[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2000069841A2 - Benzofuranylaminoalcohols - Google Patents

Benzofuranylaminoalcohols Download PDF

Info

Publication number
WO2000069841A2
WO2000069841A2 PCT/EP2000/004015 EP0004015W WO0069841A2 WO 2000069841 A2 WO2000069841 A2 WO 2000069841A2 EP 0004015 W EP0004015 W EP 0004015W WO 0069841 A2 WO0069841 A2 WO 0069841A2
Authority
WO
WIPO (PCT)
Prior art keywords
carbon atoms
chain
straight
branched alkyl
alkoxycarbonyl
Prior art date
Application number
PCT/EP2000/004015
Other languages
French (fr)
Other versions
WO2000069841A3 (en
Inventor
Gabriele Bräunlich
Mazen Es-Sayed
Rüdiger Fischer
Burkhard Fugmann
Rolf Henning
Stephan Schneider
Michael Sperzel
Karl-Heinz Schlemmer
Graham Sturton
Mary Fitzgerald
Barbara Briggs
Arnel Conception
William Bullock
Original Assignee
Bayer Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Priority to AU45616/00A priority Critical patent/AU4561600A/en
Publication of WO2000069841A2 publication Critical patent/WO2000069841A2/en
Publication of WO2000069841A3 publication Critical patent/WO2000069841A3/en

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D307/00Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D231/00Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D249/00Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/081,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to Berizofuranylaminoalcohols, processes for their preparation and their use in medicaments.
  • 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.
  • both inflammatory e.g. TNF ⁇ , IL-1 or IL-6
  • anti-inflammatory cytokines e.g. IL-10
  • Uncontrolled production of inflammatory mediators can lead to acute or chronic inflammation, auto immune diseases, tissue damage, multi-organ failure and to death.
  • elevation of phagocyte cyclic AMP leads to inhibition of oxygen radical production and that this cell function is more sensitive than others such as aggregation or enzyme release.
  • Benzofuran derivatives having phosphodiesterase IV (PDE IV)-inhibiting action are described in EP 731 099.
  • the reference describes only single-hydroxyl substituted derivatives, however.
  • Benzofuranylaminoalcohols without 3-ureido moiety are disclosed for the treatment of diseases in the circulatory system in US 4,056,626.
  • the present invention relates to Benzofuranylaminoalcohols of the general formula (I)
  • A represents hydrogen, straight-chain or branched acyl or alkoxycarbonyl, each having 1 to 6 carbon atoms, halogen, carboxyl, cyano, nitro, hydroxyl, trifluoromethyl or trifluoromethoxy, or straight-chain or branched alkyl having 1 to 6 carbon atoms, which is optionally substituted by carboxyl, alkoxy or alkoxycarbonyl each having 1 to 4 carbon atoms, phenoxy or benzoyl,
  • R 1 represents hydrogen, straight-chain or branched alkyl having 1 to 4 carbon atoms, an amino protecting group or a group of the formula -CO-R 7
  • R 7 denotes straight chain or branched alkoxy having 1 to 4 carbon atoms
  • R 2 and R 3 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 6 to 10 carbon atoms or represents a 5-, 6- or 7-membered, aromatic, saturated or unsaturated heterocycle, which can contain 1 to 3 oxygen, sulphur and/or nitrogen atoms as heteroatoms or a residue of a formula -NR 8 ,
  • R 8 denotes hydrogen or straight-chain or branched alkyl or alkoxycarbonyl each having 1 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 hydroxyl, halogen, nitro, 1H- tetrazolyl, pyridyl, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoro- methoxy, 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 carbon atoms, which is optionally substituted by carboxyl or straight-chain or branched alkoxycarbonyl having 1 to 4 carbon atoms or by a group of formula -NR 9 R 10 , -
  • R 9 and R 10 are identical or different and denote hydrogen or a straight-chain or branched alkyl having 1 to 4 carbon atoms,
  • R 9 denotes hydrogen
  • R 10 denotes straight-chain or branched acyl having 1 to 6 carbon atoms
  • R 11 denotes hydrogen or straight-chain or branched alkyl having 1 to 4 carbon atoms
  • a denotes a number 0 or 1 ,
  • R 12 and R 13 are identical or different and represent straight-chain or branched alkyl having 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
  • R 5 and R 6 represent hydrogen, straight-chain or branched alkyl having 1 to 6 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms or by a 5- to 7-membered aromatic, saturated or unsaturated heterocycle having 1 to 3 heteroatoms from the series comprising N, S, O and/or a residue of a formula -NR 14
  • R 14 denotes hydrogen or straight-chain or branched alkyl or alkoxycarbonyl each having 1 to 6 carbon atoms
  • a phenyl ring can be fused and which are optionally monosub- stituted to disubstituted by identical or different substituents from the series comprising halogen, cyano or by a straight-chain or branched alkyl or alkoxy- carbonyl each having 1 to 6 carbon atoms,
  • R 5 and R 6 together with the nitrogen atom form a 5- to 6-membered aromatic, saturated or unsaturated heterocycle having 1 to 3 heteroatoms from the series comprising N, S, O and/or a residue of a formula -NR 14 , and to which a phenyl ring can be fused and which is optionally monosub- stituted to disubstituted by identical or different substituents from the series comprising halogen, cyano or by a straight-chain or branched alkyl or alkoxy- carbonyl each having 1 to 6 carbon atoms,
  • benzofuranylaminoalcohols according to the invention can also be present in the form of their salts.
  • salts with organic or inorganic bases or acids may be mentioned here.
  • Physiologically acceptable salts are preferred in the context of the present invention.
  • Physiologically acceptable salts of the benzofuranylaminoalcohols can be metal or ammonium salts of the substances according to the invention, which contain a free carboxyhc 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 triethyl- amine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.
  • Physiologically acceptable salts can also be salts of the compounds according to the invention with inorganic or organic acids.
  • Preferred salts here are those with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or salts with organic carboxyhc or sulphonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, ethane- sulphonic acid, benzenesulphonic acid, toluenesulphonic acid or naphthalenedi- sulphonic acid.
  • the compounds according to the invention can exist in stereoisomeric forms which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers).
  • the invention relates both to the antipodes and to the racemate forms, as well as to individual diastereomers and to the diastereomer mixtures.
  • the racemate forms like the diastereomers, can be separated into the stereoisomerically uniform constituents in a known manner.
  • Heterocycle in general represents a 5- to 7-membered aromatic, saturated or unsaturated, preferably 5- to 6- membered, aromatic or saturated ring, which can contain up to 3 oxygen, sulphur, nitrogen atoms or a residue of a formula -NR 14 as heteroatoms, wherein R 14 has the abovementioned meaning, and to which further aromatic rings can be fused.
  • Preferred compounds of the general formula (I) are those
  • A represents hydrogen, halogen, carboxyl, cyano, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy or alkoxy having up to 4 carbon atoms
  • R 1 represents hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a group of the formula -CO-R 7
  • R 7 denotes straight chain or branched alkoxy having up to 4 carbon atoms
  • R 2 and R 3 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
  • R 2 and R 3 together with the nitrogen atom form a pyrrolidinyl-, piperidinyl- or morpholinyl-ring,
  • R 4 represents phenyl, pyridyl or thienyl, wherein all 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 up to 3 carbon atoms, or by straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by carboxyl or straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms
  • L represents an oxygen or sulfur atom
  • R 5 and R 6 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl, pyridyl, imidazolyl, pyrryl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, wherein the heterocycles optionally contain a residue of a formula -NR 14 ,
  • R 14 denotes hydrogen or straight-chain or branched alkyl or alkoxycarbonyl each having up to 4 carbon atoms, and wherein the ring systems are optionally monosubstituted by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms,
  • R 5 and R 6 together with the nitrogen atom form a pyrazolyl-, triazolyl-, tetrazolyl-, imidazolyl-, pyrryl-, morpholinyl-, piperidinyl-, pyrrolidinyl-, piperazinylring, wherein the heterocycles optionally contain a residue of a formula -NR 14 ,
  • ringsystem is optionally monosubstituted to trisubstituted by identical or different substituents from the series comprising halogen, cyano or by a straight-chain or branched alkyl having up to 6 carbon atoms,
  • A represents hydrogen
  • R 1 represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms or a group of the formula -CO-R 7 ,
  • R 7 denotes straight chain or branched alkoxy having up to 3 carbon atoms, R 2 and R 3 represent hydrogen,
  • R 4 represents phenyl or pyridyl, which are optionally up to difold substituted by identical or different substituents from the series fluorine, chlorine, methyl or methoxy,
  • L represents an oxygen atom
  • R 5 and R 6 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl, pyridyl, imidazolyl, pyrryl, piperidinyl, wherein the heterocycles optionally contain a residue of a formula -NR 14 ,
  • R 14 denotes hydrogen or straight-chain or branched alkyl or alkoxycarbonyl each having up to 3 carbon atoms
  • ring systems are optionally monosubstituted by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms,
  • R 5 and R 6 together with the nitrogen atom form a imidazolyl-, pyrryl-, morpholinyl-, piperidinyl-, pyrrolidinyl-, piperazinylring, wherein the heterocycles optionally contain a residue of a formula -NR 14 ,
  • R 14 have the abovementioned meaning of R 14 and is identical or different to the latter,
  • ringsystem are optionally monosubstituted to trisubstituted by identical or different substituents from the series comprising by a straight-chain or branched alkyl or alkoxycarbonyl each having up to 3 carbon atoms,
  • R 1 , R 2 , R 3 , R 4 and L have the abovementioned meaning
  • R 5 and R 6 have the abovementioned meaning
  • Suitable solvents are generally customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane or tetrahydrofurane, acetone, dimethylsulfoxide, dimethylformamide or alcohols such as methanol, ethanol, propanol or halogenohydrocarbons such as dichloromethane, trichloromethane or tetrachloromethane and mixtures of two or three of the abovementioned solvents. A mixture of methanol and tetrahydrofurane is preferred.
  • the process is in general carried out in a temperature range from -30°C to +100°C, preferably from 0°C to 50°C.
  • the process is generally carried out at normal pressure. However, it is also possible to carry out it at elevated or reduced pressure (for example in a range from 0.5 to 5 bar).
  • triphenylphosphin and diethylazodicarboxylate in the presence of triphenylphosphin and diethylazodicarboxylate in an inert solvent.
  • Suitable solvents are generally customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane or tetrahydrofurane, acetone, dimethylsulfoxide, dimethylformamide or alcohols such as methanol, ethanol, propanol or halogenohydrocarbons such as dichloromethane, trichloromethane or tetrachloromethane. Tetrahydrofurane is prefened.
  • the process is in general carried out in a temperature range from -30°C to +100°C, preferably from 0°C to room temperature.
  • the process is generally carried out at normal pressure. However, it is also possible to carry out it at elevated or reduced pressure (for example in a range from 0.5 to 5 bar).
  • elevated or reduced pressure for example in a range from 0.5 to 5 bar.
  • the compounds of the general formula (III) and (V) are known or can be prepared by customary methods.
  • a and R 4 have the abovementioned meaning
  • a and R 4 have the abovementioned meaning
  • R 2 -N OL (VIII) in which R 2 and L have the abovementioned meaning
  • A, L, R 2 und R 4 have the abovementioned meaning
  • R 1 and R 4 have the abovementioned meaning
  • halogen preferably chlorine
  • Suitable solvents for the first step of the procedure [A] (VI-VII) are generally alcohols such as methanol, ethanol or propanol. Ethanol is prefened.
  • Suitable bases for the first step are generally alkali alcoholates such as sodium methanolate, sodium ethanolate or sodium propanolate. Sodium ethanolate ist prefened. The base is employed in catalytic amounts.
  • the process is in general carried out in a temperature range from 0°C to 60°C, preferably at room temperature.
  • the process is generally carried out at normal pressure. However, it is also possible to carry out it at elevated or reduced pressure (for example in a range from 0.5 to 5 bar).
  • Suitable solvents for the second step of the procedure [A] are generally customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane or tetrahydrofurane, dimethylsulfoxide, dimethylformamide or halogenohydrocarbons such as dichloromethane, trichloromethane or tetrachloromethane. Dichloromethane is prefened.
  • the process is in general carried out in a temperature range from -30°C to +40°C, preferably from -10°C to room temperature.
  • the process is generally carried out at normal pressure. However, it is also possible to carry out it at elevated or reduced pressure (for example in a range from 0.5 to 5 bar).
  • hydroxyl-protective group is in general removed with hydrogen in ethyl acetate, diethyl ether or tetrahydrofurane.
  • Suitable catalysts are noble metal catalysts, preferably palladium and palladium on charcoal .
  • Suitable solvents for the procedure [B] are generally customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane or tetrahydrofurane, dimethylsulfoxide, dimethylformamide or halogenohydrocarbons such as dichloromethane, trichloromethane or tetrachloromethane. Dichloromethane is prefened.
  • Suitable bases of the procedure [B] are generally inorganic or organic bases.
  • alkali metal hydroxies such as, for example, sodium hydroxide, sodium hydrogencarbonate or potassium hydroxide, alkaline earth metal hydroxides such as, for example, barium hydroxide, alkali metal carbonates such as calcium carbonate, or alkaline metal or organic amines (trialkyl(C,-C 6 )amines) such as triethylamine, or heterocycles such as l,4-diazabicyclo[2.2.2]octane (DABCO), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), or amides such as sodium amides, lithium butyl amide or butyllithium, pyridine or methylpiperidine. It is also possible to employ alkali metals, such as sodium or ist hydrides such as sodium hydride, as bases. Potassium carbonate, triethylamine, sodium hydrogencarbonate and sodium hydroxide are prefened.
  • alkali metal hydroxies such as, for example
  • the base is employed in an amount from 1 mol to 10 mol, preferably from 1.0 mol to 4 mol, relative to 1 mol of the compounds of the general formulae (VIII).
  • the process is in general carried out in a temperature range from -30°C to +100°C, preferably from -10°C to +50°C.
  • the process is generally carried out at normal pressure. However, it is also possible to carry out it at elevated or reduced pressure (for example in a range from 0.5 to 5 bar).
  • the compounds of the general formula (VI) are as species new and can be prepared by reaction of compounds of the general formula (XII)
  • T represents halogen, preferably bromine
  • Suitable solvents are generally customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane or tetrahydrofurane, acetone, dimethylsulfoxide, dimethylformamide or alcohols such as methanol, ethanol, propanol or halogenohydrocarbons such as dichloromethane, trichloromethane or tetrachloromethane. Acetone and dimethylformamide are prefened.
  • Suitable bases for the procedure are generally inorganic or organic bases.
  • alkali metal hydroxides such as, for example, sodium hydroxide or potassium hydroxide
  • alkaline earth metal hydroxides such as, for example, barium hydroxide
  • alkali metal carbonates such as sodium carbonate, potassium carbonate, alkaline earth metal carbonates such as calcium carbonate. Potassium carbonate (powdered) is prefened.
  • the base is employed in an amount from 1 mol to 10 mol, preferably from 1.0 mol to 4 mol, relative to 1 mol of the compounds of the general formulae (XIII).
  • the process is in general carried out in a temperature range from -30°C to +100°C, preferably from -10°C to +60°C.
  • the process is generally carried out at normal pressure. However, it is also possible to carry out it at elevated pressure or at reduced pressure (for example in a range from 0.5 to 5 bar).
  • the compounds of the general formula (XII) are known or as species new and can be prepared by reaction of 2,4-dihydroxy-benzaldehydes with benzylbromide in one of the abovementioned solvents and bases, preferably in acetone with potassium carbonate at room temperature.
  • the compounds of the general formula (XIV) are known or as species new and can be prepared by customary methods.
  • the compounds of the general formulae (III), (V), (VIII), (IX) and (X) are known or as species new and can be prepared by customary methods.
  • the compounds of the general formula (VII) can be prepared like described above or in a single step procedure by reacting compounds of the general formula (XIII) with compounds of the general formula (XIV) in the presence of a surplus of sodium ethylate under reflux .
  • the compounds according to the invention specifically inhibit the production of super- oxide by polymorphonuclear leukocytes (PMN). Furthermore, these compounds inhibit TNF ⁇ release and potentiate IL-10 production in human monocytes in response to a variety of stimuli including bacterial lipopolysaccharide (LPS), complement-opsonized zymosan (ZymC3b) and IL-l ⁇ .
  • PMN polymorphonuclear leukocytes
  • the described effects are probably mediated by the elevation of cellular cAMP probably due to inhibition of the type IV phosphodiesterase responsible for its degradation.
  • the compounds according to the invention are preferably suitable for the treatment and prevention of acute and chronic inflammation and auto immune diseases, such as emphysema, alveolitis, shock lung, all kinds of asthma, COPD, ARDS, bronchitis, arteriosclerosis, arthrosis, inflammations of the gastro-intestinal tract, rheumatoid arthritis, myocarditis, sepsis and septic shock, arthritis, rheumatoid spondylitis and osteoarthritis, gram negative sepsis, toxic shock syndrome, acute respiratory distress syndrome, bone reso ⁇ tion diseases, reperfusion injury, graft vs host reaction, allograft rejection, malaria, myalgias, HIV, AIDS, cachexia, Cronh's disease, ulcerative colitis, pyresis, system lupus erythematosus, multiple sclerosis, type I diabetes mellitus, psoriasis, Bechet's disease, anaphy
  • the compounds according to the invention are additionally suitable for reducing the damage to infarct tissue after reoxygenation.
  • the simultaneous administration of allopurinol to inhibit xanthine oxidase is of advantage.
  • Combination therapy with superoxide dismutase is also of use.
  • Blood was taken from healthy subjects by venous puncture and neutrophils were purified by dextran sedimentation and resuspended in the buffered medium.
  • Neutrophils were then stimulated by addition of 4 x 10 "8 M FMLP and superoxide generation measured as superoxide dismutase inhibitable reduction of cytochrome C by monitoring the OD 550 in a microtitre plate spectro- photometer, such as a Thermomax microtitre plate spectrometer. Initial rates were calculated using a kinetic calculation program, e.g. a softmax programme. Blank wells contained 200 units of superoxide dismutase.
  • 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 50 values in the range 0,001 ⁇ M-l ⁇ M.
  • Example 6 exhibits a IC 50 (O 2 -)-value of 0.08 ⁇ M.
  • the compounds according to the invention were incubated with 3.7 x 10 6 PMN for 5 min at 37°C before addition of 4 x 10 "8 M FMLP. After 6 min protein was precipitated by the addition of 1% v/v cone. HCl in 96% v/v ethanol containing 0.1 mM EDTA. After centrifugation the ethanolic extracts were evaporated to dryness under N 2 and resuspended in 50 mM Tris/HCl pH 7.4 containing 4 mM
  • cyclic AMP concentration in the extracts was determined using a cyclic AMP binding protein assay supplied by Amersham International pic. Cyclic AMP concentrations were expressed as percentage of vehicle containing control incubations.
  • Monocytes were isolated from peripheral blood by density centrifugation, followed by centrifugal elutriation.
  • Monocytes (1 x 10 6 ml "1 ) were stimulated with LPS (2 ⁇ g ml '1 ) and coincubated with the compounds at different concentrations (10"* to 10 ⁇ g ml "1 ). Compounds were dissolved in DMSO/medium (2% v/v). The cells were incubated in RPMI-
  • TNF 1640 medium glutamine/FCS supplemented and at 37°C in a humidified atmosphere with 5% CO 2 . 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.
  • 0.8 mg/ml zymC3b or 10 ng/ml IL-l ⁇ 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% CO 2 at 37°C. Supernatants were harvested and stored at -70°C.
  • the TNF ⁇ 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 ⁇ 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.
  • 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.
  • solutions of the active compound can be employed using suitable liquid vehicles.
  • 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.
  • example II 10.0 g (44.0 mmol) of example II are dissolved in 200 ml ethanol, and 5.98 g (88.0 mmol) sodium ethylate and 15.4 g (48.0 mmol) of example III are added.
  • example VI To a solution of 5.0 g of example VI in 100 ml THF are added 250 mg 10% palladium on activated charcoal, and the mixture is hydrogenated at atmospheric pressure and room temperature for 1-3 d. If neccessary, further 125 mg 10% Pd C are added and the hydrogenation is continued for 24 h. The mixtures is filtered through celite and the solvent is removed in vacuo to about 1/3 of the original volume. Dichloromethane is added, the mixture is stined at 0°C and the formed precipitate is filtered off.
  • the benzofuranyl epoxide is dissolved in 1:1 dry tetrahydrofurane/methanol, 2 mol- equivalent of the amine component are added, and the reaction mixture is stined at 40 - 50°C for 1-7 days. After concentration, the residue is taken up in dichloromethane or chloroform, and washed with water several times. The organic layer is dried over sodium sulfate, concentrated, and the crude product purified by column chromato- graphy over silica gel.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Benzofuranylaminoalcohols of general formula (I), process for their preparation and their use in medicaments, especially for the treatment of inflammatory processes.

Description

Benzofuranylaminoalcohols
The invention relates to Berizofuranylaminoalcohols, 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. TNFα, IL-1 or IL-6) and anti-inflammatory cytokines (e.g. IL-10) play a pivotal role in host defence mechanism. Uncontrolled production of inflammatory mediators can lead to acute or chronic inflammation, auto immune diseases, tissue damage, multi-organ failure and to death. It is additionally known that elevation of phagocyte cyclic AMP leads to inhibition of oxygen radical production and that this cell function is more sensitive than others such as aggregation or enzyme release.
Benzofuran derivatives having phosphodiesterase IV (PDE IV)-inhibiting action are described in EP 731 099. The reference describes only single-hydroxyl substituted derivatives, however. Benzofuranylaminoalcohols without 3-ureido moiety are disclosed for the treatment of diseases in the circulatory system in US 4,056,626. In order to provide alternative compounds with similar or improved PDE IV-inhibitory activity, the present invention relates to Benzofuranylaminoalcohols of the general formula (I)
Figure imgf000003_0001
in which
A represents hydrogen, straight-chain or branched acyl or alkoxycarbonyl, each having 1 to 6 carbon atoms, halogen, carboxyl, cyano, nitro, hydroxyl, trifluoromethyl or trifluoromethoxy, or straight-chain or branched alkyl having 1 to 6 carbon atoms, which is optionally substituted by carboxyl, alkoxy or alkoxycarbonyl each having 1 to 4 carbon atoms, phenoxy or benzoyl,
R1 represents hydrogen, straight-chain or branched alkyl having 1 to 4 carbon atoms, an amino protecting group or a group of the formula -CO-R7
in which
R7 denotes straight chain or branched alkoxy having 1 to 4 carbon atoms,
R2 and R3 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 R3 together with the nitrogen atom form a 5-, 6- or 7-membered saturated heterocycle optionally having a further oxygen atom,
R4 represents aryl having 6 to 10 carbon atoms or represents a 5-, 6- or 7-membered, aromatic, saturated or unsaturated heterocycle, which can contain 1 to 3 oxygen, sulphur and/or nitrogen atoms as heteroatoms or a residue of a formula -NR8,
wherein
R8 denotes hydrogen or straight-chain or branched alkyl or alkoxycarbonyl each having 1 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 hydroxyl, halogen, nitro, 1H- tetrazolyl, pyridyl, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoro- methoxy, 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 carbon atoms, which is optionally substituted by carboxyl or straight-chain or branched alkoxycarbonyl having 1 to 4 carbon atoms or by a group of formula -NR9R10, -SR11, -(NH)a-SO2R12 or -O-SO2R13,
in which
R9 and R10 are identical or different and denote hydrogen or a straight-chain or branched alkyl having 1 to 4 carbon atoms,
or
R9 denotes hydrogen
and
R10 denotes straight-chain or branched acyl having 1 to 6 carbon atoms,
R11 denotes hydrogen or straight-chain or branched alkyl having 1 to 4 carbon atoms,
a denotes a number 0 or 1 ,
R12 and R13 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 sulfur atom
R5 and R6 represent hydrogen, straight-chain or branched alkyl having 1 to 6 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms or by a 5- to 7-membered aromatic, saturated or unsaturated heterocycle having 1 to 3 heteroatoms from the series comprising N, S, O and/or a residue of a formula -NR14
wherein
R14 denotes hydrogen or straight-chain or branched alkyl or alkoxycarbonyl each having 1 to 6 carbon atoms
and to which a phenyl ring can be fused and which are optionally monosub- stituted to disubstituted by identical or different substituents from the series comprising halogen, cyano or by a straight-chain or branched alkyl or alkoxy- carbonyl each having 1 to 6 carbon atoms,
or represent a 6-membered saturated N-heterocycle, which is optionally substituted by alkoxycarbonyl having 1 to 6 carbon atoms,
or
R5 and R6 together with the nitrogen atom form a 5- to 6-membered aromatic, saturated or unsaturated heterocycle having 1 to 3 heteroatoms from the series comprising N, S, O and/or a residue of a formula -NR14, and to which a phenyl ring can be fused and which is optionally monosub- stituted to disubstituted by identical or different substituents from the series comprising halogen, cyano or by a straight-chain or branched alkyl or alkoxy- carbonyl each having 1 to 6 carbon atoms,
and salts thereof.
The benzofuranylaminoalcohols according to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.
Physiologically acceptable salts are preferred in the context of the present invention. Physiologically acceptable salts of the benzofuranylaminoalcohols can be metal or ammonium salts of the substances according to the invention, which contain a free carboxyhc 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 triethyl- amine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.
Physiologically acceptable salts can also be salts of the compounds according to the invention with inorganic or organic acids. Preferred salts here are those with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or salts with organic carboxyhc or sulphonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, ethane- sulphonic acid, benzenesulphonic acid, toluenesulphonic acid or naphthalenedi- sulphonic acid.
The compounds according to the invention can exist in stereoisomeric forms which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers). The invention relates both to the antipodes and to the racemate forms, as well as to individual diastereomers and to the diastereomer mixtures. The racemate forms, like the diastereomers, can be separated into the stereoisomerically uniform constituents in a known manner.
Heterocycle in general represents a 5- to 7-membered aromatic, saturated or unsaturated, preferably 5- to 6- membered, aromatic or saturated ring, which can contain up to 3 oxygen, sulphur, nitrogen atoms or a residue of a formula -NR14 as heteroatoms, wherein R14 has the abovementioned meaning, and to which further aromatic rings can be fused.
The following are mentioned as preferred: thienyl, furyl, pyrrolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxazolyl, thiazolyl, dihydrothiazolyl, benzothiaazolyl, isothiazolyl, benzisothiazolyl, oxazolyl, benzoxa- zolyl, isoxazolyl, imidazolyl, benzimidazolyl, indolyl, morpholinyl, pyrrolidinyl, piperidyl, piperazinyl, oxazolinyl or triazolyl.
Preferred compounds of the general formula (I) are those
in which
A represents hydrogen, halogen, carboxyl, cyano, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy or alkoxy having up to 4 carbon atoms
R1 represents hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a group of the formula -CO-R7
in which
R7 denotes straight chain or branched alkoxy having up to 4 carbon atoms, R2 and R3 are identical or different and represent hydrogen, cyclobutyl, cyclopentyl, cyclohexyl or straight-chain or branched alkyl, alkoxycarbonyl or alkenyl each having up to 4 carbon atoms, or
or
R2 and R3 together with the nitrogen atom form a pyrrolidinyl-, piperidinyl- or morpholinyl-ring,
and
R4 represents phenyl, pyridyl or thienyl, wherein all 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 up to 3 carbon atoms, or by straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by carboxyl or straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms
L represents an oxygen or sulfur atom,
R5 and R6 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl, pyridyl, imidazolyl, pyrryl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, wherein the heterocycles optionally contain a residue of a formula -NR14,
wherein
R14 denotes hydrogen or straight-chain or branched alkyl or alkoxycarbonyl each having up to 4 carbon atoms, and wherein the ring systems are optionally monosubstituted by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms,
or represent a 6-membered saturated N-heterocycle, which is optionally substituted by alkoxycarbonyl having 1 to 6 carbon atoms,
or
R5 and R6 together with the nitrogen atom form a pyrazolyl-, triazolyl-, tetrazolyl-, imidazolyl-, pyrryl-, morpholinyl-, piperidinyl-, pyrrolidinyl-, piperazinylring, wherein the heterocycles optionally contain a residue of a formula -NR14,
and wherein the ringsystem is optionally monosubstituted to trisubstituted by identical or different substituents from the series comprising halogen, cyano or by a straight-chain or branched alkyl having up to 6 carbon atoms,
and salts thereof.
Particularly preferred compounds of the general formula (I) are those
in which
A represents hydrogen,
R1 represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms or a group of the formula -CO-R7,
in which
R7 denotes straight chain or branched alkoxy having up to 3 carbon atoms, R2 and R3 represent hydrogen,
R4 represents phenyl or pyridyl, which are optionally up to difold substituted by identical or different substituents from the series fluorine, chlorine, methyl or methoxy,
L represents an oxygen atom,
R5 and R6 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl, pyridyl, imidazolyl, pyrryl, piperidinyl, wherein the heterocycles optionally contain a residue of a formula -NR14,
wherein
R14 denotes hydrogen or straight-chain or branched alkyl or alkoxycarbonyl each having up to 3 carbon atoms,
and wherein the ring systems are optionally monosubstituted by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms,
or represent a 6-membered saturated N-heterocycle, which is optionally substituted by alkoxycarbonyl having 1 to 6 carbon atoms,
or
R5 and R6 together with the nitrogen atom form a imidazolyl-, pyrryl-, morpholinyl-, piperidinyl-, pyrrolidinyl-, piperazinylring, wherein the heterocycles optionally contain a residue of a formula -NR14,
wherein R14 have the abovementioned meaning of R14 and is identical or different to the latter,
and wherein the ringsystem are optionally monosubstituted to trisubstituted by identical or different substituents from the series comprising by a straight-chain or branched alkyl or alkoxycarbonyl each having up to 3 carbon atoms,
and salts thereof.
Very particular preferred compounds of the general formula (I) are those shown in table
A:
Table A
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
A process for the preparation of the compounds of the general formula (I) has additionally been found, characterized in that
compounds of the general formula (II)
Figure imgf000015_0001
in which
A, R1, R2, R3, R4 and L have the abovementioned meaning,
are reacted with amines of the general formula (III)
R5R6-NH (III)
in which
R5 and R6 have the abovementioned meaning,
in the presence of an inert solvent.
The process according to the invention can be illustrated by way of example by the following equations:
Figure imgf000016_0001
Suitable solvents are generally customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane or tetrahydrofurane, acetone, dimethylsulfoxide, dimethylformamide or alcohols such as methanol, ethanol, propanol or halogenohydrocarbons such as dichloromethane, trichloromethane or tetrachloromethane and mixtures of two or three of the abovementioned solvents. A mixture of methanol and tetrahydrofurane is preferred.
The process is in general carried out in a temperature range from -30°C to +100°C, preferably from 0°C to 50°C.
The process is generally carried out at normal pressure. However, it is also possible to carry out it at elevated or reduced pressure (for example in a range from 0.5 to 5 bar).
The compounds of the general formula (II) are new and can be prepared by reacting compounds of the general formula (IV)
Figure imgf000017_0001
in which,
L, R1, R2, R3 and R4 have the abovementioned meaning,
with glycidol of the formula (V)
Figure imgf000017_0002
in the presence of triphenylphosphin and diethylazodicarboxylate in an inert solvent.
It is possible to use the glycidol of formula (V) in racemic or in pure enantiomeric form.
Suitable solvents are generally customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane or tetrahydrofurane, acetone, dimethylsulfoxide, dimethylformamide or alcohols such as methanol, ethanol, propanol or halogenohydrocarbons such as dichloromethane, trichloromethane or tetrachloromethane. Tetrahydrofurane is prefened.
The process is in general carried out in a temperature range from -30°C to +100°C, preferably from 0°C to room temperature.
The process is generally carried out at normal pressure. However, it is also possible to carry out it at elevated or reduced pressure (for example in a range from 0.5 to 5 bar). The compounds of the general formula (III) and (V) are known or can be prepared by customary methods.
The compounds of the general formula (IV) are known or as species new and can be prepared characterized in that
[A] first compounds of the general formula (VI)
Figure imgf000018_0001
in which
A and R4 have the abovementioned meaning,
are reacted with a catalytic amount of alkali alcoholates, prefened sodium ethanolate to compounds of the general formula (VII)
Figure imgf000018_0002
in which
A and R4 have the abovementioned meaning,
followed by reaction with compounds of the general formula (VIII)
R2-N=OL (VIII) in which R2 and L have the abovementioned meaning,
in inert solvents, if appropriate in the presence of a base and/or in the presence of an auxiliary to compounds of a general formula (IX)
Figure imgf000019_0001
in which
A, L, R2 und R4 have the abovementioned meaning,
and in a last step the benzyl group is eliminated by hydrogenation,
or
[B] compounds of the general formula (X)
Figure imgf000019_0002
in which
A, R1 and R4 have the abovementioned meaning
are reacted with compounds of the general formula (VIII)
R2-N=C=L (VIII) in which
L and R2 have the abovementioned meaning,
in inert solvents, if appropriate in the presence of a base,
and in the case of R2/R3 = H and L = O,
compounds of the general formulae (VII) or (X) are reacted with compounds of the general formula (XI)
E-SO2-N=C=O(XI) in which
denotes halogen, preferably chlorine,
and in the case of R7RJ= H and L= S,
compounds of the general formula (X) are reacted with NH4SCN,
and in case of R1, R2 and/or R3 ≠ H the amino groups are derivated optionally by common methods.
Suitable solvents for the first step of the procedure [A] (VI-VII) are generally alcohols such as methanol, ethanol or propanol. Ethanol is prefened.
Suitable bases for the first step are generally alkali alcoholates such as sodium methanolate, sodium ethanolate or sodium propanolate. Sodium ethanolate ist prefened. The base is employed in catalytic amounts.
The process is in general carried out in a temperature range from 0°C to 60°C, preferably at room temperature.
The process is generally carried out at normal pressure. However, it is also possible to carry out it at elevated or reduced pressure (for example in a range from 0.5 to 5 bar).
Suitable solvents for the second step of the procedure [A] (VII -> IX) are generally customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane or tetrahydrofurane, dimethylsulfoxide, dimethylformamide or halogenohydrocarbons such as dichloromethane, trichloromethane or tetrachloromethane. Dichloromethane is prefened.
The process is in general carried out in a temperature range from -30°C to +40°C, preferably from -10°C to room temperature.
The process is generally carried out at normal pressure. However, it is also possible to carry out it at elevated or reduced pressure (for example in a range from 0.5 to 5 bar).
The hydroxyl-protective group is in general removed with hydrogen in ethyl acetate, diethyl ether or tetrahydrofurane. Suitable catalysts are noble metal catalysts, preferably palladium and palladium on charcoal .
Suitable solvents for the procedure [B] are generally customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane or tetrahydrofurane, dimethylsulfoxide, dimethylformamide or halogenohydrocarbons such as dichloromethane, trichloromethane or tetrachloromethane. Dichloromethane is prefened. Suitable bases of the procedure [B], if appropriate, are generally inorganic or organic bases. These preferably include alkali metal hydroxies such as, for example, sodium hydroxide, sodium hydrogencarbonate or potassium hydroxide, alkaline earth metal hydroxides such as, for example, barium hydroxide, alkali metal carbonates such as calcium carbonate, or alkaline metal or organic amines (trialkyl(C,-C6)amines) such as triethylamine, or heterocycles such as l,4-diazabicyclo[2.2.2]octane (DABCO), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), or amides such as sodium amides, lithium butyl amide or butyllithium, pyridine or methylpiperidine. It is also possible to employ alkali metals, such as sodium or ist hydrides such as sodium hydride, as bases. Potassium carbonate, triethylamine, sodium hydrogencarbonate and sodium hydroxide are prefened.
The base is employed in an amount from 1 mol to 10 mol, preferably from 1.0 mol to 4 mol, relative to 1 mol of the compounds of the general formulae (VIII).
The process is in general carried out in a temperature range from -30°C to +100°C, preferably from -10°C to +50°C.
The process is generally carried out at normal pressure. However, it is also possible to carry out it at elevated or reduced pressure (for example in a range from 0.5 to 5 bar).
The compounds of the general formula (VI) are as species new and can be prepared by reaction of compounds of the general formula (XII)
Figure imgf000022_0001
in which
has the abovementioned meaning, with hydroxylamine hydrochloride in a presence of sodium formiate to compounds of the general formula (XIII)
Figure imgf000023_0001
in which
A has the abovementioned meaning,
followed by reaction with compounds of the general formula (XIV)
R4-CO-CH2-T (XIV)
in which
R has the abovementioned meaning,
and
T represents halogen, preferably bromine,
in inert solvents and in the presence of a base.
Suitable solvents are generally customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane or tetrahydrofurane, acetone, dimethylsulfoxide, dimethylformamide or alcohols such as methanol, ethanol, propanol or halogenohydrocarbons such as dichloromethane, trichloromethane or tetrachloromethane. Acetone and dimethylformamide are prefened. Suitable bases for the procedure are generally inorganic or organic bases. These preferably include alkali metal hydroxides such as, for example, sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as, for example, barium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate, alkaline earth metal carbonates such as calcium carbonate. Potassium carbonate (powdered) is prefened.
The base is employed in an amount from 1 mol to 10 mol, preferably from 1.0 mol to 4 mol, relative to 1 mol of the compounds of the general formulae (XIII).
The process is in general carried out in a temperature range from -30°C to +100°C, preferably from -10°C to +60°C.
The process is generally carried out at normal pressure. However, it is also possible to carry out it at elevated pressure or at reduced pressure (for example in a range from 0.5 to 5 bar).
The compounds of the general formula (XII) are known or as species new and can be prepared by reaction of 2,4-dihydroxy-benzaldehydes with benzylbromide in one of the abovementioned solvents and bases, preferably in acetone with potassium carbonate at room temperature.
The compounds of the general formula (XIII) are new and can be prepared like described above.
The compounds of the general formula (XIV) are known or as species new and can be prepared by customary methods.
The compounds of the general formulae (III), (V), (VIII), (IX) and (X) are known or as species new and can be prepared by customary methods. The compounds of the general formula (VII) can be prepared like described above or in a single step procedure by reacting compounds of the general formula (XIII) with compounds of the general formula (XIV) in the presence of a surplus of sodium ethylate under reflux .
Surprisingly it was found that compounds given by the general formula (I) inhibited oxygen radical formation as well as TNFα (tumor necrosis factor) production, but potentiated the release of IL-10. These compounds elevated cellular cyclic AMP probably by inhibition of phagocyte phosphodiesterase activity.
The compounds according to the invention specifically inhibit the production of super- oxide by polymorphonuclear leukocytes (PMN). Furthermore, these compounds inhibit TNFα release and potentiate IL-10 production in human monocytes in response to a variety of stimuli including bacterial lipopolysaccharide (LPS), complement-opsonized zymosan (ZymC3b) and IL-lβ.
The described effects are probably mediated by the elevation of cellular cAMP probably due to inhibition of the type IV phosphodiesterase responsible for its degradation.
They can therefore be employed in medicaments for the treatment of acute and chronic inflammatory processes.
The compounds according to the invention are preferably suitable for the treatment and prevention of acute and chronic inflammation and auto immune diseases, such as emphysema, alveolitis, shock lung, all kinds of asthma, COPD, ARDS, bronchitis, arteriosclerosis, arthrosis, inflammations of the gastro-intestinal tract, rheumatoid arthritis, myocarditis, sepsis and septic shock, arthritis, rheumatoid spondylitis and osteoarthritis, gram negative sepsis, toxic shock syndrome, acute respiratory distress syndrome, bone resoφtion diseases, reperfusion injury, graft vs host reaction, allograft rejection, malaria, myalgias, HIV, AIDS, cachexia, Cronh's disease, ulcerative colitis, pyresis, system lupus erythematosus, multiple sclerosis, type I diabetes mellitus, psoriasis, Bechet's disease, anaphylactoid puφura nephritis, chronic glomerulo- nephtritis, inflammatory bowel disease and leukemia. 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 medium.
2. Inhibition of FMLP-stimulated production of superoxide racidal anions. Neutrophils (2.5 x 105 ml"1) 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 μM, the DMSO concentration was 0.1% v/v in all wells. After addition of cytochalasin b (5 μg x ml"1) the plate was incubated for 5 min at 37°C. Neutrophils were then stimulated by addition of 4 x 10"8 M FMLP and superoxide generation measured as superoxide dismutase inhibitable reduction of cytochrome C by monitoring the OD550 in a microtitre plate spectro- photometer, such as a Thermomax microtitre plate spectrometer. Initial rates were calculated using a kinetic calculation program, e.g. a softmax programme. Blank wells contained 200 units of superoxide dismutase.
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 IC50 values in the range 0,001 μM-lμM. Example 6 exhibits a IC50(O2-)-value of 0.08μM.
3. Measurement of PMN cyclic AMP concentration
The compounds according to the invention were incubated with 3.7 x 106 PMN for 5 min at 37°C before addition of 4 x 10"8 M FMLP. After 6 min protein was precipitated by the addition of 1% v/v cone. HCl 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/HCl pH 7.4 containing 4 mM
EDTA. The cyclic AMP concentration in the extracts was determined using a cyclic AMP binding protein assay supplied by Amersham International pic. Cyclic AMP concentrations were expressed as percentage of vehicle containing control incubations.
Compounds elavate the cAMP-level at 1 μM 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 descrete stereospecific site on the phosphodiesterase enzyme. Compounds according to the invention had IC50 values ranging from 0.001 μM to 10 μM. Example 6 exhibits a IC50(PDE IV) of 0.17 μM. 5. Assay of human platelet phosphodiesterase
This was performed essentially as described by Schmidt et al. (Biochem. Pharmacol. 42, 153-162, 1991) except that the homogenate was treated with vanadate glutathione as above. Compounds according to the invention had IC50 values greater than 100 μM.
6. Assay of binding to the rolipram binding site in rat brain membranes
This was performed essentially as described by Schneider et al. (Eur. J. Pharmacol. 127, 105-115, 1986). Compounds according to the invention had
IC50 values in the range 0,01 to 10 μM.
7. Preparation of human monocytes
Blood was taken from normal donors. Monocytes were isolated from peripheral blood by density centrifugation, followed by centrifugal elutriation.
8. Endotoxin induced TNF release
Monocytes (1 x 106 ml"1) were stimulated with LPS (2 μg ml'1) and coincubated with the compounds at different concentrations (10"* to 10 μg 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
B6D2F1 mice (n=10) were sensitized with galactosamine (600 mg/kg), and shock and lethality were triggered by LPS (0.01 μg/mouse). The compounds were administered intravenously 1 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.
10. Stimulation of human monocytes and determination of cytokine levels Human monocytes (2x105 in 1 ml) were stimulated with lOO ng/ml LPS,
0.8 mg/ml zymC3b or 10 ng/ml IL-lβ 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% CO2 at 37°C. Supernatants were harvested and stored at -70°C. The TNFα concentration was measured by ELISA using the A6 anti-TNF monoclonal antibody (Miles) as the primary antibody. The secondary antibody was the polyclonal anti-TNFα 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 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.
In spite of this, it may be necessary to depart from the amounts mentioned, in particular depending on the body weight or the type of application route, on individual behaviour towards the medicament, the manner of its formulation and the time or interval at which administration takes place. Thus, in some cases it may be sufficient to manage with less than the abovementioned minimum amount, while in other cases the upper limit mentioned must be exceeded. In the case of administration of relatively large amounts, it is advisable to divide these into several individual doses over the course of the day.
Solvents
a = dichloromethane/methanol 15 (v/v) b dichloromethane/methanol 20 c = dichloromethane/methanol 50 d dichloromethane/methanol 40 e = ethylacetate/cyclohexane 5 f chlorofoπn/methanol 10 g dichloromethane/methanol 10 h dichloromethane/methanol 30 chloroform/methanol 30 chloroform/methanol/water/acetic acid 70:30:5:5 k dichloromethane/methanol/formic acid 9:1 :0.1
1 dichloromethane/methanol/NH 9:1:0.1 m dichloromethane/methanol 5 : 1 n dichloromethane/methanol 7: 1 o dichloromethane/methanol/NH3 12:1:0.1 Starting compounds:
Example I
4-Benzyloxy-2-hydroxybenzaldehyde
Figure imgf000031_0001
13.8 g (0.1 mol) 2,4-dihydroxybenzaldehyde are dissolved in 150 ml acetone, 17.1 g
(0.1 mol) benzylbromide and 13.8 g (0.1 mol) potassium carbonate are added, and the mixture is stined at room temperature for 3 d. After filtration, the solvent is removed in vacuo and the residual crude product further purified by column chromatography on silica gel using dichloromethane as eluent. Yield: 9.2 g (40%) m.p.: 81-82°C
Η-NMR (CDC13, 400 MHz): δ = 5.11 (s, 2H; CH2): 6.51 (d, 1H, Ar-H); 6.61 (dd, 1H, Ar-H); 7.32 - 7.45 (m, 6H, Ar-H); 9.82 (s, 1H, CHO); 11.60 (s, 1H, OH) ppm.
Example II
4-Benzyloxy-2-hydroxybenzonitrile
Figure imgf000031_0002
25.0 g (0.11 mol) of the example I, 8.67 g (0.13 mol) hydroxylamine hydrochloride and 15.0 g (0.22 mol) sodium formate are dissolved in 170 ml formic acid, and the solution stined under reflux for 1-3 h. The reaction mixture is cooled to room temperature, poured into ice/water and extracted with dichloromethane. The organic layer is dried (Na2SO4), the solvent removed in vacuo and the residue trituated with dichloromethane. Alternatively, the precipitate which is formed after dilution with ice/water is filtered off and dried in a desiccator in the presence of phosphorus pentoxide. The crude product is crystallized from dichloromethane/cyclohexane. Yield: 15.0 g (61%) m.p.: 135-136°C
Η-NMR (400 MHz, DMSO-cLJ: δ = 5.13 (s, 2H, CH2); 6.58 (d, 1H, Ar-H); 6.60 (dd, 1H, Ar-H); 7.32 - 7.46 (m, 5H, Ar-H); 7.50 (d, 1H, Ar-H); 11.10 (br.s, 1H, OH) ppm.
Example III
ω-Bromo-2,4-dichloroacetophenone
Figure imgf000032_0001
To a solution of 155.2 g (788 mmol) 2,4-dichloroacetophenone in 450 ml glacial acetic acid are added 40.4 ml (788 mmol) bromine at 50°C. After 1 h at 50°C, further 4 ml (78.8 mmol) bromine are added and the mixture is stined for an additional hour. The solution is cooled to room temperature, concentrated to half of its volume and diluted with 800 ml water. The mixture is neutralized with solid sodium carbonate and extracted three times with ethyl acetate. The organic layer is dried (Na2SO4), the solvent removed in vacuo, finally under high vacuum. The crude product is used directly without further purification for the following reaction and stored in the meantime at
-20°C. Yield: 211.4 g (quant.); yellow oil Example IV
3-Amino-2-(2,4-dichlorobenzoyl)-6-benzyloxy-benzofuran
Figure imgf000033_0001
a ) Single step procedure:
10.0 g (44.0 mmol) of example II are dissolved in 200 ml ethanol, and 5.98 g (88.0 mmol) sodium ethylate and 15.4 g (48.0 mmol) of example III are added.
The mixture is stined under reflux for 4 d. During this time further 12.0 g sodium ethylate and 7.7 g of example III are added. The solvent is removed in vacuo and the residue is purified by column chromatography on silica gel (eluent: 1. dichloromethane, 2. dichloromethane/methanol 98.2). Yield: 8.1 g (44%) m.p.: 158°C NMR-data see below.
Example V
Two step procedure:
a) ω-[(5-Benzyloxy-2-cyan)-phenoxy]-2,4-dichloroacetophenone:
Figure imgf000034_0001
To a mixture of 26.6 g (118 mmol) of example II and 48.85 g (354 mmol) powdered potassium carbonate in 800 ml acetone are added 34.8 g (130 ml) of example III under reflux. After a further 1-2 h under reflux, the mixture is filtered, the solvent evaporated in vacuo and the residue triturated using dichloromethane (1st crop of product) and dichloromethane/cyclohexane (4:1) (2nd crop of product). Yield: 26.2 g (54%)
Two step procedure:
To a solution of 37.5 g (91 mmol) of the compound of example Va in 550 ml ethanol, three pellets of sodium hydroxide are added and the mixture is stined at 50°C for 30 min. After cooling to room temperature, the mixture is filtered off ( 1 st crop of product) and the filtrate is diluted with 300 ml of water. Most of the ethanol is removed in vacuo and the formed precipitate is filtered (2nd crop of product).
Yield: 36.7 g (98%)
Η-NMR (DMSO-d6, 400 MHz): δ = 5.14 (s, 2H, CH2): 6.97 (dd, 1H, Ar-H); 7.10 (d, 1H, Ar-H); 7.31 - 7.47 (m, 5H, Ar-H); 7,53 (br.s, 2H, NH2); 7.57 (s,
2H, Ar-H); 7.75 (s, 1H, Ar-H); 7.93 (d, 1H, Ar-H); ppm.
Ms (EI): 411 (M+) Example VI
N-[2-(2,4-Dichlorobenzoyl)-6-benzyloxy-benzofuran-3-yl]urea
Figure imgf000035_0001
30.9 g (75 mmol) of example IV are dissolved in 750 ml dichloromethane and cooled to 0°C. 11.6 g (82 mmol) chlorosulfonyl isocyanate in dichloromethane are added and the mixture is stined at 0°C for 30 min and at room temperature for 3 h. The solvent is removed in vacuo, the residue suspended in water and stined vigorously for 3 h at
60°C. After cooling to r.t. the suspension is filtered, the crude product dried in a desiccator in the presence of phosphorus pentoxide and triturated with diisopropylether at 40°C.
Yield: 33.7 g (98%) m.p.: 192-193°C
'H-NMR (DMSO-d6, 400 MHz): δ = 5.18 (s, 2H, CH2); 7.00 (dd, 1H, Ar-H): 7.05 (br.s,
2H, NH2): 7.20 (d, 1H, Ar-H); 7.30 - 7.47 (m, 5H, Ar-H); 7.61 (dd, 1H, Ar-H); 7.68 (d,
1H, Ar-H); 7.82 (d, 1H, Ar-H); 8.37 (d, 1H, Ar-H); 9.71 (s, 1H, NH) ppm.
MS (FAB): 455 (M+H)+ Example VII
N-[2-(2,4-Dichlorobenzoyl)-6-hydroxy-benzofuran-3-yl]urea
Figure imgf000036_0001
To a solution of 5.0 g of example VI in 100 ml THF are added 250 mg 10% palladium on activated charcoal, and the mixture is hydrogenated at atmospheric pressure and room temperature for 1-3 d. If neccessary, further 125 mg 10% Pd C are added and the hydrogenation is continued for 24 h. The mixtures is filtered through celite and the solvent is removed in vacuo to about 1/3 of the original volume. Dichloromethane is added, the mixture is stined at 0°C and the formed precipitate is filtered off.
Yield: 4.0 g (quant.) m.p.: 230-231°C
'H-NMR (DMSO-d6, 400 MHz): δ = 6.73 (d, 1H, Ar-H); 6.80 (dd, 1H, Ar-H); 7.03 (br.s, 2H, NH2): 7.60 (dd, 1H, Ar-H); 7.65 (d, 1H, Ar-H); 7.80 (s, 1H, Ar-H); 8.30 (d,
1H, Ar-H); 9.72 (s, 1H, NH); 10.40 (br.s, 1H, OH) ppm.
MS (El): 364 (M+).
In analogy to this procedure the following examples shown in table B are prepared: Table B:
Figure imgf000037_0001
Figure imgf000037_0003
Example XVI
Figure imgf000037_0002
15 g (41.1 mmol) 6-hydroxybenzofurane, 2.82 ml (41.1 mmol) R-glycidol, and 10.8 g (41.1 mmol) triphenylphosphin are dissolved in 200 ml dry THF. At 0°C 6.43 ml
(41.1 mmol) diethyl azodicarboxylate (DEAD) are added dropwise, and the reaction mixture is stined at room temperature for a total of 4 days. During this time, three additional portions of glycidol (0.94 ml, 13.7 mmol each), triphenylphosphin (3.6 g, 13.7 mmol each), and DEAD (2.1 ml, 13.7 mmol each) are added to the reaction mixture. The mixture is filtered (first crop of product), the filtrate concentrated to half of its original volume and filtered again (second crop of product). The filtrate is diluted with dichloromethane, washed with water twice, dried over sodium sulfate, and concentrated to a volume of about 200 ml. An equal volume of diethylether is added, the mixture stined for 15 min, and filtered again to yield a third crop of product. Combined yield: 15.89 g (91.8% of th.) Rf = 0.57 (chloroform/methanol (15:1))
Preparation examples:
General procedure for the synthesis of benzofuranylamino alcohols:
The benzofuranyl epoxide is dissolved in 1:1 dry tetrahydrofurane/methanol, 2 mol- equivalent of the amine component are added, and the reaction mixture is stined at 40 - 50°C for 1-7 days. After concentration, the residue is taken up in dichloromethane or chloroform, and washed with water several times. The organic layer is dried over sodium sulfate, concentrated, and the crude product purified by column chromato- graphy over silica gel.
The following examples were prepared in analogy to the general procedure:
Figure imgf000039_0001
Figure imgf000040_0001

Claims

We claim:
1. Benzofuranylaminoalcohohols of the general formula (I)
Figure imgf000041_0001
in which
A represents hydrogen, straight-chain or branched acyl or alkoxycarbonyl, each having up to 6 carbon atoms, halogen, carboxyl, cyano, nitro, hydroxyl, trifluoromethyl or trifluoromethoxy, or straight-chain or branched alkyl having 1 to 6 carbon atoms, which is optionally substituted by carboxyl, alkoxy or alkoxycarbonyl each having 1 to 4 carbon atoms, phenoxy or benzoyl,
R1 represents hydrogen, straight-chain or branched alkyl having 1 to 4 carbon atoms, an amino protecting group or a group of the formula -CO-R7
in which
R7 denotes straight chain or branched alkoxy having 1 to 4 carbon atoms,
R2 and R3 are identical or different and represent hydrogen, cycloalkyl having 3 to 6 carbon atoms, straight chain or branched alkyl, alkoxycarbonyl or alkenyl each having 1 to 8 carbon atoms, or
R2 and R3 together with the nitrogen atom form a 5- to 7-membered saturated heterocycle optionally having a further oxygen atom,
R4 represents aryl having 6 to 10 carbon atoms or represents a 5- to 7-membered, aromatic, saturated or unsaturated heterocycle, which can contain 1 to 3 oxygen, sulphur and/or nitrogen atoms as heteroatoms or a residue of a formula -NR8,
wherein
R8 denotes hydrogen or straight-chain or branched alkyl or alkoxycarbonyl each having 1 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 hydroxyl, halogen, nitro, lH-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 carbon atoms, which is optionally substituted by carboxyl or straight- chain or branched alkoxycarbonyl having 1 to 4 carbon atoms or by a group of formula -NR9R10, -SR11, -(NH)a-SO2R12 or -O-SO2R13,
in which
R9 and R10 are identical or different and denote hydrogen or a straight- chain or branched alkyl having 1 to 4 carbon atoms, or
R9 denotes hydrogen
and
R10 denotes straight-chain or branched acyl having 1 to 6 carbon atoms,
R11 denotes hydrogen or straight-chain or branched alkyl having 1 to
4 carbon atoms,
a denotes a number 0 or 1 ,
R12 and R13 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 sulfur atom
R5 and R6 represents hydrogen or straight-chain or branched alkyl having 1 to 6 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms or by a 5- to 7-membered aromatic, saturated or unsaturated heterocycle having 1 to 3 heteroatoms from the series comprising N, S, O and/or a residue of a formula -NR14
wherein
R14 denotes hydrogen or straight-chain or branched alkyl or alkoxycarbonyl each having 1 to 6 carbon atoms and to which a phenyl ring can be fused and which are optionally monosubstituted to disubstituted by identical or different substituents from the series comprising halogen, cyano or by a straight-chain or branched alkyl or alkoxycarbonyl each having 1 to 6 carbon atoms,
or represent a 6-membered saturated N-heterocycle, which is optionally substituted by alkoxycarbonyl having 1 to 6 carbon atoms,
or
R5 and R6 together with the nitrogen atom form a 5- to 6-membered, aromatic, saturated or unsaturated heterocycle having 1 to 3 heteroatoms from the series comprising N, S, O and/or a residue of a formula -NR14,
and to which a phenyl ring can be fused and which is optionally monosubstituted to disubstituted by identical or different substituents from the series comprising halogen, cyano or by a straight-chain or branched alkyl or alkoxycarbonyl each having 1 to 6 carbon atoms,
and salts thereof.
2. Compounds according to claim 1 , in which
A represents hydrogen, halogen, carboxyl, cyano, nitro, hydroxyl, trifluo- romethyl, trifluoromethoxy or alkoxy having 1 to 4 carbon atoms
R1 represents hydrogen, straight-chain or branched alkyl having 1 to 4 carbon atoms or a group of the formula -CO-R7
in which R7 denotes straight chain or branched alkoxy having 1 to 4 carbon atoms,
R2 and R3 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
R2 and R3 together with the nitrogen atom form a pynolidinyl-, piperidinyl- or moφholinyl-ring,
and
R4 represents phenyl, pyridyl or thienyl, wherein all 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 1 to 3 carbon atoms, or by methyl, ethyl, n-propyl or isopropyl which is optionally substituted by carboxyl or straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms
represents an oxygen or sulfur atom,
R5 and R6 represents hydrogen or straight-chain or branched alkyl having 1 to 4 carbon atoms, which is optionally substituted by phenyl, pyridyl, imidazolyl, pyrryl, moφholinyl, piperidinyl, piperazinyl, pynolidinyl, wherein the heterocycles optionally contain a residue of a formula -NR14, wherein
R14 denotes hydrogen or straight-chain or branched alkyl or alkoxycarbonyl each having 1 to 4 carbon atoms,
and wherein the ring systems are optionally monosubstituted by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having 1 to 3 carbon atoms,
or
R5 and R° together with the nitrogen atom form a pyrazolyl-, triazolyl-, tetrazolyl-, imidazolyl-, pyrryl-, moφholinyl-, piperidinyl-, pynolidinyl-, piperazinylring, wherein the heterocycles optionally contain a residue of a formula -NR14',
and wherein the ringsystem is optionally monosubstituted to trisubstituted by identical or different substituents from the series comprising halogen, cyano or by a straight-chain or branched alkyl having 1 to 6 carbon atoms,
and salts thereof.
3. Compounds according to claim 1 or 2, in which
A represents hydrogen,
R1 represents hydrogen, methyl, ethyl, n-propyl or isopropyl or a group of the formula -CO-R7,
in which R7 denotes methoxy, ethoxy, n-propoxy or isopropoxy,
R2 and R3 represent hydrogen,
R4 represents phenyl or pyridyl, which are optionally up to difold substituted by identical or different substituents from the series fluorine, chlorine, methyl or methoxy,
L represents an oxygen atom,
R5 and R6 represents hydrogen or straight-chain or branched alkyl having 1 to 4 carbon atoms, which is optionally substituted by phenyl, pyridyl, imidazolyl, pyrryl, piperidinyl, wherein the heterocycles optionally contain a residue of a formula -NR14,
wherein
R14 denotes hydrogen or straight-chain or branched alkyl or alkoxy- carbonyl each having 1 to 3 carbon atoms,
and wherein the ring systems are optionally monosubstituted by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having 1 to 3 carbon atoms,
or represent a 6-membered saturated N-heterocycle, which is optionally substituted by alkoxycarbonyl having 1 to 6 carbon atoms,
or R5 and R6 together with the nitrogen atom form a imidazolyl-, pyrryl-, moφholinyl-, piperidinyl-, pynolidinyl-, piperazinylring, wherein the heterocycles are optionally contain a residue of a formula -NR14,
and wherein the ringsystem are optionally monosubstituted to trisubstituted by identical or different substituents from the series comprising by a straight-chain or branched alkyl or alkoxycarbonyl each having 1 to 3 carbon atoms,
and salts thereof.
Compounds according to any one of claims 1 to 3, selected from the group consisting of:
Figure imgf000048_0001
Figure imgf000048_0002
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000050_0002
Figure imgf000050_0003
5. A process for the preparation of compounds according to claim 1, characterized in that compounds of the general formula II
Figure imgf000051_0001
in which
A, R1, R2, R3, R4 and L have the abovementioned meaning,
are reacted with amines of the general formula (III)
R5R6-NH (III)
in which
R5 and R6 have the abovementioned meaning,
in the presence of an inert solvent.
6. Benzofuranylaminoalcohols according to any one of claims 1 to 4 for therapeutic use.
7. The composition containing at least one Benzofuranylaminoalcohol 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.
. The process for the preparation of composition according to claim 7 and 8 characterized in that the Benzofuranylaminoalcohol together with customary auxiliaries is brought into a suitable application form.
10. Use of Benzofuranylaminoalcohols according to anyone of claims 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 inflammatory processes.
PCT/EP2000/004015 1999-05-17 2000-05-04 Benzofuranylaminoalcohols WO2000069841A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU45616/00A AU4561600A (en) 1999-05-17 2000-05-04 Benzofuranylaminoalcohols

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9911453A GB2350110A (en) 1999-05-17 1999-05-17 Pharmaceutically active benzofurans
GB9911453.0 1999-05-17

Publications (2)

Publication Number Publication Date
WO2000069841A2 true WO2000069841A2 (en) 2000-11-23
WO2000069841A3 WO2000069841A3 (en) 2002-05-02

Family

ID=10853621

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2000/004015 WO2000069841A2 (en) 1999-05-17 2000-05-04 Benzofuranylaminoalcohols

Country Status (3)

Country Link
AU (1) AU4561600A (en)
GB (1) GB2350110A (en)
WO (1) WO2000069841A2 (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004009557A1 (en) * 2002-07-19 2004-01-29 Memory Pharmaceuticals Corporation 6-amino-1h-indazole and 4-aminobenzofuran compounds as phosphodiesterase 4 inhibitors
US7087625B2 (en) 2002-11-19 2006-08-08 Memory Pharmaceuticals Corporation Phosphodiesterase 4 inhibitors
US7144885B2 (en) 2002-02-22 2006-12-05 Bayer Pharmaceuticals Corporation Fused tricyclic heterocycles useful for treating hyper-proliferative disorders
US7153871B2 (en) 2001-01-22 2006-12-26 Memory Pharmaceuticals Corporation Phosphodiesterase 4 inhibitors, including aminoindazole and aminobenzofuran analogs
US7351735B2 (en) 2002-02-22 2008-04-01 Bayer Pharmaceuticals Corporation Benzofuran and benzothiophene derivatives useful in the treatment of hyper-proliferative disorders
US7405230B2 (en) 2002-07-19 2008-07-29 Memory Pharmaceuticals Corporation Phosphodiesterase 4 inhibitors, including N-substituted aniline and diphenylamine analogs
US9856263B2 (en) 2014-04-28 2018-01-02 Pfizer Inc. Heteroaromatic compounds and their use as dopamine D1 ligands

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0146243A1 (en) * 1983-10-31 1985-06-26 Merck Frosst Canada Inc. Lipoxygenase inhibitors
EP0731099A1 (en) * 1995-03-06 1996-09-11 Bayer Ag N-(3-benzofuranyl)urea-derivatives
EP0779291A1 (en) * 1995-12-11 1997-06-18 Bayer Ag Heterocyclylcarbonyl substituted benzofuranyl-ureas
WO1998002440A1 (en) * 1996-07-12 1998-01-22 Bayer Aktiengesellschaft 3-ureido-pyridofurans and -pyridothiophenes for the treatment of inflammatory processes

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4056626A (en) * 1971-05-13 1977-11-01 Kakenyaku Kako Co., Ltd. Pharmaceutical composition containing benzofuran derivative

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0146243A1 (en) * 1983-10-31 1985-06-26 Merck Frosst Canada Inc. Lipoxygenase inhibitors
EP0731099A1 (en) * 1995-03-06 1996-09-11 Bayer Ag N-(3-benzofuranyl)urea-derivatives
EP0779291A1 (en) * 1995-12-11 1997-06-18 Bayer Ag Heterocyclylcarbonyl substituted benzofuranyl-ureas
WO1998002440A1 (en) * 1996-07-12 1998-01-22 Bayer Aktiengesellschaft 3-ureido-pyridofurans and -pyridothiophenes for the treatment of inflammatory processes

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7153871B2 (en) 2001-01-22 2006-12-26 Memory Pharmaceuticals Corporation Phosphodiesterase 4 inhibitors, including aminoindazole and aminobenzofuran analogs
US7144885B2 (en) 2002-02-22 2006-12-05 Bayer Pharmaceuticals Corporation Fused tricyclic heterocycles useful for treating hyper-proliferative disorders
US7351735B2 (en) 2002-02-22 2008-04-01 Bayer Pharmaceuticals Corporation Benzofuran and benzothiophene derivatives useful in the treatment of hyper-proliferative disorders
US7384947B2 (en) 2002-02-22 2008-06-10 Bayer Healthcare Llc Fused tricyclic heterocycles useful for treating hyper-proliferative disorders
US7585888B2 (en) 2002-02-22 2009-09-08 Bayer Pharmaceuticals Corporation Benzofuran and benzothiophene derivatives useful in the treatment of hyper-proliferative disorders
WO2004009557A1 (en) * 2002-07-19 2004-01-29 Memory Pharmaceuticals Corporation 6-amino-1h-indazole and 4-aminobenzofuran compounds as phosphodiesterase 4 inhibitors
US7405230B2 (en) 2002-07-19 2008-07-29 Memory Pharmaceuticals Corporation Phosphodiesterase 4 inhibitors, including N-substituted aniline and diphenylamine analogs
US7655802B2 (en) 2002-07-19 2010-02-02 Memory Pharmaceuticals Corporation Phosphodiesterase 4 inhibitors, including aminoindazole and aminobenzofuran analogs
US7087625B2 (en) 2002-11-19 2006-08-08 Memory Pharmaceuticals Corporation Phosphodiesterase 4 inhibitors
US7700631B2 (en) 2002-11-19 2010-04-20 Memory Pharmaceuticals Corporation Phosphodiesterase 4 inhibitors
US9856263B2 (en) 2014-04-28 2018-01-02 Pfizer Inc. Heteroaromatic compounds and their use as dopamine D1 ligands

Also Published As

Publication number Publication date
GB2350110A (en) 2000-11-22
WO2000069841A3 (en) 2002-05-02
AU4561600A (en) 2000-12-05
GB9911453D0 (en) 1999-07-14

Similar Documents

Publication Publication Date Title
EP0731099B1 (en) N-(3-benzofuranyl)urea-derivatives
US6169092B1 (en) 3-Ureido-pyridofurans and -pyridothiophenes for the treatment of inflammatory processes
EP0779291B1 (en) Heterocyclylcarbonyl substituted benzofuranyl-ureas
WO2005075429A1 (en) Novel quinoline-carbaxamides as jack3 kinase modulators
KR19990071894A (en) Benzofuran carboxamide and sulfonamide
US6610687B1 (en) Benzofuranylsulfonates
US5721240A (en) 9-substituted-8-unsubstituted-9-deazaguanines
JPH05213940A (en) Novel benzopyran derivative
WO2000069841A2 (en) Benzofuranylaminoalcohols
WO2004111044A1 (en) Tricyclic compounds useful for the treatment of inflammatory and allergic disorders:process for their preparation
WO2000069844A1 (en) Oligohydroxyl substituted benzofuran-3-yl and pyridofuranylurea derivatives as phosphodiesterase iv inhibitors
WO2000069843A2 (en) Cycloalkyl substituted 3-urea-benzofurane-and -pyridofurane-derivatives
KR20010033842A (en) N-oxides of heterocyclic compounds with tnf and pde-iv inhibiting activity
JP2005531550A (en) 5-Ethyl-imidazo (5,1-F) (1,2,4) triazin-4 (3H) -one as a phosphodiesterase inhibitor
MXPA00006346A (en) N-oxides of heterocyclic compounds with tnf and pde-iv inhibiting activity

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: JP