GB2350112A

GB2350112A - Pharmaceutically active cycloalkyl ketones

Info

Publication number: GB2350112A
Application number: GB9911458A
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: GB9911458D0; WO2000069843A3; WO2000069843A2; AU4755200A

Abstract

Compounds of the general formula (I) <EMI ID=1.1 HE=25 WI=82 LX=671 LY=884 TI=CF> <PC>wherein the various symbols are as defined in the specification, and salts thereof are useful for the treatment of inflammatory conditions. Corresponding intermediates in which NR<SP>1</SP> (C=L) NR<SP>2</SP>R<SP>3</SP> is replaced by R<SP>27</SP> and the ring containing A and D is substituted by R<SP>28</SP>-CH<SB>2</SB>-O or R<SP>29</SP>-CH<SB>2</SB>-O, the symbols being as defined in the specification, are novel compounds.

Description

2350112 Cycloalkyl. substituted 3-Urea-benzofurane- and

-pyridofurane-derivatives The invention relates to Cycloalkyl substituted 3-urea-benzofurane- and - pyridofuranederivatives, 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. TNFcc, IL-1 or IL-6) and anti- inflammatory cytokines (e.g. IL-10) play a pivotal role in host defence 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 oxygen radical production and that Us cell function is more sensitive than others such as aggregation or enzyme release. 15 Benzofuran- and benzothiophene derivatives having phosphodiester (PDE IV)inhibiting action are described in the publication EP 731 099. In order to provide alternative compounds with similar or improved PDE IV-inhibiting action, the present invention relates to Cycloalkyl substituted 3-urea-benzofurane- and -pyridofurane20 derivatives of the general formula 0) L NR'U- NR 2 R 3 E CO-R 4 in which A and D including the double bond connecting them together form a phenyl-, pyridyl-, pyrimidyl, pyridazinyl- or thienyl-ring, which are substituted by a group of a formula -OR' wherein R' denotes straight-chain or branched alkyl having up to 10 carbon atoms, which is substituted difold to fivefold by hydroxyl or difold to fivefold by straight-chain oder branched alkoxy having up to 6 carbon atoms and wherein alkyl is optionally substituted by straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms, halogen, carboxyl or by phenyl, which is optionally substituted by nitro or halogen, or denotes a group of a formula R 6 R 7 N or _S02-G, OH in which R' and R' denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms or by a 5 to 7 membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the series comprising N, S and 0 and to which a phenyl. ring can be fused and which is optionally, including the nitrogenfunction 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 up to 6 carbon atoms, or b.

R6 and R' together with the nitrogen atom form a 5 to 6 membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the series comprising N, S and 0 and to which a phenyl ring can be fused and which is optionally, including the nitrogenfunction, 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 up to 6 carbon atoms, and G denotes a residue of a formula H 3C CH3 or 111MV-11, H or aryl having 6 to 10 carbon atoms or a 5 to 7-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the series comprising N, S and 0 and to which a phenyl ring can be fused, wherein all abovementioned. residues and ring systems are optionally monosubstituted. to trisubstituted by halogen, carboxyl, straight-chain or branched alkyl or alkoxy carbonyl each having up to 6 carbon atoms, pyridyl and/or by a residue of a formula -NR 8_M-R!, -NR'O-CO-NR"R 12, -NR 13_SO2- N14 15 17 18 R R, -S02-R" or-(S02),,-NR R, wherein a denotes a number 0 or 1, m denotes a residue of formula SO, or CO R, W0, R", R 12, R 13, R 14, M, R 17 and M are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, denotes straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, R 16 denotes benzyl, phenyl or methyl, or G denotes straight-chain or branched alkyl or alkenylen having up to 8 carbon atoms, which optionally are monosubstituted to tri substituted by halogen, aryl having up 6 to 10 carbon atoms or a 5 to 7-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the series comprising N, S and 0 and to which a phenyl ring can be fused or by a residue of a formula -NW9R20 or 0 N 0 wherein R and R 2' have the abovementioned meaning of W' and R 12 and are identical or different to the latter, E represents an oxygen or sulfur atom, R' represents hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, an aminoprotecting group or a group of the formula -CO-R" in which R 21 denotes hydroxyl, straight chain or branched alkoxyearbonyl having up to 4 carbon atoms, R' and R' are identical or different and represent hydrogen, cycloalkyl having up to 6 carbon atoms, straight chain or branched alkyl, alkoxycarbonyl or alkenyl each having up to 8 carbon atoms, or R 2 and W together Aith the nitrogpn atom form a 5- to 7-membered saturated heterocycle optionally having a further 0 atom, R' represents cycloalkyl having up 3 to 8 carbon atoms which is optionally monosubstituted to trisubstituted by identical or different substituents from the series comprising hydroxyl, halogen, nitro, IH-tetrazolyl, pyridyl, trifluoro methyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, cyano, carboxy, straight-chain or branched alkoxy, alkoxycarbonyl or acyl each having up to 6 carbon atoms or by straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by carboxyl or straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms or by a group of formula -NR 22 R2', -SR 24, -(NH)b-SO2R25 or _O_SO2R 26, 1 in which R and W' are identical or different and denote hydrogen or a straight- chain or branched alkyl having up to 4 carbon atoms, 5 or W' denotes hydrogen and W' denotes straight-chain or branched acyl having up to 6 carbon atoms R' denotes straight-chain or branched alkyl having up to 4 carbon atoms, b denotes a number 0 or 1, R and " are identical or different and represent straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or phenyl, which are optionally substituted by trifluoromethyl, halogen or straight-chain or branched alkyl having up to 4 carbon atoms, L represents an oxygen or sulfur atom and salts thereof.

The cyclcoalkyl substituted 3-Urea-benzofurane- and -pyridofuranederivatives according 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 cycloalkyl substituted 3-Ureabenzofurane and -pyridofurane-derivatives 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 ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediarnine.

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, ftimaric acid, malic acid, citric acid, tartaric acid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphomic acid or naphthalenedi sulphonic acid. Preferred pyridinium 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 racernate forms, as well as the diastereomer mixtures and individual diastereomers. 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 saturated or unsaturated, preferably 5- to 6- membered, saturated or unsaturated ring which can contain up to 3 oxygen, sulphur and/or nitrogen atoms as heteroatoms and to which further aromatic ring can be fused.

The following are mentioned as preferred: thienyl, furyl, pyrrolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxazolyl, cinnolyl, 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 and D, including the double bond connecting them form together a phenyl- , pyridyl or pyridazinyl-ring, which are substituted by a group of a formula -OR' wherein R 5 denotes straight-chain or branched alkyl having up to 8 carbon atoms, 15 which is substituted difold to fourfold by hydroxyl, and wherein alkyl is optionally substituted by straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms, fluorine, chlorine or by phenyl, which is optionally substituted by nitro, fluorine or chlorine, 20 or denotes a group of a formula R 6 R 7 N or -S02-G, HH in which R' and R' represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl, pyddyl, imidazolyl, pyrryl, morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl, wherein the ring systems are optionally, including the nitrogen function, 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 pyrazolyl-, triazolyl-, tetrazolyl-, imidazolyl-, pyrryl-, morpholinyl-, piperidinyl-, pyrrolidinyl- or piperazinylring, wherein the ringsystern are optionally including the nitrogen function are 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 D represents a residue of a formula H 3C CH3 or H or phenyl, pyridyl, pyrimidyl, thienyl, ftiryl, pyrazolyl, isoxazol yl, thiazolyl, imidazolyl, tetrazolyl, morpholinyl, piperidinyl, pyrrolidinyl or piperazinyl, wherein all abovementioned residues and ring systems are optionally monosubstituted to trisubstituted by halogen, carboxyl, straight-chain or branched alkyl or alkoxy carbonyl each having up to 4 carbon atoms, pyridyl and/or by a residue of a formula -NW-M-W, -NR'O-CO-NR"R 12, -NR B_S02NR 14 R", -S02-R 16 or -(S02)a-NR"R", wherein 5 a denotes a number 0 or 1, m denotes a residue of formulaS02 or CO R8, WO, C, R 12, R 13, R 14, R's, R 17 and W' are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms, denotes straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms, R 16 denotes benzyl, phenyl or methyl, or -20 G represents straight-chain or branched alkyl or alkenylen having up to 6 carbon atoms, which are optionally monosubstituted to trisubstituted by halogen, phenyl, pyridyl, pyrimidyl, thienyl, furyl, imidazolyl, tetrazolyl, morpholinyl, piperidinyl, pyrroli25 dinyl, piperazinyl or by a residue of a formula -NCWO or 0 C N- o wherein W9 and C have the abovementioned meaning of W' and R and are identical or different to the latter, E represents an oxygen or sulfur atom, R' represents hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a group of the formula -CO-W' in which W' denotes hydroxyl, straight chain or branched alkoxycarbonyl having up to 4 carbon atoms, R' and W 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 W and R' together with the nitrogen atom form a pyrrolidinyl-, piperidinyl- or morpholinyl-ring, and represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, which are optionally monosubstituted to trisubstituted by identical or different substituents from the series comprising hydroxyl, fluorine, chlorine, bromine, nitro, tetrazolyl, pyridyl, trifluoromethyl, trifluoromethoxy, difluoromethyl, 30 difluoromethoxy, cyano, carboxy, straight-chain or branched alkoxy, alkoxycarbonyl or acyl each having up to 4 carbon atoms, or by straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by carboxyl or straight-chain or branched alkoxycarbonyl having up to 4 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 up to 8 carbon atoms, which is substituted difold to fourfold by hydroxyl, and wherein alkyl is 20 optionally substituted by methoxycarbonyl, fluorine or by phenyl, which is optionally substituted by nitro or fluorine, or denotes a group of a formula R 6 R 7 N or -S02-G, H in which R6 and R' denote 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 or pyrrolidinyl, wherein the ring systems are optionally, including the nitrogen function, 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- or piperazinylring, wherein the ringsystern are optionally including the nitrogen function are 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, G represents phenyl, pyridyl, pyrimidyl, thienyl, furyl, pyrazolyl, isoxazolyl, thiazolyl, imidazolyl, tetrazolyl, morpholinyl, piperidinyl, pyrrolidinyl or piperazinyl, wherein all above mentioned residues and ring systems are optionally mono substituted to trisubstituted. by halogen, carboxyl,'straight-chain or branched alkyl or alkoxycarbonyl each having up to 3 carbon atoms, pyridyl and/or by a residue of a formula -NR-M-W, -NR'O-CO-NR"R 12, -NR D_S02-NR 14 M5 -SO2-R 16 or _(SOANR 17 R's, wherein 30 a denotes a number 0 or 1, M denotes a residue of formulaS02 or CO R', WO, R", R 12, R 13, R 14, R", R 17 and W' are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 3 carbon atoms, R' denotes straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms, R denotes benzyl, phenyl or methyl, or G represents straight-chain or branched alkyl or alkenylen having up to 4 carbon atoms, which are optionally monosubstituted to trisubstituted by halogen, phenyl, pyridyl, pyrimidyl, thienyl, furryl, imidazolyl, tetrazolyl, morpholilnyl, piperidinyl, pyrroli dinyl, piperazinyl or by a residue of a formula -NR'9W' or 0 N 0 wherein R and R20 have the abovementioned meaning of R and R 12 and are identical or different to the latter, E represents an oxygen or sulfur atom, R' represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms or a group of the formula -CO-W', in which R2' denotes hydroxyl, straight chain or branched alkoxycarbonyl having up to 3 carbon atoms, R2 and W are identical or different and represent hydrogen, cyclobutyl, cyclopentyl, cyclohexyl or straight-chain or branched alkyl, alkoxycarbonyl or alkenyl each having up to 3 carbon atoms, represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl which are optionally up to trifold substituted by identical or different pyridyl, fluorine, chlorine, bromine, methoxy, trifluoromethyl, cyano, 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 atom, and salts thereof.

Very particularly preferred compounds of the general formula (I) are those, in which E and L represent an oxygen atom 30 and W, R' and R' represent hydrogen and salts thereof A process for the preparation of the compounds of the general formula (I) has additionally been found, characterized in that, that in the case in which R' denotes alkyl substituted by two vicinal hydroxyl-groups [A] compounds of the general formula (II) R 27 HO E CO-R in which R, A, D and E have the abovementioned meaning, and R denotes a residue of a formula L 11 -NH2 or -NH-C-NH2 first are reacted with compounds of the general formula (Ill) C-CH2-Br (Ill) 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, 5 in inert solvent and in presence of a base to compounds of the general formula (IV) A 7 4 R 28 _ H2C _OG1Ef--CO-R (IV) in which 10 A, D, E, W, R27 and R2' have the abovementioned meaning, and in a last step reacted vAth osmiumtetroxide(OS04) / N- methyImorpholino-N-oxide in inert solvents, 15 or 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) R2'-CH20H (V) in which W' 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) A R 29 - H2C-OC E CO-R 4 (VI) in which A, D, E, R4, Rand R2' have the abovementioned meaning and in a last step are reacted withoS04/N-methylmorpholino-N-oxide in solvents, or compounds of the general formula (II) are reacted with alcohols of the general formula (V11) W-0H (V11) in which 20 R' has the abovementioned meaning in inert solvents and in presence of triphenylphosphine / diethylazodicarboxylate or [D] compounds of the general formula (II) are reacted with the compound of the formula (VIII) CH 2-OH (VIII) 0 in inert solvens and in the presence of a base and titanium- QV)isopropylate 5 and in the case in which W, W and/or W # H the 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 A' NH2 HN -D' NH2 0 ", 1 0 HO 0 K2C031acetone 0 0 + 0 HN -' NH2 0 0s04INMO 1) 1 0 HO"^'O J:) 0 waterlacetone, t-butanol OH [B] 0 0 HN ''NH2 HN-R-NH2 0 0 HO JC 0 HO DEAD2), Ph3 P3) HO ""C 0 0 + -y -H- OH 0 HN-Jt-NH2 0s04INMO 0 OH 5 HO 0 0 waterlacetone, t-butanol HO 1) N-Methyimorpholino-N-oxide 2) diethylazodicarboxylate 3) triphenylphosphine [C] 0 HN -JL NH2 0 HO 0 HO OH DEAD, Ph P :C + -- P, HO THF 0 HN J, NH 2 0 H 0 0 0 j: 0 HO:r [D] 0 HN -JI' NH 2 0 1 HO 0 JO 0 CH 2 OH NaH 0 10 Ti(OiPr)4 THF 0 HN Al NH 2 0 HO 0 0 OH 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, dioxan or tetrahydrofuran, ethylacetate, acetone, dimethyl sulfoxide, dimethylformamide or alcohols such as methanol, ethanol, propanol, butanol or t-butanol, or halogenohydrocarbons such as dichloromethane, dichloroethane, trichloromethane or tetrachloromethane. Acetone is prefer-red for the first step of [A] and water/acetone/t-butanol for all processes with OsO,/Nmethylmorpholino-N-oxide.

Tetrahydroftirane is preferred for the process with the systems triphenylphosphine diethylazodicarboxylate Suitable bases are generally inorganic or organic bases. These preferably include alkali metal hydroxides 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 sodium carbonate, potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or organic amines (trialkyl WX6)amines) such as triethylamine, or heterocycles such as 1,4- diazabicyclo[2.2.21 octane (DABCO), 1,8-diazabicyclo[5.4.Olundec-7-ene (DBU), pyridine or methyl piperidine, or amides 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. Sodiurnhydride for process [D] and potassium carbonate for the first step of [A] are 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 formula (I1).

The processes are in general carried out in a temperature range from 30'C to + 1 OWC, preferably from - 1 O'C to +50'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 (I1) are known or new and can be prepared by 20 reacting compounds of the general formula (IX) R 27 4 (IX) 1 1 R 0:1 EI'' CO-R in which A, D, E, W and W' have the abovementioned meaning and C Oenotes a hydroxylprotecting group, preferably methyl or benzyl, by evaluation of the protecting group by hydrogenation, wherein in the case of R' 2 = -NI12 first compounds of the general formula (IX) are reacted with 5 compounds of the general formula (X) C-N=C=L (X) in which L has the abovementioned meaning and 15 R has the above mentioned meaning of R2and R' in inert solvents, if appropriate in the presence of a base, and in the case of W1W = H and L = 0, compounds of the general formula (IX) are reacted with compounds of the general formula (M) X-S02 -N=C=0 (M) in which X denotes halogen, preferably chlorine, 30 and in the case von CW = H and L = S, compounds of the general formula (IX) are reacted with NH,SCN, The hydroxyl-protective group is in case of R'O = benzyl, in general removed with hydrogen ethyl acetate, diethyl ether or tetrhydrofuran. Suitable catalysts are the abovementioned catalysts, preferably palladium and palladium on charcoal.

Suitable solvents for the steps (IX/X and IX/XI) are generally customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxan or tetrahydrofuran, ethylacetate, dimethylsulfoxide, dimethyl formarnide or halogenohydrocarbons such as dichloromethane, dichloroethane, tri chloromethane or tetrachloromethane. Dichloromethane is preferred.

Suitable bases for these steps are generally inorganic or organic bases. These preferably include alkali metal hydroxides 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 sodium carbonate, potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or alkaline metal or organic amines (trialkyl(C,-C6)amines) such as triethylamine, or heterocycles such as 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8diazabicyclo[5.4.01 undec-7-ene (DBU), pyridine or methylpiperidine or amides 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, triethylamine, sodium hydrogencarbonate and sodiurnhydroxide 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 fon-nula (IX).

The process is in general carried out in a temperature range from -30'C to +100'C, preferably from -I 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 characterized in that, first compounds of the general formula (XII) A CN R 300 0 in which A, D, E, W and R 3' have the abovementioned meaning, are reacted with a catalytic amount of alkali alcoholates such as sodium methanolate, sodium ethanolate or sodium propanolate. Sodium ethanolate ist preferred. Suitable solvents for the the procedure are generally alcohols such as methanol, ethanol or propanol. Ethanol is preferred. 20 The process is in general carried out in a temperature range from O'C to + 60'C, preferably from room temperature to 60'C. The process is generally carried out at normal pressure. However, it is also possible to 25 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 (M1) are as species new and can be prepared by reaction of compounds of the general formula (M11) CHO R 30 01 (XIII) D: iE-H in which A, D, E and WO have the abovementioned meaning, with hydroxylamine hydrochloride in a presence of sodiumformiate to compounds of the general formula (XIV) CN R 30 0- 1 (XIV) 1 D1E-H in which A, D, E and WO have the abovementioned meaning, and in a next step are reacted with compounds of the general formula (XV) W-CO-CH2-T (XV) in which W has the abovernentioned 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, dioxan or tetrahydrofurane, aceton, dimethylsulfoxide, dimethylfon-namide or alcohols such as methanol, ethanol, propanol or halogenohydrocarbons such as dichlormethane, trichloromethane or tetrachloromethane. Acetone and dimethylfonnamide are pre ferred.

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" denotes NH2can 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.

The compounds of the general formula (XIII) can be prepared by reaction of compounds of the general formula (XVI) Al CHO (XVI) HO D E-H in which 25 A, D and E have the abovementioned meaning with hydroxyl protecting agents of the general formula (XVII) R 30_Z (XVII) in which R30 has the abovementioned meaning and Z1 denotes halogen, preferably chlorine or bromine in inert solvents, preferably acetone or dirnethylformarnide, and in the case of A and D = heterocycle, by reaction of compound of the general formula (XVIII) A, CH2-OH 31 (XVIII) R 30 0 ', D E-R in which A, D, E and WO have the abovementioned meaning, and W' denotes methyl, 25 with Mn02,followed by BC13/ CH2C12.

The compounds of the general formulae (III), (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 and can be prepared like described above.

Surprisingly it was found that compounds given by the general formula 0) inhibited oxygen radical formation as well as TNFa (tumor necrosis factor) production. These compounds elevated cellular cyclic AMP by inhibition of phagocyte phosphodiesterase activity.

The compounds according to the invention specifically inhibit theproduction of superoxide by polymorphonuclear leukocytes (PMN). Furthermore, these compounds inhibit TNFcc release 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 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 kind of COPD, ARDS, asthma and bronchitis, cystic fibrosis, eosinophilic granuloma, arteriosclerosis, arthrosis, inflammations of the gastro-intestinal tract, myocarditis, bone resorption diseases, reperfusion injury, Crohn's disease, ulcerative colitis, system lupus erythematosus, type I 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, myalgias, multiple sclerosis, malaria, AIDS, cachexia, prevention of tumor growth and invasion of tissue, leukemia, depression, memory impairment and acute stroke. The compounds according to the invention are additionally suitable for reducing the damage to infarct 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

1. 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' ml-') were mixed with cytochrorne 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 pM, the DMSO concentration was 0. 1% v/v in all wells. After addition of cytochalasin b (5 tg 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 Thermomax microtitre plate spectrophotometer. Initial rates were calculated using a Softmax. kinetic calculation programme. Blank wells contained 200 units of superoxide dismutase. 30 The inhibition of superoxide production was calculated as follows:

[1-((Rx-Rb))] ((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,O values in the range 0,07 pM-10 [LM.

3. Measurement of PMN cyclic AMP concentration The compounds according to the invention were incubated Arith 3.7 x 10' PMN for 5 min at 3 TC before addition of 4 x 10-' M FMLP. After 6 min protein was precipitated by the addition of 1% 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 AMP concentrations were expressed as percentage of vehicle containing control incubations.

Compounds elavate the cAMP-level at I VM 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. 1291, 389-395, 1993). Particulate fractions were treated with sodiurn vanadate / glutathione as described by the authors to express the descrete, stereospecific, site on the phosphodiesterase enzyme. Compounds according to the invention had 'C50 values ranging from 0,00 1 Lm to 10 PM.

5. Assay of human platelet phosphodiesterase This was perfon-ned 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 IC,, values greater than 100 VM 6. Assay of binding to the roliprarn 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 IC,O values in the range 0,0 1 to 10 gM.

7. Preparation of human monocytes Blood was taken from normal donors. Monocytes were isolated from peripheral blood by density centrifugation, followed by centrifugal clutriation.

8. Endotoxin induced TNF release Monocytes (I X 106 MI-1) were stimulated with LPS (2 gg ml-') and coincubated with the compounds at different concentrations (10' to 10 pg ml-1). Compounds were dissolved in DMSO/medium (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 B6D2FI mice (n=10) were sensitized with galactosamine (600 mg/kg), and shock and lethality were triggered by LPS (0.01 Vg/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.

The galactosamine / LPS mediated mortality was reduced. 5 10. Stimulation of human monocytes and determination of cytokine levels Human monocytes (2xlO' in I ml) were stimulated with 100 ng/mI LPS, 0.8 mg/ml zymC3b or 10 ng/ml IL-IB 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 -70T. The TNFcc concentration was measured by ELISA using the A6 anti-TNF monoclonal antibody (Miles) as the primary antibody. The secondary antibody was the polyclonal anti-TNFoc 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 inert, 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 particular perlingually or intravenously.

In the case of parenteral administration, solutions of the active compound can be employed 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. 10 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 15 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. Experimental Procedures 20 Thin Layer Chromatography Solvent Mixtures:

1 methylene chloride: methanol 100: 2 II methylene chloride: methanol 100:5 111 methylene chloride: methanol 10: 1 IV petrolium. ether: ethyl acetate 3 A IV petrolium ether: ethyl acetate 1 A v methylene chloride Starting compound Example 1 A

Bromomethyl cyclohexyl ketone 0 Br,..

Prepared according to literature precident (Gaudry, M.; Marquet, A. Tetrahedron 1970, 26, 5611): To a solution containing methyl cyclohexyl ketone (10 g, 79 mmol) in methanol (50 ml) at O'C was added bromine (12 g, 79 mmol) dropwise over a period of 10 min. The resulting solution was allowed to stir at this temperature for 1 h and then water (25 ml) and ether (50 ml) was added. The two phases were separated and the aqueous phase extracted with ether (3 x 50 ml). The combined organic extracts were dried (Na2S04), concentrated and vacuum distilled i'l70'C_ 17 mm Hg) to afford the title compound ( 11.8 g, 72%) as a yellow oil: NMR (300 MHz, C13C13) d 3.95 (s, 2H), 2,80-2.66 (m, I H), 1.92-1.63 (m, 511), 1.48-1.15 (m, 5 H); MS (CI) 222 (M + NH4)' The following examples were prepared in an analogous manner:

0 Br--'R 4 Table 1A

Couple No. W BP ('C / mm Hg) Yield (% of theory) 2 A C-CA 75/0.9 47 g (100) 3 A c-C4H, 10010.5 26 g (94) 4 A c-CHg nd 4.4 g (95) A c-C.,H,, 15011.0 3.9 g (5 1) Preparation samples Example 1 (3-Amino-6-benzyloxy-benzofuran-2-yl)-cyclohexyl-methanone NH 2 0 H5C-H 2C0 0 A suspension containing bromomethyl cyclohexyl ketone (8.37 g, 41 nimol), 5 benzyloxy-2-cyano-l-hydroxybenzene (7.48 g, 33 mmol) and caesium carbonate (21.9 g, 67 mmol) in DMF (80 ml) was heated to 6M for 18 h. The resulting mixture was cooled to room temperature, concentrated to remove the DMF and partitioned between EtOAc (75 ml) and water (150 ml). The phases were separated and the aqueous phase extracted with EtOAc (2 x 50 mi). The combined organic extracts were washed with brine (50 ml), dried (NaSO,) and concentrated. The resulting residue was column chromatographed on silica gel (petrolium ether:

EtOAc; 11) to afford the title compound (7.69 g, 66 %) as an off white solid:

Rf 0.48 (IV), MP: 21 OOC.

The following examples were prepared in an analogous manner:

NH 2 0 H 5 Cj-H 2C0 0 R Table 1

Couple No. W MP ('C) TLC Yield (%of theory) 2 C-C3145 156 0.31 (IV) 12 g (90) 3 C-C4117 136 0.49 (1) 9.3 g (8 1) 4 c-CHg 112 0.52 (1) 5.1 g (81) C-C71111 oil 0.33 (V) 3.7 g (77) Example 6 (6-Benzyloxy-2-eyclohexanecarbonyl-benzofuran-3-yl)-urea H 2 N- NH 0 0 H 5 C-H2C0 % To a solution containing (3-amino-6-benzyloxy-benzofuran-2-yl)-cyclohexyl- methanone (8.25 g, 24 mmol) in CH2C12 (120 ml) at O'C was added chlorosulfonyl- isocynate (3.51 g, 25 mmol) dropwise over 30 min. The reaction mixture was maintained at this temperature for 4 h and then concentrated. Water (250 mi) was added to the resulting residue and the mixture stirred for 18 h. The resulting suspention was filtered, the filter cake was washed with methanol and dried under vacuum to afford the title compound (6.83 g, 74%) as an off white solid: R. 0.23 (1), MP: 21 O'C. 5 The following examples were prepared in an analogous manner (Table 2):

0 H 2 N N H 0 4 H5Cd-H 2 COJWO R Table 2

Example No. R 4 TLC MP CC) Yield (%of theory) 7 C-CA 0.29(11) 219 6.0 g (43) 8 C-C4H7 0.31(l) 184 3.9 g (40) 9 C-C5Hq 0.44(11) 173 4.2 g (76) C-C7Hjj 0.63(11) oil 1.9 g (25) Examples 11 (2-cyclohexanecarbonyl-6-hydroxy-benzofuran-3-yl)-urea 0 2 NH 0 HO 0 To a suspension containing (6-benzyloxy-2-cyclohexanecarbonyl-benzofuran3-yl)- urea (6.83 g, 17 mmol) in ethanol (700 nil), sodium formate (1. 18 g, 17 mmol), formic acid (2.4 mI, 63 mmol) unter argon was added palladium on carbon (10%, 0.34 g). The resulting suspention was heated to reflux for 3 h and was then cooled to room temperature. The reaction mixture was filtered through celite and the filtrated concentrated. The resulting residue was purified by silica gel chromatography (CH2C12: ethanol; 100:5) to afford the title compound (4.58 g, 87%) as a pale yellow solid: Rf 0. 10 (1), MP: 243'C.

The following examples were prepared in an analogous manner (Table 3):

H2N- NH 0 4 HO"O 0 R Table 3

Example No. R4 TLC MP ('C) Yield (% of theory) 12 C-CA 0.26 (11) oil 1.8 g (68) 13 C-C4117 0.25 (11) oil 2.8 g (64) 14 c-C.5H9 0.25 (11) 218 2.9 g (91) C-C7141 1 0.22 (11) oil 3.0 g (100) Examples 16 (2-cyclohexanecarbonyl-6-methoxy-benzofuran-3-yl)-urea 0 H 2N NH 0 0 CH30 To a solution containing (2-cyclohexanecarbonyl-6-hydroxy-benzofuran-3yl)-urea (500 mg, 1.6 mmol) in DMF (10 ml) and potassium carbonate (273 rrig, 2.0 mmol) was added methyl iodide (281 mg, 2.0 mmol) and the resulting suspention was stirred at room temperature for 18 h. Water (20 ml) was added to the reaction mixture at which time a solid precipitated from solution. This solid collected and washed with pentane to afford the title compound (520 mg, 99%) as a white solid: Rf 0.38 (H), mp: 227C.

The following examples were prepared in an analogous manner (Table 4):

0 H2N NH CH30,0 0 R Table 4

Example No. R 4 TLC MP ('C) Yield (% of theory) 17 C-CA 0.36Q1) 227 58 mg (36) 18 C-C4117 0.46(11) 218 250 mg (50) 19 C-CA 0.41Q1) 228 320 mg (61) C-C7F111 0.52Q1) 203 60 mg (58) Examples 21 5 Methanesulfonic acid 2-cyclohexanecarbonyl-3-ureido- benzofuran-6-yI ester H 2 N-- NH 0 0 CHF-SO 0 To a solution containing (2-cyclohexanecarbonyl-6-hydroxy-benzofuran-3- yl)-urea (25 0 mg, 0.83 mmol) and triethylamine (0. 17 mI, 1.2 mmol) in DMF (15 ml) at O'C was added methane sulfonylchloride (0.07mI, 0.9mmol) and the resulting suspention was stirred at this temperature for 2 h. The ice bath was then removed and the reaction mixture stirred for an additional 2 h. To reaction mixture was added 15 water (10 ml) at which time a solid precipitated from solution. This solid was collected and washed with pentane and the resulting residue purified on a silica gel column (CH2C122: ethanol; 10: 1) to afford the title compound (230 rng, 73%) as a white solid: Rf 0.47 (11), mp: 190 'C. 20 The following examples were prepared in an analogous manner (Table 5):

0 2 NH 0 11 CHS-S0,0 0 R 11 0 Table 5

Examples 26 [2-Cyclohexanecarbonyl-6-(2-hydroxymethyl-allyloxy)-benzofuran-3 -yll urea 0 2 NH 0 HO"^ 0 0 To a solution containing triphenylphosphine (2.12, 8.1 mmol) in THF (40 M1) at O'C was added diethyldiazodicarboxylate (1.3 mI, 8.1 mmol) and the resulting solution stirred at this temperature for 15 min. 2-Methylene-1, 3-propanediol (0.72 g, is 8,1 mmol) in THF (10 ml) was then added to the reaction mixture followed by (2cyclohexanecarbonyl-6-hydroxy-benzofuran-3-yl)-urea (400 mg, 1.3 mmol) in THF Example No. W TLC MP (C) Yield (%of theory) 22 C-CA'S 0.50(11) 236 61 mg (48) 23 c-C4H7 0,51 (11) 204 406 rng(79) 24 c-C5H9 0.20(11) 228 125 mg (20) C-CA, 0.49Q1) 212 107 mg (21) (10 ml). The resulting reaction mixture was maintained at O'C for 3 0 min, the ice bath was then removed and the reaction stirred for an additional 18 h. The reaction mixture was then concentrated and the resulting residue purified on a silica gel column (CH2C12: ethanol; 100:5) to afford the title compound (355 mg, 72%) as a white solid: Rf 0.30 (11), mp: 175 'C.

The following examples were prepared in an analogous manner (Table 6):

0 H2N NH HO""0'0 0 R Table 6

Example No. R' TLC MP (OC) Yield (% in theory) 27 C-CA 0.32Q1) 198 217 mg (52) 28 C-C41-17 0.30 (11) 171 257 mg (44) 29 c-C5H9 0.22 (V) 198 345 mg (56) c-C,H,, 0.33 (Ill) 205 107 ing (22) Examples 31 15 (6-Allyloxy-2-cyclohexanecarbonyl-benzofuran-3-yl)-urea 0 H 2 N-A NH 0 0 J 0- To a solution containing (2-cyclohexanecarbonyl-6-hydroxy-benzofuran-3yl)-urea (500 mg, 1.6 mmol) in DMF (10 mi) and potassium carbonate (285 rng, 2.1 mmol) was added allyl bromide (0. 18 ml, 2.1 mmol) and the resulting suspention was stirred at room temperature for 18 h. Water (20 ml) was added to the reaction mixture at which time a solid precipitated from solution. This solid collected and washed with pentane, to afford the title compound (366 mg, 65%) as a white solid: Rf 0.24 (H), mp: 178 'C. 10 The following examples were prepared in an analogous manner:

0 2 NH 0 4 0 R Table 7

Example No. W TLC MP ('C) Yield (% in theory) 32 C-C3115 0.27Q1) 195 494 mg (7 1) 33 C-C4H7 0.38(11) 190 390 mg (68) 34 C-CA 0.33(11) 165 530 mg (92) c-C,H11 0.38Q1) 170 618 mg (55) Examples 36

2-Cyclohexanecarbonyl-6-(2,3-dihydroxy-propoxy)-benzofuran-3-yl]-urea 0 2 NH 0 HO"O cc 0 H H To a solution containing N-methylmorpholine-n-oxide (115 mg, 0.98 mmol) in water (7.5 ml) and acetone (15 ml) at room temperature was added Osmium (IV) oxide (0.31 ml of a 2.5% solution in butanol) followed by (6-Allyloxy-2- cyclohexane carbonyl-benzofuran-3-yl)-urea (316 mg, 0.92 mmol). The resulting reaction mixture was heated to 40'C stirred at this temperature for 18 h. The resultion reaction mixture was cooled to room temperature and partitioned betweell ethy! acetate (25 ml) and water (25 ml). The phases were separated and the aqueous phase extracted with ethyl acetate (2 x 25 ml). The combined organic extracts were dried (Na2S04), concentrated and chromatographed on a silica gel column (CH2C'2:

ethanol; 10:1) to afford the title compound (238 mg, 67%) as a white solid: Rf 0.36 (111), mp: 232 'C.

The following examples were prepared in an analogous manner (Table 8):

H 2 N- NH 0 HO""';R 4 HCO'CCO Table 8

Example No. W TLC MP ('C) Yield (%in theory) 37 C-C31-15 0.28(111) 207 210 mg (44) 38 C-C4H7 0.42(111) 170 260 mg (75) 39 c-C,Hg 0.35(111) 193 65 mg (30) C-C71-111 0.36(111) 195 88 mg (26)

Claims

We claim:

1 Cycloalkyl substituted 3-urea-benzofurane- and -pyridofuranederivatives of the general formula (I) 5 L 2 NJ-W R3 4 E CO-R in which A and D including the double bond connecting them together form a phenyl-, pyddyl-, pyrimidyl, pyridazinyl- or thienybring, which are substituted by a group of a formula -OR' wherein R 5 denotes straight-chain or branched alkyl having up to 10 carbon atoms, which is substituted difold to fivefold by hydroxyl or difold to fivefold by straight-chain oder branched alkoxy having up to 6 carbon atoms and wherein alkyl is optionally substituted by straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms, halogen, carboxyl or by phenyl, which is optionally substituted by nitro or halogen, or denotes a group of a formula R 6 R 7 N or _S02-G, OH in which R' and R' denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms or by a 5 to 7 membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the series comprising N, S and 0 and to which a phenyl ring can be fused and which is optionally, including the nitrogenfunction monosubstituted 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 up to 6 carbon atoms, or R' and R' together with the nitrogen atom form a 5 to 6 membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the series comprising N, S and 0 and to which a phenyl. ring can be fused and wf&h is optionally, including the nitrogenfunction, 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 up to 6 carbon atoms, and G denotes a residue of a formula H3C CH or H or aryl having 6 to 10 carbon atoms or a 5 to 7membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the series comprising N, S and 0 and to which a phenyl ring can be fused, wherein all abovementioned residues and ring systems are optionally 10 monosubstituted. to trisubstituted by halogen, carboxyl, straight-chain or branched alkyl or alkoxycarbonyl each having up to 6 carbon atoms, pyridyl and/or by a residue of a formula -NR8-M-R, -NR'O-CO-NR"R 12 _NR13 -S02-NR 14 R", _S02-R 16 or -(S02),-NR 17 R 18, 15 wherein a denotes a number 0 or 1, M denotes a residue of formula S02 or CO R8, R'O, R", R 12, R 13, R 14, R", R 17 and R" are identical or different and denote hydrogen, phenyl or straight chain or branched alkyl having up to 6 carbon atoms, R' denotes straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, R denotes benzyl, phenyl or methyl, or G denotes straight-chain or branched alkyl or alkenylen having up to 8 carbon atoms, which optionally are monosubstituted to trisubstituted. by halogen, aryl having up 6 to 10 carbon atoms or a 5 to 7-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the series comprising N, S and 0 and to which a phenyl ring can be fused or by a residue of a formula -NCW'or 0 Nwherein R and W' have the abovementioned meaning of W' and R and are identical or different to the latter, E represents an oxygen or sulfar atom, R' represents hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, an aminoprotecting group or a group of the formula -CO-W' in which R" denotes hydroxyl, straight chain or branched alkoxycarbonyl having up to 4 carbon atoms, R2 and R' are identical or different and represent hydrogen, cycloalkyl 5 having up to 6 carbon atoms, straight chain or branched alkyl, alkoxycarbonyl or alkenyl each having up to 8 carbon atoms, or W and R' together with the nitrogen atom form a 5- to 7-membered saturated heterocycle optionally having a finther 0 atom, R' represents cycloalkyl having up 3 to 8 carbon atoms which is optionally monosubstituted to trisubstituted by identical or 15 different substituents from the series comprising hydroxyl, halogen, nitro, I Htetrazolyl, pyridyl, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, cyan(-), carboxy, straight-chain or branched alkoxy, alkoxycarbonyl or acyl each having up to 6 carbon atoms or by straightchain or branched 20 alkyl having up to 4 carbon atoms, which is optionally substuted by carboxyl or straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms or by a group of formula _NR22R23' _SRII, _(NH)b_S02R' or -0-S02 W6,

25 in which R22 and R 23 are identical or different and denote hydrogen or a straight-chain or branched alkyl having up to 4 carbon atoms, or W' denotes hydrogen and W' denotes straight-chain or branched acyl having up to 6 carbon atoms R' denotes straight-chain or branched alkyl having up to 4 carbon atoms, b denotes a number 0 or 1, and W' are identical or different and represent straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or phenyl, which are optionally substituted by trifluoromethyl, halogen or straight-chain or branched alkyl having up to 4 carbon atoms, L represents an oxygen or sulfur atom 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 pyridazinyl-ring, which are substituted by a group of a formula -OR' 30 wherein R 5 denotes straight-chain or branched alkyl having up to 8 carbon atoms, which is substituted difold to fourfold by hydroxyl, and wherein alkyl is optionally substituted by straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms, fluorine, chlorine or by phenyl, which is optionally substituted by nitro, fluorine or chlorine, or denotes a group of a formula R 6 R 7 N"or -S02-GY HH in which 15 W and R7 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 or pyrrolidinyl, wherein the ring systems are optionally, including the nitrogen function, 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 pyrazolyl-, triazolyl-, tetrazolyl-, imidazolyl-, pyrryl-, morpholinyl-, piperidinyl-, pyrrolidinyl- or piperazinylring, wherein the ringsystem are optionally including the nitrogen function are 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 D represents a residue of a formula 10 H3C CH 3 0 or H or phenyl, pyridyl, pyrimidyl, thienyl, ftiryl, pyrazolyl, isoxazol-yl, thiazolyl, imidazolyl, tetrazolyl, morpholin yl, piperidinyl, pyrrolidinyl or piperazinyl, wherein all abovementioned residues and ring systems are optionally monosubstituted to trisubstituted by halogen, carboxyl, straight-chain or branched alkyl or alkoxycarbonyl each having up to 4 carbon atoms, pyridyl and/or by a residue of a formula -NR!-M-R!, -NR"-CO-NR"R 12, -NR 13_SO2 NR 14 R 15, -S02-R'6 or -(S02),,-NR"R", wherein a denotes a number 0 or 1, M denotes a residue of formula SO, or CO R', WO, R", R 12, R 13, R 14, R", R 17 and M are identical or different and denote hydrogen, phenyl or straightchain or branched alkyl having up to 4 carbon atoms, denotes straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms, R denotes benzyl, phenyl or methyl, 10 or G represents straight-chain or branched alkyl or alkenylen having up to 6 carbon atoms, which are optionally monosubstituted to trisubstituted by halogen, phenyl, pyridyl, pydmidyl, thienyl, fliryl, imidazolyl, tetrazolyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl or by a residue of a formula -NCWO or 0 N c 0 wherein W9 and W' have the abovementioned meaning of C and R 12 and are identical or different to the latter, E represents an oxygen or sulfur atom, R' represents hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a group of the formula -CO-R in which 5 W' denotes hydroxyl, straight chain or branched alkoxycarbonyl having up to 4 carbon atoms, R' and W 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 W and R' together with the nitrogen atom form a pyrrolidinyl-, piperidinyl- or morpholinyl-ring, and R 4 represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, which are optionally monosubstituted to trisubsti tuted by identical or different substituents from the series comprising hydroxyl, fluorine, chlorine, bromine, nitro, tetrazol yl, pyridyl, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, cyano, carboxy, straight-chain or branched alkoxy, alkoxycarbonyl or acyl each having up to 4 carbon atoms, or by straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by carboxyl or straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms L represents an oxygen or sulfur atom.

3. Compounds according to claim 1 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 up to 8 carbon atoms, which is substituted difold to fourfold by hydroxyl, and wherein alkyl is optionally substituted by methoxycarbonyl, fluorine or by phenyl, which is optionally substituted by nitro or fluorine, or denotes a group of a formula R 6 R 7 N or -S02-G5 H in which R' and R' denote 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 or pyrrolidinyl, wherein the ring systems are optionally, including the nitrogen function, 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-, pynyl-, morpholinyl-, piperidinyl-, pyrrolidinyl- or piperazinylring, wherein the ringsystern are optionally including the nitrogen ftmction are 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, G represents phenyl, pyridyl, pyrimidyl, thienyl, ftiryl, pyrazolyl, isoxazolyl, thiazolyl, imidazolyl, tetrazolyl, morpholinyl, piperidinyl, pyrrolidinyl or piperazinyl, wherein all abovementioned residues and ring systems are optionally monosubstituted to trisubstituted by halogen, carboxyl, straight-chain or branched alkyl or alkoxycarbonyl each having up to 3 carbon atoms, pyridyl and/or by a residue of a formula -NW-M-W, -NR"-CO-NR"R 12, -NR 0_S02-NR 14 R", -S02-R 16 or _(S02)jNR 17 C, wherein a denotes a number 0 or 1, m denotes a residue of formula SO, or CO 1 R', WO, C, R 12, W 3, R 14, R", R 17 and W' are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 3 carbon atoms, denotes straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms, R denotes benzyl, phenyl or methyl, or G represents straight-chain or branched alkyl or alkenylen having up to 4 carbon atoms, which are optionally monosubstituted to trisubstituted by halogen, phenyl, pyridyl, pyrimidyl, thienyl, furryl, imidazolyl, tetrazolyl, morpholilnyl, piperidinyl, pyrroli dinyl, piperazinyl or by a residue of a formula -NCR2' or 0 N 0 wherein W9 and W' have the abovementioned meaning of W' and R 12 and are identical or different to the latter, E represents an oxygen or sulfur atom, R' represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms or a group of the formula -CO-W', in which W' denotes hydroxyl, straight chain or branched alkoxycarbonyl having up to 3 carbon atoms, R' and W are identical or different and represent hydrogen, cyclobutyl, cyclopentyl, cyclohexyl or straight-chain or branched alkyl, alkoxycarbonyl or alkenyl each having up to 3 carbon atoms, represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl which are optionally up to trifold substituted by identical or different pyridyl, fluorine, chlorine, bromine, meth oxy, trifluoromethyl, cyano, 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 atom, and salts thereof.

4. Compounds according to any one of claims 1 to 3, in which E and L represent an oxygen atom and 2 R', R and W represent hydrogen and salts thereof

5. A process for the preparation of the compounds according to any one of claims I to 4, characterized in that, 5 that in the case in which R' denotes alkyl substituted by two vicinal hydroxylgroups [A] compounds of the general formula (II) 10 R 27 HO --(D XE I CO-R4 in which W, A, D and E have the abovementioned meaning, and R2' denotes a residue of a formula L I I -NH 2 or -NH-C-NH2 first are reacted with compounds of the general formula (III) R 28_CH2-Br (111) in which R 28 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, 5 in inert solvent and in presence of a base to compounds of the general formula QV) 7 A 4 R 28 - H 2 C_OGrEtCO-R (IV) in which 10 A, D, E, R4, R27 and R2' have the abovementioned meaning, and in a last step reacted with osmiurntetroxide (0s04) / NmethyImorpholinoN-oxide in inert solvents, 15 or 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) R 2'-CH20H (V) in which R 29 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 (VI) R 27 R 29 _ H 2C _OC'E'CO-R 4 (VI) in which A, D, E, W, R27 and R2' have the abovementioned. meaning and in a last step are reacted with OsO,/N-methylmorpholino-N-oxide in solvents, or [C] compounds of the general formula (11) are reacted with alcohols of the general fon-nula (VII) R'-OH (VII) in which W has the abovementioned meaning in inert solvents and in presence of triphenylphosphine / diethylazodicarb oxylate or [D] compounds of the general flormula (I1) are reacted with the compound of the formula (VIII) 77"' CH 2-OH (VIII) 0 in inert solvpns and in the presence of a base and titanium- (IV)isopropylate and in the case 1 in which R', W and/,or W:# H the amino grQups are derivated optionally by common methods.

R25 and-R26 have the abovementioned meaning of R21 and R22 and are identical or different to the latter wid salts thereof

6. Compounds according to any one of claims 1 to 4 for therapeutic kise.

7. The composition containing at least one compound according to any one of claims 1 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 compositions according to claim 7 and 8 characterized in that the cycloalkyl substituted 3-urea-benzofurane and pyridofurane derivative together with customary auxiliaries is brought into a suitable application form.

10. Use of compounds according to any one of claims 1 to 4 for the preparation of medicaments.

11. Use according to claim, 10 for the preparation of medicaments for the 5 treatment and prevention of acute and chronic inflammatory processes.

12. Compounds of the general formula (IV) A R 27 R 28 H2C-0 Ef--CO-R 4 (IV) in which A, D, E and R4 have the abovementioned meaning, L 11 R27 denotes a residue of a formula -NI12 or -NH-C-NH 2 R28 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 general formula (V1) R 27 1 1 R 29 -H2C-0 C'ECO-R 4(V1) in which A, D, E, R4 and R27 have the abovementioned meaning and 9 R29 denotes straight-chain or branched alkenyl haing up to 9 carbon atoms, which is optionally substituted by hydroxyl.