benzofuranylalcohol according to any one of claims I to 4 and a pharmacologically acceptable diluent.
8. A composition according to claim 7 for the treatment and prevention of acute and chronic inflammatory processes.
9. The process for the preparation of composition according to claim 7 and 8 characterized in that the Benzofuranylaminoalcohol together with customary auxiliaries is brought into a suitable application form.
10. Use of Benzofuranylaminoalcohols according to anyone of claims I to 4 for the preparation of medicaments.
11. Use according to claim 10 for the preparation of medicaments for the treatment and prevention of acute and chronic inflammatory processes.