GB2350111A

GB2350111A - Oligohydroxyl substituted 3-urea-benzofuran and pyridofuran derivatives

Info

Publication number: GB2350111A
Application number: GB9911456A
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: WO2000069844A1; GB9911456D0; AU4917000A

Abstract

Oligohydroxyl 3-urea-benzofuran- and pyridofuran-derivatives of the general formula (I) <EMI ID=1.1 HE=28 WI=82 LX=576 LY=1050 TI=CF> <PC>their preparation and their use in medicaments for the treatment of inflammatory processes, wherein A, D, E, L and R<SP>1</SP> - R<SP>4</SP> are as set out in claim I.

Description

2350111 Oligohydroxyl substituted 3-Urea-benzofurane- and -pyridofurane-

derivatives The invention relates to oligohydroxyl 3-urea-benzofurane- and - pyridofurane-derivatives, 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. TNF(x, ILI or IL-6) and anti- inflammatory cytokines (e.g. IL-10) play a pivotal role in host de- fence mechanisms. Uncontrolled production of inflammatory mediators can lead to acute and chronic inflammation, tissue damage, multi-organ failures and to death. it is additionally known that elevation of phagocyte cyclic AMP leads to inhibition of oxy gen 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)-inhibifing action are described in the publication EP 0 731099 A2: The reference describes only single hydroxyl substituted derivatives, however. In order to provide alternative compounds of similar or improved PDE IV-inhibitory activity the present invention relates to oligohydroxyl 3-urea-benzofurane- and -pyridofurane-derivatives of the general formu la (1) L R 2 R 3 4 ,_z)E CO-R in which 1 A and D including the double bond connecting them together form a phenyl-, pyridyl-, pyrimidyl, pyridazinyl-, pyrazinyl- or thienyl-ring, which is substituted by a group of a formula -OR5 wherein R' denotes straight-chain or branched alkyl having 1 to 15 carbon atoms, which is substituted difold to fivefold by hydroxyl or by straight-chain oder branched alkoxy having 1 to 6 carbon atoms and wherein alkyl is optionally substituted by straight-chain or branched alkoxycarbonyl having 1 to 6 carbon atoms, halogen, carboxyl, (C,-Q-cycloalkyl or by phenyl, which is optionally substituted monofold to fivefold by nitro, halogen or phenyl, E represents an oxygen or sulfur atom, R' represents hydrogen, straight-chain or branched alkyl having 1 to 4 carbon atoms, an aminoprotecting group or a group of the formula -CO-W in which 0 R' denotes straight chain or branched alkoxy having 1 to 4 carbon atoms, 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 1 to 8 carbon atoms, or R2 and R' together with the nitrogen atom form a 5-, 6- or 7-membered saturated heterocycle optionally having a further oxygen atom, 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 7 wherein R7 denotes hydrogen or straight-chain or branched alkyl or alkoxycarbonyl 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 dif ferent substituents from the series comprising hydroxyl, halogen, nitro, I H tetrazoly], pyridyl, trifluoromethyl, trifluoromethoxy, 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 -NRR, -SR", _(NMa_S02R" or_O_SO2R 12 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 denotes straight-chain or branched acyl having 1 to 6 carbon atoms WO denotes hydrogen or straight-chain or branched alkyl having 1 to 4 5 carbon atoms, a denotes a number 0 or 1, W' and R are identical or different and represent straight-chain or branched 0 10 alkyl having 1 to 6 carbon atoms, benzyl or phenyl, which are optionally substituted by trifluoromethyl, halogen or straight-chain or branched alkyl having 1 to 4 carbon atoms, L represents an oxygen or sulfur atom and salts thereof.

The oligohydroxyl substituted 3-urea-benzofurane- and -pyridofuranederivatives ac cording to the invention can also be present in the form of their salts and pyridinium oxide. 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 oligohydroxyl substituted 3-ureabenzofurane and -pyridoftirane-derivatives can be metal or ammonium salts of the substances ac cording to the invention, which contain a free carboxylic group. Those which are par ticularly preferred are, for example, sodium, potassium, magnesium or calcium salts, and also ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexyl amine, 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, furnaric acid, malic acid, citric acid, tartaric acid, ethanesul phonic acid, benzenesulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid. Preferred pyridiniurn salts are salts in combination with halogen.

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 image and mirror image (diastereomers). The invention relates both to the antipodes and to the racemate forms, as well as the diastereomer mixtures and individual dia stereomers. The racernate forms, like the diastereomers, can be separated into the stereoisomerically uniforrn constituents in a known manner.

Heterocycle in general represents a 5- to 7-membered, aromatic saturated or unsatu rated, preferably 5- to 6- membered, saturated or unsaturated ring which can contain I to 3 oxygen, sulphur and/or nitrogen atoms as heteroatoms and to which ftirther aro matic rings can be fused.

The following are mentioned as preferred: thienyl, filryl, pyrrolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxazolyl, cinnolyl, thi azolyl, dihydrothiazolyl, benzothiaazolyl, isothiazolyl, benzisothiazolyl, oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl, benzimidazolyl, indolyl, morpholinyl, pyrrolid inyl, piperidyl, piperazinyl, oxazolinyl or triazolyl.

Preferred compounds of the general formula (1) are those in which 30 A and D, including the double bond connecting them form together a phenyl- , pyridylor pyrimidyl-ring, which are substituted by a group of a formula -OR' wherein 5 R' denotes straight-chain or branched alkyl having 1 to 14 carbon atoms, which is substituted difold to fourfold by hydroxyl, and wherein alkyl is optionally substituted by methoxycarbonyl, ethoxycarbonyl, npropoxycarbonyl or isopropoxycarbonyl, fluorine, chlorine, cyclopentyl, cyclohexyl or by phenyl, which is optionally substituted monofold to fivefold by nitro, fluorine or chlorine, E represents an oxygen or sulfur atom, R' represents hydrogen, straight-chain or branched alkyl having 1 to 4 carbon atoms or a group of the formula -CO-R6 in which R' denotes straight chain or branched alkoxy having 1 to 4 carbon atoms, W and R' 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 25 or R 2 and R' together with the nitrogen atom form a pyrrolidinyl-, piperidinyl- or mor- pholinyl-ring, 30 and R' 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, 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 1 to 3 carbon atoms L represents an oxygen or sulfur atom, and salts thereof.

Particularly preferred compounds of the general formula (1) are those in which A and D, including the double bond connecting them form together a phenyl- or pyridyl-ring, which are substituted by a group of a formula -OR' wherein R' denotes straight-chain or branched alkyl having 1 to 11 carbon atoms, which is substituted difold to fourfold by hydroxyl, and wherein alkyl is 25 optionally substituted by methoxycarbonyl, cyclohexyl, fluorine or by phenyl, which is optionally substituted monofold to fivefold by nitro or fluorine, E represents an oxygen or sulfur atom, no R' represents hydrogen, methyl, ethyl, n-propyl or isopropyl or a group of the formula -CO-R, in which 5 R 6 denotes methoxy, ethoxy, n-propoxy or isopropoxy, R 2 and W represent hydrogen, represents phenyl or pyridyl, which are optionally up to trifold substituted by identical or different substituents from the series chlorine or methyl, L represents an oxygen atom, and salts thereof.

Very particularly preferred compounds of the general formula (1) are those, which are shown in table A:

Table A:

Structure NH 0 --- NH c 1 0 HO -,-o ', 0 cl OH cl NH 0 NH ) 0 1 1 H 0 "' -Z "^ 0 j 0 cl OH Cl R-ENANTIOMER NH 0 NH 1 0 ) HO -"-o J 0 cl OH Cl S-ENANTIOMER 0 Structure NH 0 --A NH 0 HO --o J: c 0 OH 11 NH 0-- NH 0 OH 1 cl 1 HO\', 0) 0 - ' HO cl 0 y NH 2 OH NH ko J' 1 0 1 0 OH 1 1-z cl 1.

cl 0 y NH 2 OH NH 0 0 0 OH 1 'I cl cl Structure NH 0== 2 NH H 0 1 cl 1 1 0" ') o HO zl"'O OH Cl 0 y NH 2 OH 1 NH 0 0 0 OH 1 cl lli::

cl 0 _y NH 2 OH 0 1 0 1 NH 0 'H cl 1 cl 0 _y NH 2 Imn HO -"-O N 0 0 OH cl 1 cl Structure 0 y NH 2 OH HO ---"o 0 cl 1 cl 0 y NH 2 NH 0 1 0 OH cl 1 cl NH 0 N H 0 1 cl HO""CO Jao - c 4 0 H % c 1 0 y N H 2 N H H 0 -"-o 0 0 0 0 0 H c 1 c 1 Structure 0 y NH 2 inn OH 0 1 cl cl 0 NH 2 y N H HO " "'OH 0 1 1 0 0 cl 1 cl R-ENANTIOMER 0 y NH 2 Inn HO -"'no 0 0 OH cl 1 0 y NH 2 Inn HO 0 0 OH cl 1 cl Structure 0 y NH 2 OH 0 0 0 OH cl 1 cl 0 y NH 2 NH OH 0 0 0 OH cl lill cl 0 H 2 N-- NH 1 \,\ co cl HO --o, lo 0 0 OH Cl \ / 0 NH -CO cl 0 H b Structure 0 y NH 2 NH 0 HO 0 0 H bH cl H0-)-,,,, Oz NH 2 HO 0 NH G1 0 y NH2 N H 0 HO 0 0 0 6H i cl cl R-ENANTIOMER 0 y NH 2 OH 1 NH 0 0 OH cl 1 cl Structure NH 2 0--:-:( NH HO- 1 "-. \" co cl 00 úCO\ - 1.-1 OH cl OH NH OH o-:::: NH OH 1 cocl HO"' 0 0 H - cl NH 0 ---- 1 N H "-z '\ 1 coc 1 H 0 -;5 o OH cl 0 H 2 N"NH 0 OH Cl c F 1-", 0 "',o 0 - HO cl Structure 0 y NH 2 NH 0 HO 0 0 H bH cl NH NH 0 HO -"-no 0 OH NH 2 0 NH 0 HO"" 0 0 - HO N 1 HO 0 y NH 2 NH HO'- 0 0 0 OH H cl 1 cl Structure 0 y NH 2 INN H OH 0 0 0 OH 1 "Z cl 1,051 cl 0 y NH 2 NH OH 1 r-- 0 0 OH cl 1 cl NH 2 NH 0 HO F 0 0 OH N 0 y NH2 N. H HO"'O 0 0 OH 1 -: cl 11-1 cl R-ENANTIOMER Structure 0 Y NH 2 NH HO -"-o 0 OH cl cl S-ENANTIOMER 0 Y NH 2 - 2 1 1 0 0 0 HO H - cl OH 1 cl 0 NH 2 0 HO 0 0 H cl OH 1 cl 0 A process for the preparation of the compounds of the general formula (1) has additionally been found, characterized in that, 5 that in the case in which R' denotes alkyl substituted by two vicinal hydroxyl-groups [A] compounds of the general formula (11) A R 14 1 HO 4 CD CO-R in which R 4, A, D and E have the abovementioned meaning, 5 and R 14 denotes a residue of a formula W L 11 -NH 2 or -P4M-1-INM 2 wherein L has the abovernentioned meaning, first are reacted with compounds of the general formula (111) M-CH2-Z' (111) in which W' denotes straight-chain or branched alkenyl having up to 9 carbon atoms, which is optionally substituted by phenyl or optionally nitro or halogen- substituted phenyl and/or halogen, and z? denotes a leaving group such as mesyl, tosyl, chlorine, bromine or iodine in inert solvent and in presence of a base to compounds of the general formula (IV) R 14 R M2C _ 0 E CO-R in which A D, E, R', R 14 and R have the abovementioned meaning, 5 and in a last step reacted with osmiumtetroxide(OS04) / N-methyImorpholino-N-oxide in inert solvents, or 10 in the case in which R' denotes alkyl substituted by two to five hydroxyl groups [B] compounds of the general formula (II) are reacted with compounds of the general formula (V) 15 R 16_CH20H (V) in which R 16 denotes straight-chain or branched alkenyl having up to 9 carbon atoms, which is optionally substituted by hydroxyl, in inert solvents and in the presence of triphenylphosphine / diethylazodicarboxylate to compounds of the general formula (V1) R 14 4 1 R 16 -H2C _ 0 G E CO-R (VI) in which A, D, E, R, C and W' have the abovementioned meaning and in a last step are reacted with OsO,/N-methyImorpholino-N-oxide in solvents, or [C] compounds of the general formula (11) are reacted with alcohols of the general formula (V11) W-0H (V11) in which 15 R 5 has the abovementioned meaning in inert solvents and in presence of triphenylphosphine / diethylazodicarboxylate or [D] compounds of the general formula (11) are reacted vrith the compound of the formula (VIII) K CH -OH (Vill) 0 in inert solvens and in the presence of a base and titanium- (IV)Isopropylate and in the case in which W, R 2 and/or R':# H the free amino groups are derivated optionally by common methods.

The process according to the invention can be illustrated by way of example by the following equations:

[A] 0 0 HN J- NH2 HN J_ NH2 0 0 c N 1 cl K2C0,1acetone --z 1 cl HO'CX% + B r 0 'N 0 cl cl 0 HN J_ NH2 0 0S04INMO 1) 1 cl c 0 waterlacetone, t-butanol HO 0 "N OH cl [B] 0 0 HN -- NH HN J- NH 2 1 0 2 cl ', c 1 0 cl HO 0 +H 0 DEAD2), Ph3 P3)HO --,r 0 0 TH-F --- > cl OH cl 0 HN -U- NH2 0 OS041NMO 1 OH 1 cl waterlacetone, t-butanol HO HO 0 0 cl 1) N-Methyirnorpholino-N-oxide 2) diethylazodicarboxylate 3) triphenylphosphine [C] 0 HN JL NH 2 OH 0 cl HO ---- DEAD, Ph3P HO'0 0 - + - THF HO cl 0 - HN J1, NH 2 0 1 cl HO "',o 0 - HOr 0 cl [D] 0 HN -JL NH 2 0 HO 0 cl 77"' CH 2 OH NaH cl 0 Ti(OPr)4 1 THF 0 HN -JL NH 2 0 1 cl c HO "' 0 0 - OH cl Suitable solvents for the different processes [A] - [D] are generally water or customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane or tetrahydrofurane (THF), ethylacetate, acetone, dimethylsulfoxide, dimethylformamide or alcohols such as methanol, ethanol, propanol, butanol or t-butanol, or halogenohydrocarbons such as dichloromethane, dichloroethane, trichloromethane or tetrachloromethane. Acetone is preferred for the first step of [A] and water/acetone/t-butanol for all processes with OsO, /N-methyl morpholino-N-oxide.

Tetrahydrofarane is preferred for the process with the system triphenylphosphine / di ethylazodicarboxylate.

Suitable bases 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 car bonates such as calcium carbonate, or organic ainines (trialkyl(C,- C6)amines) 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), pyridine or methylpiperidine or amide such as sodium amides, lithium butyl amide or butyllithium. It is also possible to employ alkali metals, such as sodium, or their hydrides such as sodium hydride, as bases. Potassium carbonate for the first step of [A] and sodium hydride for process [D] 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 formula (II).

The processes are in general carried out in a temperature range from -3 O'C to +I OO'C, preferably from -I O'C to +5 O"C.

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

The compounds of the general formula (11) are known or new and can be prepared by cleavage of the protecting group, e.g. by hydrogenation (R17 = benzyl) of compounds of the general formula QX) R 14 (1x) R 17 0 4 -A 1 -D' E CO-R in which 10 A, D, E, R' and R 14 have the abovementioned meaning and R 17 denotes a hydroxyl protecting group, preferably methyl or benzyl, wherein in the case of W' = -NH2 compounds of the general formula (IX) are first reacted with compounds of the general formula (X) M-N=C=L (X) in which L has the abovementioned meaning and R 18 has the abovementioned meaning of R 2 and R' in inert solvents, if appropriate in the presence of a base, 5 and in the case of R2/R' = H and L = 0, compounds of the general formula (IX) are first reacted with compounds of the general formula (Xl) 10 X-SO,-N=C=0 (M) in which X denotes halogen, preferably chlorine, and in the case von R 2/R3 = H and L = S, compounds of the general formula (IX) are first reacted with NH,SCN. 20 The hydroxyl-protective group is in case of R = benzyl, in general removed with hydrogen in ethyl acetate, diethyl ether or tetrahydrofurane. Suitable catalysts are preferably palladiw-n and palladium on charcoal.

Suitable solvents for the steps (IX/X and IX/X1) are generally customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane or tetrahydrofurane, ethylacetate, dimethylsulfoxide, dimethylfon-namide or halogenohydrocarbons such as dichloromethane, dichloroethane, trichloromethane or tetrachloromethane. Dichloromethane is preferred. 30 Suitable bases for these steps 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, or alkaline metal or organic amines (tri alkyl(C,-C6)amines) such as triethylamine, or heterocycles such as 1,4diazabi cyclo[2.2.2] octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine or methylpiperidine or amides such as sodium amids, lithium butyl amide or butyllithium.

It is also possible to employ alkali metals, such as sodium, or their hydrides, such as sodium hydride, as bases. Potassium carbonate, triethylamine, sodium hydrogen carbonate 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 formula (IX).

The process is in general carried out in a temperature range from -30'C to +100'C, preferably from -1 O'C to +5 O'C.

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

The compounds of the general formula (IX) are as species new and are prepared char acterized in that, first compounds of the general formula (XII) CN R 17 O-CD 11 E 0 (XII) R 4 in which A, D, E, R' and R" have the abovementioned meaning, are reacted with a catalytic amount of base such as alkali alcoholates e. g. sodium methanolate, sodium ethanolate or sodium propanolate. Sodium ethanolate ist pre ferred.

Suitable solvents for the the procedure are generally alcohols such as methanol, ethanol or propanol. Ethanol is preferred.

The process is in general carried out in a temperature range from O'C to + 60'C, pref erably from room temperature 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 as species new and can be prepared by reaction of compounds of the general formula (XIII) CHO R 17 (XIII) 0- 1 D'E-H in which A, D, E and R" have the abovementioned meaning, 25 with hydroxylamine hydrochloride in the presence of sodium formiate to compounds of the general formula (XIV) CN R 17 0 (XIV) D:E-H in which A, D, E and R" have the abovementioned meaning, 5 and in a next step are reacted with compounds of the general fon-nula (XV) R 4_CO-CH2-T (XV) in which 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 acetone, ethers such as diethyl ether, dioxane or tetrahydrofurane, aceton, dimethylsulfoxide, dimethylfonnamide or alcohols such as methanol, ethanol, propanol or halogenohydrocarbons such as dichlormethane, trichloromethane or tetrachloromethane. Acetone and dimethylforrnamide are preferred. 25 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 (IX) in which R 14 denotes NF12 can be prepared like described above or in a single step procedure by reacting compounds of the general formula (XIV) with compounds of the general formula (XV) in the presence of a surplus of sodium ethylate under reflux 5 The compounds of the general formula (XIII) can be prepared by reaction of compounds of the general formula (XVI) CHO HO_CA I (XVI) D E-H in which 10 A, D and E have the abovementioned meaning with hydroxyl protecting agents of the general formula (XVII) R 17_Zt (XVII) in which R 17 has the abovernentioned meaning 20 and ZY denotes a leaving group such as halogen, preferably chlorine, bromine, mesyl or tosyl, 25 in inert solvents, preferably acetone or dimethylfonnarnide, and in case A and D form a heterocycle, by reaction of compound of the general formula (XVIII) A CH 2 -OH R 17 0 ' D 1_ E-R 18 (XVIII) in which A, D, E and R have the abovementioned meaning, and R 18 denotes methyl, with MnoJollowed by BCI, / CH2Cl2' The compounds of the general formulae (111), (V), (VII), (VIII), (X), (XI), (XV) and (XVIII) are known and in some cases new and can be prepared by customary methods.

The compounds of the general formulae (11), (IV), (VI), (IX), (XII), (XIII), (XIV), (XVII) and (XVIII) are new or can be prepared like described above.

Surprisingly it was found that compounds given by the general formula (I) inhibited oxygen radical formation as well as TNFcc (tumor necrosis factor) production. These compounds elevated cellular cyclic AMP by inhibition of phagocyte phosphodiesterase (PDE) activity.

The compounds according to the invention specifically inliibit the production of super oxide by polymorphonuclear leukocytes (PNIN). Furthermore, these compounds inhibit TNFoc release in human monocytes in response to a variety of stimuli including bacte rial lipopolysaccharide (LPS), complement-opsonized zymosan (ZymC)b) and IL-13.

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

They can therefore be employed in medicaments for the treatment and prevention 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 em physema, alveolitis, shock lung, all kind of COPD, ARDS, asthma and bronchitis, cys tic fi brosis, eosinophilic granuloma, arteriosclerosis, arthrosis, inflammations of the gastro-intestinal tract, myocarditis, bone resorption diseases, reperfasion injury, Crohn's disease, ulcerative colitis, system lupus erythematosus, type 1 diabetes mellitus, psoriasis, anaphylactoid purpura nephritis, chronic glomerulonephtritis, inflammatory bowel disease, other benign and malignant proliferative skin diseases, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, sepsis and septic shock, toxic shock syndrome, grafts vs host reaction, allograft rejection, treatment of cytokine mediated chronic tissue degeneration, rheumatoid arthritis, arthritis, rheumatoid spondylitis and osteoarthritis and coronary insufficiency, myal gias, multiple sclerosis, malaria, AIDS, cachexia, prevention of turnor growth and inva sion of tissue, leukernia, depression, memory impairment and acute stroke. The com pounds according to the invention are additionally suitable for reducing the damage to infarct tissue after reoxygenation. In this case the simultaneous administration of al lopurinol to inhibit xanthine oxidase is of advantage. Combination therapy with super oxide 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 me dium.

2. Inhibition of FMLP-stimulated production of superoxide racidal anions.

Neutropl-iils (2.5 x 10' ml-') were mixed with cytochrome C (1.2 mg/ml) in the wells of a microtitre plate. Compounds according to the invention were added 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 tg x ml-1) the plate was incubated for 5 min at 37'C. Neutro phils were then stimulated by addition of 4 x 10-' M FMLP and superoxide gen eration measured as superoxide dismutase inhibitable reduction of cytochrome C by monitoring the OD,,, in a microtitre plate spectrophotometer, e.g. a Ther momax microtitre plate spectrophotometer, Initial rates were calculated using a kinetic calculation programme such as a softmax programme. Blank wells con tained 200 units of superoxide dismutase.

The inhibition of superoxide production was calculated as follows:

[1-((Rx-Rb))] -100 % inhibition ((Ro - Rb)) Rx = Rate of the well containing the compound according to the invention.

Ro = Rate in the control well.

Rb = Rate in the superoxide dismutase containing blank well.

Compounds according to the invention have IC,, values in the range 0.00 1 [tM- I M (see Table B).

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 3 7'C before addition of 4 x I V M FMLP. After 6 min protein was precipitated by the addition of I% v/v cone. HCI in 96% v/v ethanol containing 0.1 mM EDTA. After centrifugation the ethanolic extracts were evaporated to dryness under N2 and resuspended in 50 mM Tris/HCI 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 Amersharn International p1c.

Cyclic AI\4P concentrations were expressed as percentage of vehicle containing control incubations.

Compounds elavate the cAMP-level at I pM compound 0-400% 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 discrete stereospecific site on the phosphodiesterase en zyme. Compounds according to the invention had IC50 values ranging from 0,00 1 pM to I tM (see Table 3).

5. Assay of human platelet phosphodiesterase This was performed essentially as described by Schmidt et al. (Biochem. Phar macol. 42, 153-162, 1991) except that the homogenate was treated with vanadateglutathione as above. Compounds according to the invention had 'C50 values greater than 100 iM.

6. Assay of binding to the rolipram binding site in rat brain membranes This was performed essentially as described by Schneider et al. (Eur. I Pharmacol. 127, 105-115, 1986). Compounds according to the invention had IC,, values in the range 0. 0 1 to 10 iM.

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 0 10 Monocytes (I x 10' ml-') were stimulated with LP S (2 pg ml-') and coincubated with the compounds at different concentrations (10' to 10 [tg ml-'). Compounds were dissolved in DMSO/medium (2% v/v). The cells were incubated in RPMI 1640 mediw-n glutaniine/FCS supplemented and at YC in a humidified atmos phere with 5% C02. After 18 to 24 hours TNF was determined in the super natants by an human TNF specific ELISA (medgenix). Controls were non stimulated and LPS stimulated monocytes without compounds.

9. Endotoxin induced shock lethality in mice B6D2FI 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 chal lenged mice without compound. Mice were dying 8 to 24 hours post LPS chal lenge.

The galactosamine / LPS mediated mortality was reduced.

10. Stimulation of human monocytes and determination of cytokine levels Human monocytes (2xlO' in I ml) were stimulated with 100 ng/ml LPS, 0. 8 mg/mI zymC3 b or 10 ng/mI IL- 113 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 37'C. 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-TNF(x antibody IP300 (Genzyme) and the detection antibody was a polyclonal anti-rabbit IgG alkaline phosphatase conjugate (Sigma). IL- 10 was determined by ELISA (Bio source).

Table B

Ex.-No. IC5002- 1AM1 IC50PDE IV [AM] 1 0.008 0.006 6 0.07 0.05 8 0.01 0.015 11 0.008 0.01 24 0,025 0.04 33 0.03 0.016 0.03 0.009 43 0.047 0.042 The new active compounds can be converted in a known marmer into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, nontoxic, pharmaceutically suitable excipients or solvents. In this connection, the therapeutically active compound should in each case 15 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, 20 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 em ployed using suitable liquid vehicles.

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 minimurn 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 for thin layer chromatography:

a) Dichloromethane/methanol 15:1 b) 11 it 20:1 c) 11 ri 50:1 d) Ethyl acetate e) Cyclohexane/acetone 2:1 f) Toluene/Ethyl acetate 1:1 g) Dichloromethane/methanol 40:1 h) Chorofonrl/methanol/water/acetic acid 70:30:5:5 i) Dichloromethane/methanol 10:1 Starting compounds Example 1

4-Benzyloxy-2-hydroxy-benzonitrile o',aCN OH 3 4 g (0, 15 mol) 4-benzyloxy-2-hydroxy-benzaldehyde, 12 g (0, 17 mol) hYdroxylarnme hydrochloride and 19 g (0,29 mol) sodium formiate in 170 ml fonnic acid were stirred at 5TC for 19 h. After cooling the mixture was poured on 200 mI ice/water. Extraction with CH2C12. evaporation of the solvent and chromatography on silica gel Arith tolu ene/ethyl acetate yielded 12 g (35%) of the title compound.

m.p.: 135-136'C Example 11

4-Allyloxy-2-hydroxy-benzonitril CN 0 'la 0 H Example 11 was prepared from 4-allYloxy-2-hydroxy-benzaldehyde in analogy to ex ample 1.

Example 111

3-Amino-6-benzyloxy-2-(2,4-dichlorbenzoyl)-benzofuran NH 2 0 0 0 cl 1 g compound of example 1 (44 mmol) and 5,98 g sodium ethylate (88 mmol) were refluxed in 180 ml ethanol. 30.8 g (o-bromo-2,4-dichloroacetophenone (96 mmol) were added dropAise over a period of I hour to the refluxing reaction mixture. After 7 hours the mixture was cooled to room temperature, the solvent was distilled off and the resi- due further purified by chromatography (CH2CI2, Silicagel 60).

Yield: 11. 6 g (63 %) Mp.: 150'C The following examples were prepared in analogy to example III: 15 Table 1:

0 0- 0 R 23 R 19 R 22 R 20 R 21 Example R 191R2/ R 2V R 22 / R 23 Mp. C0 1V Cl M/11/IM 140 v H/WC1M/F1 1 -3 7 V1 WCM 155 Vil CL1H/H/C1/F1 141 Vill F1/C1/C1/11/H 163 IX Cl/CUI-11" 171 Example X

6-Benzyloxy-2-(2,4-dichlorobenzoyl)-3-ureido-benzofilran NH-CO-NH 2 0 0 0 0" Cl 1 Cl To 12 g (29 mmol) compound of example III in 350 rril dry CH2C12 2,6 mI (29,8 mmol) chlorosulfonyl isocyanate was added at O'C. After 1 h at room temperature the mixture was evaporated to dryness. After the addition of 380 ml water, the mixture was stirred for 1.5 h at WC. Filtration yielded 12,4 g (95%) of the title compound.

M.p.: 189-19PC The examples shown in Tables Ila and b are prepared in analogy to the procedure for the compound of example X Table Ila structure NH-CO-NH 2 CCO" I -CO R C H lo 6 5 -R 11 NO, R R III Ex,No. R1 R11 R1II RIV Yield Rf (% of theory) X a OCH3 H OCH3 H 69 0.30b) X b F H F H 82 0.279) X c cl H H H 90 0. 1 8c) X d H H cl H 48 0.5 1 b) X c cl H H cl 92 0,47b) Xf CH3 H CH3 H 57 0,45b) Table 11 b:

0 NH2 N H 0 0 0 R 23 R 19 R 22 R 20 R 21 Example R 19/R2'/R"/R 22/R23 Mp. (00 X g Cl/F1/C1/11/H > 280 X h F1/C1/H1H/14 180

Claims

X i CIAIMIC1/H 229 xi Cl/H/H/WCI 230 k CH/H 205 1 Cl/C1/11/H1H 223 m F1/C1/CU" 214 n H/H/C1M/F1 220 Example Xl 2-(2,4-Dicl-dorobenzoyl)-6-hydroxy-3-ureido-benzofuran 0 z:::( N H 2 N H 0 HO 0 Cl 1 Cl 700 mg (1,5 rnmol) compound of example X in 15 mI THF were hydrogenated at atmospheric pressure with 10% palladium on charcoal. Filtration over silica gel and evaporation gave the title compound in quantitative yield. m.p.: 23 0-23 I'C 5 The following examples were prepared in analogy to example XL Table Illa: 0 NH 2 y HO 0 R R [v R 11 R Ex.-No. R' W' R R Yield R (% of th.) f XI a F H F H 90 0,76 h) X1 b H H cl H 40 0,38 a) xl c OCH3 H OCH3 H 88 0,38 a) X1 d cl H H H 91 0,3 6 a) X1 e cl H H cl 91 0,3) 1 b) X1 f CH3 H CH3 H 58 0,26 b) Table 111 b: Ex.-No. Structure XI g NH 2 NH 0 f 1 1 CH 3 HO 0 - 'N CH 3 Example XII 2-Hydroxy-6-methoxy-nicotinaldehyde H 3CC) ---nN 0 H 8,4 g (0,05 mol) 2,6-dimethoxynicotinaldehyde was dissolved in 75 ml methylene chloride. At O'C 200 mI (0,2 mol) 13C13 as 1 -molar solution in methylene chloride was added and stirred at room temperature for 20 h. The mixture was poured on ice/water, neutralised and extracted with methylene chloride. Evaporation of the solvent afforded 5,7 g (75%) of the title compound. Example XIII 2-Hydroxy-6-methoxy-rcotinordtrile CN H 3C0 N OH Starting from Example XII, the title compound was prepared in analogy to example 1. Yield: 22% m.p.: 232'C 10 Example XIV 3-Amino-6-methoxy-3a,7a-dihydro-furo[2,3-b]pyridin-2-yl)-(2,4dichlorophen yl)methanone NH 2 H 3 C, 1 1 0 0 N 0 cl 1 cl Starting from example XIII, the title compound was prepared in analogy to example III. Yield: 94% m.p.: 259-60'C Example XV 3-Amino-6-hydroxy-3a,7a-dihydro-furo[2,3-b]pyridin-2-yl)-(2,4-dichloropheny l)methanone NH 2 H 0 N 0 0 1 cl cl 1 g (3 mmol) of the compound of Example XIV was dissolved in 25 mI toluene. 2,8 g (21 mmol) AIC13 was added in portions at 25'C. The mixture was then stirred under reflux for 1 h. After cooling the mixture was poured on ice. Extraction from ethylacetate, evaporating the solvent and recrystallisation from ethylacetate yielded 0,73 g (75,3%) of the title compound. m.p.: > 305'C Example XVI 15 [2-(2,4Dichloro-benzoyl)-6-hydroxy-3 a,7a-dihydro-furo [2, 3 -b] pyridin-3 -yl]urea 0 z:: N H 2 N H 0 HO N 0 c 1 cl The title compound was prepared in analogy to example X, starting from example XV. Yield: 86% Rf: 0.26 (i) Example XVII 2-(2,4-dichlorobenzoyl)-6-(3-hydroxy-2-methylene-l-propyloxy)-3-urcidoben 7-ofuran 5 0 NH2 N H a HO "-r 0 1 0 1 1 0 cl cl To a solution of 4,5 g (12 mmol) compound of example Xl, 1 nil (12 mmol) 2-meth ylen-1,3-propanediol and 3,2 g (12 mmol) triphenylphosphine in 90 mI dry Tetra hydrofurane 2 ml (12 nunol) diethyl azodicarboxylate was added at O'C. After 4 h at O'C the solution was diluted with methylene chloride, water was added and the organic layer was separated. Evaporation and chromatography on silica gel with toluene ethyl acetate yielded 3,5 g (66%) of the title compound. Rf. 061 (d) Example XVIII 2-(2,4-Dichlorobenzoyl)-6-(4-hydroxy-buty-2-enyl- 1 -ox)-')-ureidobenzofuran 0 zz N H 2 HO N H 0 0 0 cl cl Example XVIII was obtained from example M in analogy to example XVII. m.p.: 175-177C Example XIX [6-Allyloxy-2-(2,4-dichloro-benzoyl)-3a,7a-dihydro-furo(2,3-b)pyridin-3 3y1Jurea 0 z:: N H 2 N H 0 0 N 0 cl 1 cl 1,1 g (3 mmol) of the compound of Example XVI, 0,42 g (345 mmol) 3- brompropene and 0,41 g (3 mmol) K2CO3were mixed in 30 ml acetone and refluxed for 3 h. After cooling the mixture was poured in 20 rril water. Extraction with ethyl acetate, evapora- tion of the solvent and recrystallisation from ethanol afforded 0,12 g (9, 8%) of the title compound. m. p.: 222'C 0 15 The compounds in table IV are prepared in analogy to example XIX Table IV: oz"t NH Feb Q 0 0 4 Fe Ex,No. R's Q R24 Yield M.P. (%) (OC) a CH3 CH 93 163-4 cl CH 3 XIX b C H 3 CH cl 57 193-4 1 cl XIX C CH 3 CH 50 175-6 cl XIX d C H3 CH cl 71 189-90 1 cl X1X e CH 2 CH &Cl 83 180 - 0 Ex,No. R 25 Q R24 Yield M.P. (%) (00 XIX f CH 2 CH cl 42 226 XIX g F " CH cl 91 122-4 CH 2 1 Z, cl )C[X h C H 2 CH 71 214 S cl xix i CH2 CH cit cl 60 230 xixj F N cl 45 Rf: 0.45 CH 2:' 1 1.1 1 1 1 cl 1 1 0 Preparation Examples Example 1 2-(2,4-Dichlorobenzoyl)-6-(2,3-dihydroxy-l-propyloxy)-3-ureido-benzofuran 0 z:::( N H 2 N H H 0 "" 0 0 1 0 0 H cl c 1 To a solution of 129 mg (1,1 mmol) N-methyl morpholine-N-oxide (NMO) and 0,3 mI osmium tetroxide (2,5% solution in t-butanol) in 5 m.I water and 10 ml acetone 405 mg (1 nimol) compound of example X g and 5 ml acetone were added at room temperature. After 47 h additional 129 mg NMO and 0,3 mI osmium tetroxide were added. After another 3 d dichloromethane and 1 N hydrochloric acid was added. The precipitate was separated and triturated with methanol to give 289 mg (66%) of the title compound. m.p.: 194-195'C The following examples were prepared in analogy to example 1: Table V Ex, Structure isomer m p. ("c) yield Rf No. (% of N1t 0 NH (R)- 2 0 ENANTIOM 35 0.30 d) cl ER OF Ex, HO"' 0 No. 1 OH cl NI 0 J1, NH (s)- 3 1 0 ENANTIOM 18 0.30 d) HO 0 U cl ER OF Ex. No. 1 OH CA N H 0 -_: NH 0 4 CH. RACEMATE 191-95 HO -,-o OH CH 3 W 0 ---- NH 0 OH cl 180-85 HO Ex, yield No. Structure isomer m p. ('C) Rf (% of 0 W OH 6 0 RACEMATE 157-8 91 OH a cj 0 W OH 1 MIXTURE ---o 0 OF 7 277-8 55 OH cj DIASTEREO MERS cl 2 0=NH NH 8 HO 0 RACEMATE 180-4 91 a HO":-"'0 0 OH 0 Y W OH MIXTURE 0 9 --,---no 0 OF 201-2 31 OH DIASTEREO MERS EX, Structure isomer mp. (CC) yield Rf No. (% of 0 Y NH2 OH 1 1 0 0 OH cl RACEMATE 186-7 48 i cl 0 Y M 1 1 0 HO ---o N 0 11 OH Cl RACEMATE 150-2 61 1 0 Y N1-12 OH 1 1 0 0 12 HOI---0 RACEM-ATE 184-6 90 Cl 0 Y NH 2 NH 0 MIXTURE 0 OF 13 OH Cl DIASTEREO 115-7 94 1 MERS cl 0 Ex, Structure isomer m p. (I C) yield Rf No. (% of NH2 0 NH 0 14 1 cl 175 43 HO'COX 0 OH 0 Y W HO 0 0 0 RACEMATE 211 70 0.46 d) OH cl 1 cl 0 Y NH2 OH 1 1 0 " F 0 0 16 t0H 137-8 98 cl 1 1 0 Y NH2 1 1 0 (R) 0 0 HO 17 "OH ENANTIOM 204-5 cl ER OF Ex. No. 12 OyNH 2 18 0 208 64 0.46 d) HO -no 0 OH cl 1 0 Ex, Structure isomer mp. (OC) yield Rf No. (% of 0 Y NH 2 1 0 19 HO 0 0 224 90 0.52 d) OH cl 1 cl 0 Y NH2 NH OH 0 0 0 ENANTIOM OH cl ER A OF Ex.- 192 No. 10 cl 0 Y NH2 NH OH 0 0 0 ENANTIOM 21 ER B OF Ex.- 192 OH cl 1 No. 10 cl 0 H2N NH 22 1 \\ C0 cl 223 1,5 0.16 a) oiro HO I'n 0 cl- OH Ex, Structure isomer rup. (OC) yield Rf No. (% of 0 NH 23 C0 179-83 25 0,33 a) OúCO HO OH 0 Y NH 2 1 MIXTURE 24 HO 0 0 OF 163 H OH cl DIASTEREO j MERS cl Q NH2 NH HO 0 0 218 50 0 Y NH2 1 1 R- 26 HO"- 0 0 ENANTIOM 1 16-8 32 > 0 OH cl ER 1 cl __j 0 0 Ex, yield Structure isomer mp. (0 C) Rf No. (% of 0 Y NH2 HO 0 0 0 DIASTEREO C 27 125 H MER A OH cl 1 cl 0 Y NH2 0 DIASTEREO HO 0 0 28 125 H OH cl MER B 1 cl NH2 1 0-5:::", NH 29 1 C0 Cl DIASTEREO 130 27 d) ojc:co\, HC)" MER A 0.40 OH cl 0 NH MIXTURE 01 - C0 a OF 0.30 0"Cl 110-120 60 d) HO"-"' DIASTEREO 0.40 OH 0 MERS CA Ex, Structure isomer mp. (0c) yield R No. (% of W 0,J, NH MIXTURE OH ', \\ C0 cl OF 31 HO 130-3 30 0,16 b) 0, DIASTERE0 MERS 0 0 1 cl W 0 --, NH MIXTURE 32 1 '-'- \\ C0 cl OF 92-120 65 0, 16 (b) DIASTEREO HO 0 0 MERS OH 0 cl 1 NH 2 0 NH MIXTURE x OF 33 C0 cl 98-108 68 0,2 (b) HO" 0"' 0 DIASTEREO MERS OH}i cl 0 Y NF OH 34 0 0 RACEMATE 198-9 94 OH cl 1 cl NH 0 --- NH HO-C C0 cl 216-218 78 0, 14 (a) OH 0, C.;'. 0\11 0H OH cl--z Ex- Structure isomer mp. (OC) yield Rf No. (% of NH 2 OH 0 NH 36 OH i \, C0 a 170-80 20 0,02 (b) i -: \ HO"' 0 OH 0 cl NH 2 NH MIXTURE 37 \\ C0 a OF 107 83,5 0,14 (c) HT' 0 DIASTEREO MERS OH Nb 0 --i\ NH 38 1 \\ C0 cl 153-9 84 0, 1 (b) HO L 0 r, \- 0 OH cl NF NH 39 C0 a DIASTERE 231 50 0,6 (a) HO'' "0' 0 OMER A H cl 0 H,N'NH 0 OH 1 cl RACEMATE 191-2 25 HOI" cl Ex, Structure isomer m p. CC) yield Rf No. (% of 0 bN-kNH 0 MIXTURE 41 OH 1 cl OF 1156 71 0 DIASTEREO MERS OH cl 0 Y NF- NH HO 0 0 DIASTEREO c 42 122 13 H OH cl MER A 1 cl 0 Y NH2 NH OH 43 HO 0 J 0 RACEMATE 115-6 89 cl 1 __1 cl oym- W HO OH 0 44 0 cl RACENIATE 134-5 81 cl W 0 NH 0 67 0.25 HO -,-o U - OH Ex, Structure isomer nip. (0 C) yield Rf No. (% of NH2 0 NH 0 46 HO- quant.0. 12 0 H10 N _r HO 0 Y Nft NH 47. HO 0 0 0 DIASTEREO H C 140-1 16 OH cl MER B cl O"N' 0 0,, 48 0 DIASTERF-0 102-3 6 HO 0 0 MER A H C OH cl 0 Y NI. OH ENANTIOM 49 0 0 0 ER A OF Ex.- 198-9 13 No. 34 OH cl 1 cl 0 Y W OH 1 0 ENANTIOM 0 0 ER B OF Ex.- 198-9 15 OH cl No. 34 1 cl 1 1 1 1 Ex, Structure isomer mp. CC) yield Rf No. (% of W OH o5 NH OH i \\ CO CA DIASTEREO 105 d) \1 51 0) 1.- 0 MER A (dec.) 30 0.88 cl NF OH 0 NH OH 52 CO a DIASTERE 110 40 0.72 d) 0 OMER A cl,, 0 cl NH 2 OH 0 -- NH 0 53 F F CO cl DIASTEREO 136 8 0.86 d) H \1 1 o, 0 MER A F: F 0 F cl NH OH NH OH 54 F CO a DIASTERE0 115-120 10 0.82 d) 0 0 MER A (deC.) F NH2 OH NH 0 1 5 0 o\ CO cl DIASTEREO 116-124 20 0.68 d) -1 '1, l. i cl 0 MER A 0-0 Ex, Structure isomer mp. (0c) yield Rf No. (% of NH2 OH 0 NH 56 0\1 C0 Cl DIASTEREO 130 20 0.70 d) 1 0 MER A (dec.) i "C 0 0 Cl 1 1 Nb OH 0 --- NH 57 OH 1 -,, \, 00 Cl DIASTERE0 170 7 0.20 ') 0 i ' --; 0 MER A (dec.) Cl W OH 0 --- NH MIXTURE C0 Cl OF 0.65 - 58 11 0\ 1 -110 25 d) 0 DIASTEREO 0.70 1: 0 MERS GIC, NH2 NH 0 59 HO:r 1 460.2 0 C 0 - OH N W 1 OH NH OH MIXTURE 1 Go a OF 10 0.20 C 0 0 DIASTERED 0.26 c) 0 MERS a Ex, yield No. Structure isomer mp. C0 (% of Rf NF OH 0 --1, NH 0 61 F cl 200 22 0.80 d) H CO o',' 0 (dec.) OH 0 NH ) MER A 62 DIASTEREO 133-140 20 0.74 d) 0 cl OH CO, NH 0 H 63 CO Cl DIASTEREO 152-154 22 0,28 0 CA 0 MER A W 1 OH CO, NH OH C0 c MIXTURE 64 0 A OF 10 0.29 f) el3 C) DIASTEREO MERS cl 1 NH2 1 C0 OH "NH OH i "- \, C0 cl DIASTEREO 38 0. 16 f i 11.1- MER A C99 0 0 0 cl Ex, Structure isomer m p. ('C) yield Rf No. (% of NV 1 C0 OH NH OH MIXTURE 66 C0 cl OF 15 0.72 f) cgig 0 0 DIASTERE0 0 MERS CA 0 Y NH2 1 0 R 67 0 ENANTIOM 200 18 d) 0.46 OH cl ER 1 cl 0 Y NH 2 NH 1 1 SO- 68 0 ENANTIOM 205 23 d) HO -,-,o 0 0.46 OH cl ER 1 cl 0 Y NH2 , r, 69 1 0 RACEMATE 209-214 95 0.26 d) HO -'^o 0- OH S cl 0 Y W NH "", 0 RACEMATE 200 42 0.35 d) H0 1"ro 0 0 %J cl OH CA We claim:

1. Oligohydroxyl 3-urea-benzofurane- and pyridofurane-denivatives of the general formula (I) 5 L NRI1- NR 2 R 3 U CO-R 4 in which A and D including the double bond connecting them together form a phenyl-, pyridyl-, pyrimidyl, pyridazinyl-, pyrazinyl- or thienyl-ring, which is substituted by a group of a formula -OR' wherein R 5 denotes straight-chain or branched alkyl having 1 to 15 carbon atoms, which is substituted difold to fivefold by hydroxyl or di fold to fivefold by straight-chain oder branched alkoxy having 1 to 6 carbon atoms and wherein alkyl is optionally substituted by straight-chain or branched alkoxycarbonyl having 1 to 6 carbon atoms, halogen, carboxyl, (C3-C,)-cycloalkyl or by phenyl, which is optionally substituted monofold to fivefold by rdtro, halogen or phenyl, E represents an oxygen or sulfur atom, R' represents hydrogen, straight-chain or branched alkyl having I to 4 carbon atoms, an aminoprotecting group or a group of the formula -CO-R 6 in which 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, or R' and R' together with the nitrogen atom form a 5-, 6- or 7-membered saturated heterocycle optionally having a further oxygen atom, R 4 represents aryl having up 6, 7, 8, 9 or 10 carbon atoms or 20 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 7 25 wherein R 7 denotes hydrogen or straight-chain or branched alkyl or alkoxycarbonyl 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 hy droxyl, halogen, nitro, 1H-tetrazolyl, pyridyl, trifluoromethyl, trifluo romethoxy, difluoromethyl, difluoromethoxy, cyano, carboxy, straight chain or branched alkoxy, alkoxycarbonyl or acyl each having 1 to 6 carbon atoms or by straight-chain or branched alkyl having 1 to 5 car bon 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 -NRY, -SR", -(NH),-S02R" or -0-S02R 12 in which R' and R' are identical or different and denote hydrogen or a straight chain or branched alkyl having 1 to 4 carbon atoms, or R 8 denotes hydrogen and R' denotes straight-chain or branched acyl having 1 to 6 carbon atoms, W" denotes hydrogen or straight-chain or branched alkyl having 1 to 4 carbon atoms, a denotes a number 0 or 1, W' and W' are identical or different and represent straight-chain or branched alkyl having 1 to 6 carbon atoms, benzyl or phenyl, which are optionally substituted by trifluoromethyl, halogen or straight- chain or branched alkyl having 1 to 4 carbon atoms, L represents an oxygen or sulfar atom 5 and salts thereof.

2. Compounds according to claim 1, in which A and D, including the double bond connecting them form together a phenyl- , pyridyl- or pyrimidyl-ring, which are substituted by a group of a formula -OR' wherein R 5 denotes straight-chain or branched alkyl having 1 to 14 carbon 20 atoms, which is substituted difold to fourfold by hydroxyl, and wherein alkyl is optionally substituted by methoxy, ethoxy, npropoxy, isopropoxy, fluorine, chlorine, cyclopentyl, cyclohexyl or by phenyl, which is optionally substituted monofold to fivefold by nitro, fluorine or chlorine or phenyl, 25 E represents an oxygen or sulfur atom, R' represents hydrogen, straight- chain or branched alkyl having 1 to 4 carbon atoms or a group of the formula -CO-R' in which R 6 denotes straight chain or branched alkoxy having I to 4 carbon atoms, R 2 and R' are identical or different and represent hydrogen, cyclobutyl, cyclo- pentyl, cyclohexyl or straight-chain or branched alkyl, alkoxycarbonyl or alkenyl each having I to 4 carbon atoms, or or R 2 and R' together with the nitrogen atom form a pyrrolidinyl-, piperidinyll- or morpholinyl-ring, and R 4 represents phenyl, pyridyl or thienyl, wherein both rings are optionally monosubstituted to trisubstituted by identical or different substituents from the series comprising hydroxyl, fluorine, chlorine, bromine, nitro, carboxy, straight-chain or branched alkoxy, alkoxycarbonyl or acyl each having I to

3 carbon atoms, or by straight-chain or branched alkyl having I to 3 carbon atoms, which is optionally substituted by carboxyl or methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or iso propoxycarbonyl, L represents an oxygen or sulfur atom, and salts thereof 3. Compounds according to claim I or 2, in which A and D, including the double bond connecting them form together a phenyl- or pyridyl-ring, which are substituted by a group of a formula -OR' wherein R' denotes straight-chain or branched alkyl having 1 to 11 carbon atoms, which is substituted difold to fourfold by hydroxyl, and wherein alkyl is optionally substituted by methoxycarbonyl, cyclohexyl, fluorine or by phenyl, which is optionally substi tuted monofold to fivefold by nitro or fluorine or phenyl, E represents an oxygen or sulfur atom, R' represents hydrogen, methyl, ethyl, n-propyl, isopropyl or a group of the formula -CO-W, in which R 6 denotes denotes methoxy, ethoxy, n-propoxy or iso propoxy, R' and R' represent hydrogen, R 4 represents phenyl or pyridyl, which are optionally up to trifold substituted by identical or different substituents from the series chlorine or methyl, L represents an oxygen atom, and salts thereof.

4. Compounds according to anyone of claims 1 to 3, selected from the following group:

Structure 0:::::::: NH 0 1 cl 1 HO -,--o j) 0 OH cl NH 2 0NH 0 i cl HO""O ""0 0 OH cl o.::::::: - NH 0 1 cl HO -""o J G 0 OH cl Structure NH 2 0NH 0 1 HO "no j) 0- OH NH 2 0 -_:: -- ( NH 0 OH 1 cl 1 HO," 0 1 0 - ' HO cl 0 y NH 2 OH 1 1 NH 0 ,o 0 OH cl 1 cl 0 _y NH 2 ---- OH 0 1 o- 1 NH 0 OH cl 1 cl Structure 0=NH 2 NH HO- 0 cl HO"O 1 0 ", GC( OH cl 0 y NH 2 OH 1 1 NH 0 ---o 0 OH 0 y NH 2 1 14 r-i OH 1 1 o 0 0 H cl 1 cl 0 y NH 2 llin 1 1 0 HO ---O N 0 OH cl 1 cl Structure 0 y NH 2 NH HO OH 0 0 1 0 cl 1 cl 0 NH 2 y 1 0 0 0 OH cl 1 cl NH NH 2 0 -A NH 0 1 cl HO "" 0 0 - OH cl OYNH 2 Wi HO 1"ro 1 0 1 0 OH cl 1 cl Structure 0 y NH 2 NH OH 0 --OH 1 cl 0 NH 2 0 cl 1 cl 0 y NH 2 114 v] HO"'T""O 1 0 1 0 OH cl 0 y NH 2 0 HO 0 OH cl 1 cl Structure 0 y NH 2 114 n OH 0 0 0 OH cl 1 cl 0 y NH 2 OH 0 0 OH cl i cl 0 H 2 N- NH 1 \" co cl HO --"-oil 0 - OH Cl H 2 W NH 1 ' -, z \" co HO --Oil 0 cl OH 0b- Structure 0 y NH 2 NH 0 HO 0 0 H OH cl I - 1 cl HO---\--- 0-/ NH 2 NH HO 0 cl 0 y NH 2 0 HT' O OH cl 1 cl 0 _y NH 2 NH OH J ", 0 1 0 OH %, cl cl Structure NH 2 NH HO 1 ' --, \" co c 1 0,-CCO 0 H C, NH 2 OH NH OH 1 \,, co cl HO',' 0 ajo H cl 0 NH 2 0-- 1 NH i co cl 1,1 ll.;

5 \" , "",c 1 0 HO 0 OH cl 0 H 2 N-']NH 0 OH 1 cl F ",-r 0 JJ 0 - ' HO cl Structure 0 y NH 2 NH 0 HO 0 0 H 5H cl - 1 cl NH 2 0--, NH 0 HO 0 OH NH2 0 -- NH 0 HO" 0 J:D 0 - HO N HO 0 _y NH 2 NH HO co 0 OH cl 1 ci Structure 0 y NH 2 OH N Hn 0 0 0 OH cl 1 cl 0 y NH 2 OH 1 1 0 --- 0 0 OH cl INJ H 0 rio cl, NH 2 0 --- NH 0 HO F 0 j 0 N OH 0 y NH 2 mn H 0 0 OH 1 "Z cl 1 11ll cl A Structure 0 NH 2 NH 0 HO 0 0 OH ci 1 cl 0 Y NH 2 NH HO 0 0 H OH cl cl 0 Y NH 2 NH 0 HO 0 0 1 cl -:,1 cl 5. A process for the preparation of the compounds of the general formula (1) characterized in that, that in the case in which R' denotes alkyl substituted by two vicinal hydroxylgroups [A] compounds of the general formula (11) A A R 14 F I - 11 4 HO _CD E CO-R in which R', A, D and E have the abovementioned meaning, 5 and R 14 denotes a residue of a formula L -NH 2 or 2 wherein L has the abovementioned meaning, first are reacted with compounds of the general formula (III) R 15 -CH2-Z' all) in which R" denotes straight-chain or branched alkenyl having I to 9 carbon atoms, which is optionally substituted by phenyl, biphenyl or optionally nitro or halogen-substituted phenyl and/or halogen, and zi denotes a leaving group such as mesyl, tosyl, chlorine, bromine or io dine in inert solvent and in presence of a base to compounds of the general formula (IV) A R 14 R 1 5 -H C 0 E CO-R 4 in which 5 A, D, E, R4, R 14 and W' have the abovementioned meaning.

and in a last step reacted with osmium-tetroxide (0s04) / NmethyImorpholinoN-oxide in inert solvents, 10 or in the case in which R' denotes alkyl substituted by two to five hydroxyl groups [B] compounds of the general formula (11) are reacted with compounds of the general flonnula (V) C-CH201-1 (V) in which R 16 denotes straight-chain or branched alkenyl having 1 to 9 carbon atoms, which is optionally substituted by hydroxyl, in inert solvents and in the presence of triphenylphosphine / diethylazodicarboxylate to compounds of the general formula (V1) A R 14 4 R'6-H2C-OC E CO-R (VI) in which A, D, E, R 4, R 14 and R 16 have the abovementioned meaning and in a last step are reacted with OsO,/N-methylmoipholino-N-oxide (in solvents, or [C] compounds of the general fonnula (11) are reacted with alcohols of the general formula (VII) R'-OH (VII) in which R' has the abovementioned meaning 20 in inert solvents and in presence of triphenylphosphine / diethylazodicarboxylate or 25 [D] compounds of the general forrnula (II) are reacted with the compound of the formula (VIII) CH 2-OH (Vill) 0 in inert solvens and in the presence of a base and titanium-(IV) isopropylate and in the case in which R1, R 2 and/or R':P-- H the free amino groups are denvated optionally by common methods.

6. Oligohydroxyl-substituted 3-urea-benzofurane- and -Pyndofurane derivatives according to any one of claims 1 to 4 for therapeutic use.

7. The composition containing at least one oligohydroxyl 3-ureabenzofurane- or pyridofurane-derivative according to any one of claims 1 to 4 and a pharmaco logically 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 compositions accoding to claim 7 and 8 char actenzed in that the oligohydroxyl-3-urea-benzofurane- or pyndofurane derivative together with customary auxiliaries is brought into a suitable application form.

10. Use of oligohydroxyl 3-urea-benzofurane- or pyridofurane-derivatives ac cording to anyone of claims 1 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 infiammatory processes.

12. Oligohydroxyl substituted 3-urea-benzofurane and pyridofurane derivatives of the general forn-lula (IV) R 14 4 (M R is- H 2 C_OG1E CO-R in which A, D, E and R4 have the abovementioned meaning, R14 denotes a residue of a formula L 11 -NH 2 or -NH-C-NH 2 in which L has the abovernentioned meaning 15 and R15 denotes straight-chain or branched alkenyl having up to 9 carbon atoms, which is optionally substituted by phenyl or optionally nitro- or halogen-substituted phenyl and/or halogen.

13.Compounds of the generala formula (V1) R 14 4 (VI) i j R 16 _ H2 C_OCE CO-R 1 in which A, D, E, R4 and R14 have the abovementioned meaning and R16 denotes straight-chain or branched alkenyl having up to 9 carbon atoms, which is optionally substituted by hydroxyl.