WO2000069841A2 - Benzofuranylaminoalcools - Google Patents

Benzofuranylaminoalcools Download PDF

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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
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carbon atoms
chain
straight
branched alkyl
alkoxycarbonyl
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PCT/EP2000/004015
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English (en)
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WO2000069841A3 (fr
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
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Bayer Aktiengesellschaft
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Priority to AU45616/00A priority Critical patent/AU4561600A/en
Publication of WO2000069841A2 publication Critical patent/WO2000069841A2/fr
Publication of WO2000069841A3 publication Critical patent/WO2000069841A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic 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
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic 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
    • C07D231/12—Heterocyclic 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic 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
    • C07D233/56—Heterocyclic 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic 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
    • C07D405/02—Heterocyclic 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
    • C07D405/12—Heterocyclic 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des benzofuranylaminoalcools de formule générale (I), ainsi que leur méthode de préparation et leur utilisation dans des médicaments, en particulier pour traiter les inflammations.
PCT/EP2000/004015 1999-05-17 2000-05-04 Benzofuranylaminoalcools WO2000069841A2 (fr)

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AU45616/00A AU4561600A (en) 1999-05-17 2000-05-04 Benzofuranylaminoalcohols

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GB9911453.0 1999-05-17
GB9911453A GB2350110A (en) 1999-05-17 1999-05-17 Pharmaceutically active benzofurans

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WO2000069841A2 true WO2000069841A2 (fr) 2000-11-23
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WO2004009557A1 (fr) * 2002-07-19 2004-01-29 Memory Pharmaceuticals Corporation Composes de 6-amino-1h-indazole et de 4-aminobenzofurane utilises en tant qu'inhibiteurs de phosphodiesterase 4
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

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EP0146243A1 (fr) * 1983-10-31 1985-06-26 Merck Frosst Canada Inc. Inhibiteurs de la lipoxygénase
EP0731099A1 (fr) * 1995-03-06 1996-09-11 Bayer Ag Dérivés de N-(3-benzofuranyl)urée
EP0779291A1 (fr) * 1995-12-11 1997-06-18 Bayer Ag Benzofuranyl-urée substitué par un héterocycliquecarbonyle
WO1998002440A1 (fr) * 1996-07-12 1998-01-22 Bayer Aktiengesellschaft 3-ureido-pyridofurans et -pyridothiophenes pour le traitement des troubles inflammatoires

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Publication number Priority date Publication date Assignee Title
EP0146243A1 (fr) * 1983-10-31 1985-06-26 Merck Frosst Canada Inc. Inhibiteurs de la lipoxygénase
EP0731099A1 (fr) * 1995-03-06 1996-09-11 Bayer Ag Dérivés de N-(3-benzofuranyl)urée
EP0779291A1 (fr) * 1995-12-11 1997-06-18 Bayer Ag Benzofuranyl-urée substitué par un héterocycliquecarbonyle
WO1998002440A1 (fr) * 1996-07-12 1998-01-22 Bayer Aktiengesellschaft 3-ureido-pyridofurans et -pyridothiophenes pour le traitement des troubles inflammatoires

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 (fr) * 2002-07-19 2004-01-29 Memory Pharmaceuticals Corporation Composes de 6-amino-1h-indazole et de 4-aminobenzofurane utilises en tant qu'inhibiteurs de phosphodiesterase 4
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
GB9911453D0 (en) 1999-07-14
WO2000069841A3 (fr) 2002-05-02
GB2350110A (en) 2000-11-22
AU4561600A (en) 2000-12-05

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