WO1989005299A1 - Nouveaux derives benzoglyoxaline - Google Patents

Nouveaux derives benzoglyoxaline Download PDF

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Publication number
WO1989005299A1
WO1989005299A1 PCT/EP1988/001120 EP8801120W WO8905299A1 WO 1989005299 A1 WO1989005299 A1 WO 1989005299A1 EP 8801120 W EP8801120 W EP 8801120W WO 8905299 A1 WO8905299 A1 WO 8905299A1
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Prior art keywords
methoxy
hydrogen
benzyloxy
compounds
benzimidazole
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PCT/EP1988/001120
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German (de)
English (en)
Inventor
Bernhard Kohl
Ernst Sturm
Richard Riedel
Georg Rainer
Volker Figala
Gerhard Grundler
Hartmann Schaefer
Jörg Senn-Bilfinger
Uwe Krüger
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Takeda GmbH
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Byk Gulden Lomberg Chemische Fabrik GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the invention relates to new benzimidazole derivatives, processes for their preparation, their use and medicaments containing them.
  • the compounds according to the invention are used in the pharmaceutical industry as intermediates and for the manufacture of medicaments.
  • the invention relates to new benzimidazole derivatives of the formula I.
  • R1, R2 and R3 can be at any position in the benzo part of the benzimidazole and wherein R1 is hydrogen, halogen, trifluoromethyl, 1-6C-alkyl, 1-6C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy, phenyl, phenoxy, phenoxy-1 Is -4C-alkyl, phenoxy-1-4C-alkoxy, phen-1-4C-alkyl or phen-1-4C-alkoxy,
  • R2 is hydrogen, 1-6C-alkyl, 1-6C-alkoxy, completely or predominantly substituted by fluorine-1-4C-alkoxy, chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or together with R3, if desired in whole or in part by fluorine substituted 1-2C-alkylenedioxy or chlorotrifluoroethylene dioxy means
  • R3 is hydrogen, 1-6C-alkyl, 1-6C-alkoxy, completely or predominantly substituted by fluorine, 1-4C-alkoxy, chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or together with R2, if desired in whole or in part by fluorine substituted 1-2C-alkylenedioxy or chlorotrifluoroethylene dioxy means
  • R4 denotes hydrogen or a group which can easily be split off under physiological conditions
  • R5 denotes hydrogen or 1-6C-alkyl
  • R6 represents hydrogen or 1-6C-alkyl
  • R7 denotes 1-6C-alkoxy, 2-5C-alkenyloxy, 2-5C-alkynyloxy, 1-4C-alkoxy-1-4C-alkoxy, aryloxy or aryl-1-4C-alkoxy and
  • R8 means aryloxy or aryl-1-4C-alkoxy
  • R9 and RIO are the same or different and are hydrogen (H), 1-4C-alkyl, 1-4C-alkoxy, halogen, nitro, hydroxy or trifluoromethyl, and n represents the number 0 or 1, and the salts of these compounds.
  • Halogen in the sense of the present invention is bromine, chlorine and fluorine.
  • 1-6C-Alkyl stands for straight-chain and branched alkyl residues.
  • Straight-chain alkyl radicals are the hexyl, pentyl, butyl, propyl, ethyl and in particular the methyl radical.
  • Branched AI kylreste are, for example, the neopentyl, i-butyl sec-butyl, t-butyl and the isopropyl.
  • 1-6C-Alkoxy stands for straight-chain or branched alkoxy radicals. Examples include the hexyloxy, neopentyloxy, butoxy, i-butoxy, sec.-butoxy, t-butoxy, propoxy, isopropoxy, ethoxy and especially the methoxy radical.
  • 1-4C-alkoxy represents straight-chain or branched alkoxy radicals; Examples include the butoxy, i-butoxy, sec.-butoxy, t-butoxy, propoxy, isopropoxy, ethoxy and especially the methoxy radical.
  • 1-4C-alkyl represents straight-chain or branched AI kylreste;
  • the butyl, i-butyl, sec-butyl, t-butyl, propyl, isopropyl, ethyl and especially the methyl radical may be mentioned.
  • 1-4C-Alkoxy-1-4C-alkyl represents 1-4C-alkyl which is substituted by 1-4C-alkoxy.
  • the ethoxymethyl, propoxybutyl, methoxymethyl and especially the methoxyethyl and ethoxyethyl radicals may be mentioned.
  • 1-4C-Alkoxy-1-4C-alkoxy stands for 1-4C-alkoxy which is substituted by 1-4C-alkoxy.
  • the methoxypropoxy, ethoxymethoxy and especially the ethoxyethoxy and methoxyethoxy radical may be mentioned.
  • Phenoxy-1-4C-alkyl stands for 1-4C-alkyl which is substituted by a phenoxy radical.
  • phenoxypropyl and the phenoxyethyl radical may be mentioned.
  • Phenoxy-1-4C-alkoxy stands for 1-4C-alkoxy which is substituted by a phenoxy radical.
  • the phenoxyethoxy and the phenoxypropoxy radical may be mentioned.
  • Phen-1-4C-alkyl stands for 1-4C-alkyl which is substituted by a phenyl radical. Examples include the phenethyl and especially the benzyl radical.
  • Phen-1-4C-alkoxy stands for 1-4C-alkoxy which is substituted by a phenyl radical. Examples include the 2-phenyl-ethoxy and the benzyloxy radical.
  • Examples of the fully or predominantly fluorine-substituted 1-4C-alkoxy include 1,1,2-trifluoroethoxy, perfluoropropoxy, perfluoroethoxy and in particular 1,1,2, 2-tetrafluoroethoxy, trifluoromethoxy 2,2,2-trifluoroethoxy and the difluoromethoxy radical called.
  • 1-2C-Alkylenedioxy stands for Ethyl endioxy (-O-CH 2 -CH 2 -O-) or Methyl endioxy (-O-CH 2 -O-).
  • Examples of all or part fluorine-substituted 1-2C-alkylenedioxy include 1,1-difluoroethylendioxy- (-O-CF 2 -CH 2 -O-), 1,1,2,2-tetrafluoroethylendioxy- ( -O-CF 2 -CF 2 -O-) and especially the di fluoromethyl endioxy (-O-CF z -O-) and the 1,1,2-trifluoroethylene dioxy radical (-O-CF 2 -CHF-O-) .
  • a group R4 which can easily be split off under physiological conditions, is a substituent which is separated from the nitrogen atom by formation of an NH bond by - optionally enzymatically catalyzed - hydrolysis, whereby itself - with the connection of a hydroxyl group - is converted into a physiologically acceptable and in particular pharmacologically acceptable compound .
  • All types of substituted carbonyl groups such as the alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl group or the optionally substituted carbamoyl group, may be mentioned in particular as the R4 groups which can be removed. Examples include the methoxycarbonyl, t-butoxycarbonyl, benzoyl, phenylcarbamoyl and dimethylcarbamoyl groups.
  • 2-5C-alkenyloxy stands for alkenyloxy radicals such as the pent-2-enyloxy, but-1-enyloxy and in particular the allyloxy radical.
  • 2-5C-alkynyloxy represents alkynyloxy radicals such as the ethynyloxy and in particular the prop-2-ynyloxy radical.
  • aryloxy radicals are the 4-chlorophenoxy radical, the 4-fluorophenoxy radical, 3,5-dichlorophenoxy radical and in particular the phenoxy radical.
  • Exemplary aryl-1-4C-alkoxy radicals are the 4-phenylbutoxy, the 3-phenylpropoxy, the 2-phenylethoxy, the 4-methoxybenzyloxy, the 4-fluorobenzyloxy and the 4-chlorobenzyloxy 3,5-dichlorobenzyloxy and especially the benzyloxy radical.
  • Suitable salts for compounds of the formula I in which n is the number 0 (sulfides), are preferably all acid addition salts. Particular mention should be made of the pharmacologically acceptable salts of the inorganic and organic acids commonly used in galenics.
  • Pharmacologically incompatible salts which may initially be obtained as process products in the manufacture of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art.
  • Suitable as such are, for example, water-soluble and water-insoluble acid addition salts, such as the hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulfosalicylate, maleate, laurate, malate, fumarate, succinate Oxalate, tartrate, amsonate, embonate, metembonate, stearate, tosilate, 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate or mesilate.
  • the preferred salts are basic salts, in particular pharmacologically acceptable salts with inorganic and organic bases commonly used in galenics.
  • Lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium or guanidinium salts may be mentioned as examples of basic salts.
  • R2 and R3 together mean all or part of fluorine-substituted 1-2C-alkyl endioxy or chlorotrifluoroethylene dioxy, the substituents R2 and R3 are bonded to the benzo part of the benzimidazole ring in adjacent positions.
  • One aspect of the invention are compounds of the formula I in which R2 is hydrogen, 1-6C-alkyl or 1-6C-alkoxy, R3 is hydrogen, 1-6C-alkyl or 1-6C-alkoxy and R1, R4 , R5, R6, R7, R8, R9, R10 and n have the meanings given above, and the salts of these compounds.
  • Preferred representatives of this aspect 1 of the invention are compounds of the formula I in which R1 is hydrogen, chlorine, fluorine, trifluoromethyl, methyl, ethyl, methoxy or
  • Ethoxy means, R2 means hydrogen, methyl, ethyl, methoxy or ethoxy, R3 means hydrogen, R4 means hydrogen, R5 means hydrogen, R6 means hydrogen or methyl, R7 means methoxy or benzyloxy, R8 means benzyloxy and n represents the number 0 or 1 , and the salts of these compounds.
  • R1 is hydrogen, trifluoromethyl or methoxy
  • R2, R3, R4 and R5 denote hydrogen
  • R6 represents hydrogen or methyl
  • R7 means methoxy
  • R8 represents benzyloxy and n represents the number 0 or 1, and the salts of these compounds.
  • a further aspect of the invention are compounds of the formula I in which R2 together with R3 denotes 1-2C-alkylenedioxy and R1, R4, R5, R6, R7, R8, R9, R10 and n have the meanings given above, and the salts of these compounds.
  • Preferred representatives of this aspect 2 of the invention are compounds of the formula I in which
  • R1 means hydrogen
  • R2 and R3 together mean ethylenedioxy or methylenedioxy
  • R4 means hydrogen
  • R5 means hydrogen
  • R6 means hydrogen or methyl
  • R7 means methoxy or benzyloxy
  • R8 means benzyloxy
  • n represents the number 0 or 1
  • Particularly preferred representatives of aspect 2 of the invention are compounds of the formula I in which
  • R1 means hydrogen
  • R2 and R3 together mean ethylenedioxy or methylenedioxy
  • R4 means hydrogen
  • R5 means hydrogen
  • R6 represents hydrogen or methyl
  • R7 means methoxy
  • R8 represents benzyloxy and n represents the number 0 or 1, and the salts of these compounds.
  • a further aspect of the invention are compounds of the formula I in which
  • R2 is hydrogen, 1-6C-alkyl, 1-6C-alkoxy, completely or predominantly substituted by fluorine-1-4C-alkoxy, chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or together with R3 completely or partly substituted by fluorine 1-2C-alkyl endioxy or chlorotrifluoroethylene dioxy means
  • R3 is completely or predominantly substituted by fluorine-1-4C-alkoxy, chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or together with R2 completely or partly by fluorine-substituted 1-2C- Alkylenedioxy or Chlortrifluorethylenendioxy means, and
  • R1, R4, R5, R6, R7, R8, R9, R10 and n have the meanings given above.
  • a particular aspect of aspect 3 of the invention are compounds of the formula Ia,
  • R1 means hydrogen
  • R2 is hydrogen, methyl, ethyl, methoxy, ethoxy, 1,1,2,2-tetrafluoroethoxy
  • Trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or together with R3 di fluoromethylene dioxy, 1,1,2-trifluoroethyl endioxy or 1-chloro-1,2,2-trifluoroethylene dioxy means
  • R3 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or together with R2 difluoromethy1 endioxy, 1,1,2-trifluoroethylene dioxy or 1 -Chlor- 1,2,2-trifluoroethylene dioxy means
  • R4 means hydrogen
  • R5 denotes hydrogen, methyl or ethyl
  • R6 represents hydrogen or 1-4C-alkyl
  • R7 denotes 1-4C-alkoxy, aryloxy or aryl-1-4C-alkoxy
  • R8 means aryloxy or aryl-1-4-C-alkoxy
  • R9 is hydrogen, methyl, methoxy or chlorine
  • R10 represents hydrogen, methyl, methoxy, chlorine, nitro, hydroxy or trifluoromethyl, and n represents the number 0 or 1, and the salts of these compounds.
  • R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and n have the meanings given for the embodiment a, and their salts.
  • R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and n have the meanings given for the configuration a, and their salts.
  • R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and n have the meanings given for the configuration a, and their salts.
  • Preferred compounds according to the invention are those of the formulas I, Ia, Ib, Ic and Id in which
  • R1 means hydrogen
  • R2 is hydrogen, methoxy or together with R3 difluoromethyl endioxy,
  • 1,1,2-trifluoroethylene dioxy or 1-chloro-1,2,2-trifluoroethylene dioxy means, R3 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-1, 1,2-trifluoroethoxy or together with R3 means difluoromethylene dioxy, 1,1,2-trifluoroethylene dioxy or 1-chloro-1,2,2-trifluoroethylene dioxy, R4 means hydrogen, R5 means hydrogen, R6 means hydrogen or methyl, R7 means methoxy or ethoxy means R8 means benzyloxy and n represents the number 0 or 1, and the salts of these compounds.
  • Particularly preferred compounds according to the invention are those of the formulas I, Ia, Ib, Ic and Id in which R1 means hydrogen
  • R2 is hydrogen or together with R3 difluoromethylene dioxy
  • R3 means difluoromethoxy or together with R2 difluoromethylene dioxy
  • R4 means hydrogen
  • R5 means hydrogen
  • R6 represents hydrogen or methyl
  • R7 means methoxy
  • R8 represents benzyloxy and n represents the number 0 or 1, and the salts of these compounds.
  • the 5-substitution in the benzimidazole is identical to the 6-substitution. Accordingly, in the compounds in which R2 and R3 together represent a substituted ethylenedioxy radical, the 6-position in the [1,4] -dioxino [2,3-f] benzimidazole part is identical to the 7-position.
  • the invention further relates to a process for the preparation of the compounds of the formula I in which R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and the meanings given above and their salts.
  • Y, Y ", Z, V and Z" represent suitable leaving groups
  • Y ' represents a leaving or reactive group
  • M represents an alkali metal atom (Li, Na or K)
  • M' represents the equivalent of a metal atom
  • R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and n have the meanings given above.
  • the compounds II-XIV can be used as such or, if appropriate, in the form of their salts.
  • a suitable leaving group Y is, for example, a group which together with the sulfinyl group to which they are attached is bound, forms a reactive sulfinic acid derivative.
  • suitable leaving groups Y are alkoxy, dialkylamino or alkyl mercapto groups.
  • a suitable leaving or reactive group Y ' is a group which is able to react with a secondary amino group with elimination of HY' or with addition.
  • R4 ' is, for example, a leaving group which, together with the carbonyl group to which it is attached, forms a reactive carboxylic acid derivative, for example an acid halide.
  • the general formula R4'-Y '(XIII) also encompasses those compounds (precursors of the group R4 which can easily be split off under physiological conditions) in which Y' represents a reactive group (for example isonitriles) which are involved in the reaction with the secondary amino group no condensation with elimination of HY 'but an addition to form the desired elimination group R4.
  • the leaving group Y ′′ is a group familiar to the person skilled in the art of alkylation reactions, which in alkylation - e.g. with dialkyl sulfate, fluorosulfonic acid alkyl ester or alkyl iodide.
  • Suitable leaving groups Z, V and Z ′′ are halogen atoms, in particular chlorine atoms, or hydroxyl groups activated by esterification (e.g. with p-toluenesulfonic acid).
  • a metal atom M ' is, for example, an alkali metal (Li, Na or K), or an alkaline earth metal atom (eg Mg) which is substituted by a halogen atom (eg Br, Grignard reagent) or any other optionally substituted metal atom , which is known to react in substitution reactions of organometallic compounds such as the metals mentioned above.
  • a metal atom M is, for example, an alkali metal (Li, Na or K), or an alkaline earth metal atom (eg Mg) which is substituted by a halogen atom (eg Br, Grignard reagent) or any other optionally substituted metal atom , which is known to react in substitution reactions of organometallic compounds such as the metals mentioned above.
  • the reaction of II with III is carried out in a manner known per se in suitable, preferably polar, protic or aprotic solvents (such as methanol, isopropanol, dimethyl sulfoxide, acetone, dimethylformamide or acetonitrile) with or without water. It is carried out, for example, in the presence of a proton acceptor.
  • suitable, preferably polar, protic or aprotic solvents such as methanol, isopropanol, dimethyl sulfoxide, acetone, dimethylformamide or acetonitrile
  • a proton acceptor Alkali metal hydroxides such as sodium hydroxide, alkali metal carbonates such as potassium arbonate or tertiary amines such as pyridine, triethylamine or ethyldiisopropylamine are suitable as such.
  • reaction can also be carried out without a proton acceptor, with - each depending on the nature of the starting compounds - if necessary, the acid addition salts can be separated off in a particularly pure form.
  • the reaction temperature can be between 0 ° and 150 ° C, with temperatures in the presence of proton acceptors between 20 ° and 80 ° C and without proton acceptors between 60 ° and 120 ° C - especially the boiling point of the solvents used are preferred.
  • the response times are between 0.5 and 12 hours.
  • reaction of VI with VII is preferably carried out in polar, optionally water-containing solvents in the presence of a strong acid, e.g. Hydrochloric acid, especially at the boiling point of the solvent used.
  • a strong acid e.g. Hydrochloric acid
  • Suitable oxidants are all reagents commonly used for the oxidation of sulfides to sulfoxides, in particular peroxy acids, such as e.g. Peroxyacetic acid, trifluoroperoxyacetic acid, 3,5-dinitroperoxybenzoic acid, peroxymalic acid, magnesium monoperoxiphthalate or preferably m-chloroperoxybenzoic acid.
  • the reaction temperature is (depending on the reactivity of the oxidizing agent and
  • the reaction of IX with X is preferably carried out in inert solvents, as is usually used for the reaction of enolate ions with alkylating agents.
  • inert solvents such as benzene or toluene may be mentioned.
  • aromatic solvents such as benzene or toluene may be mentioned.
  • the reaction temperature (depending on the nature of the alkali metal atom M and the leaving group Z) is generally between 0 ° and 120 ° C, with the boiling point of the solvent used being preferred.
  • M represents Li (lithium) and Z Cl (chlorine) and the reaction is carried out in benzene]
  • the boiling temperature of benzene 80 ° C is preferred.
  • the compounds XI are reacted with the compounds XII in a manner known per se, as is known to the person skilled in the art for the reaction of organometallic compounds.
  • reaction according to process variant f) is carried out in a manner known to the person skilled in the art in suitable solvents such as tetrahydrofuran or acetonitrile, optionally with the addition of a base (if Y 'represents a leaving group) or without addition of base (if Y' represents a reactive group). If the substituents R1, R2 and R3 are asymmetrically distributed, this reaction gives mixtures of isomers which have to be separated by suitable separation processes (e.g. chromatography).
  • suitable solvents such as tetrahydrofuran or acetonitrile
  • Solvolysis according to process variant g) is carried out in a manner known to those skilled in the art in suitable water-containing or water-splitting alkaline or acidic solutions, at room temperature or, if desired, with heating to the boiling point of the solvent used.
  • the alkylation according to process variant h) is carried out - if appropriate after prior deprotonation - in a manner familiar to those skilled in the art in suitable inert solvents.
  • the compounds according to the invention are initially obtained either as such or in the form of their salts.
  • the salts are obtained by dissolving the free compounds in one Suitable solvents, for example in a chlorinated hydrocarbon, such as methylene chloride or chloroform, a low molecular weight aliphatic alcohol (ethanol, isopropanol), an ether (diisopropyl ether), a ketone (acetone) or water, which contains the desired acid or base, or which the desired acid or base - optionally in the precisely calculated stoichiometric amount - is then added.
  • a chlorinated hydrocarbon such as methylene chloride or chloroform
  • a low molecular weight aliphatic alcohol ethanol, isopropanol
  • an ether diisopropyl ether
  • a ketone acetone
  • the salts are obtained by filtration, reprecipitation, precipitation or by evaporation of the solvent.
  • Salts obtained can be alkalized or acidified, e.g. with aqueous sodium hydrogen carbonate or with dilute hydrochloric acid, are converted into the free compounds, which in turn can be converted into the salts. In this way, the compounds can be purified or pharmacologically unacceptable salts can be converted into pharmacologically acceptable salts.
  • the sulfoxides according to the invention are optically active compounds. Depending on the nature of the substituents R1 to R8, there may be additional chiral centers in the molecule (e.g. if R5 is not hydrogen).
  • the invention therefore includes the enantiomers and diastereomers as well as their mixtures and racemates.
  • the enantiomers can be separated in a manner known per se (for example by preparing and separating corresponding diastereoisomeric compounds). However, the enantiomers can also be obtained by asymmetric synthesis, for example by enantioselective oxidation of the sulfides, e.g. with tert.
  • the compounds according to the invention are preferably synthesized by reacting II with III and, if appropriate, subsequent oxidation of the sulfide VIII formed.
  • the compounds II, IV, VI, IX and XI are known for example from WO86 / 02646.
  • the compounds III can be prepared in various ways, for example as follows: 1.
  • R6 1-6C-alkyl (in the 3-position)
  • R7 1-6C-alkoxy (in the 4-position)
  • R8 aryl-1-4C-alkoxy (in the 5-position).
  • connections are e.g. proceeding from known 2-methyl-3-alkyl-4-alkoxypyridines (see eg EP-A 0 080 602) by N-oxidation (eg with 30% hydrogen peroxide), targeted acetoxylation and subsequent saponification in 5 -Position (e.g. with acetic anhydride and then sodium hydroxide solution), alkylation of the 5-hydroxy group (e.g. with aryl-1-4C-alkyl bromide and sodium hydroxide solution in dimethyl sulfoxide), N-oxidation (e.g.,
  • R6 hydrogen (in the 3-position)
  • R7 and R8 1-6C-alkoxy or aryloxy or aryl-1-4C-alkoxy.
  • connections are e.g. starting from known 5-hydroxy-2-methylpyridines by alkylation of the hydroxy group (for example with 1-6C-alkyl iodide or aryl-1-4C-alkyl bromide and potassium hydroxide in dimethyl sulfoxide), N-oxidation (for example with 30% hydrogen peroxide), nitration in 4-position (e.g.
  • R6 hydrogen (in 5 position)
  • R7 and R8 1-6C-alkoxy or aryloxy or aryl-1-4C-alkoxy.
  • A. These compounds are, for example, starting from known 3-hydroxy-2-methylpyridines by alkylation of the hydroxyl group (for example with potassium hydroxide and alkyl iodide or arylalkyl iodide in dimethyl sulfoxide), N-oxidation (for example with 30% hydrogen peroxide), nitration in the 4-position (e.g. with nitrating acid), exchange of the nitro for the aryloxy, arylalkoxy or alkoxy group, conversion to the 2-acetoxymethylpyridine (e.g. with hot acetic anhydride), saponification to the hydroxymethyl group and introduction of the escape group Z '(e.g. by reaction with Thionyl chloride) prepared.
  • these compounds are prepared from known 3-hydroxy-2-methyl-4-pyrones by alkylation of the hydroxy group (for example with potassium carbonate and alkyl iodide or arylalkyl bromide in acetone), conversion of the pyrone into the corresponding pyridone (for example by Reaction with aqueous ammonia), chlorination to 4-chloropyridine (e.g. with phosphorus oxychloride), N-oxidation (e.g. with 30% hydrogen peroxide), exchange of the chlorine for the alkoxy, aryloxy or arylalkoxy group (e.g.
  • the compounds V, VII and XII are prepared, for example, starting from the compounds III in ways known to those skilled in the art.
  • Example 3 The procedure described in Example 3 is obtained by reacting 1.08 g (5 mmol) of 5-difluoromethoxy-2-mercapto-1H-benzimidazole with 1.43 g (4 mmol) of 3-benzyloxy-2-chloromethyl-4 -methoxypyridinium chloride in 7 ml of ethanol with the addition of 6 ml of 2N sodium hydroxide solution 2 - [(3-benzyloxy-4-methoxy-2-pyridyl) methylthio] -5-difluoromethoxy-1H-benzimidazole as a yellow oil.
  • Example Aa According to the procedure given in Example Aa), 5.1 g (85 g) are obtained by reacting 4.86 g of 4-benzyloxy-2-hydroxymethyl-3-methoxypyridini umchl ori d with 3 g of thionyl chloride in 50 ml of methylene chloride at + 5 ° C % of theory) the title compound as a colorless solid of mp 117-118 ° C (dec.).
  • Example Ab According to the procedure given in Example Ab) is obtained by reacting 50 g of 4-benzyloxy-3-methoxy-2-methylpyridine-1-oxide first with 104 g of acetic anhydride, subsequent saponification with 74 ml of 6N sodium hydroxide solution, extraction with methylene chloride and Removal of the solvent a yellow solid residue. Stirring with warm diisopropyl ether gives 37.2 g (75% of theory) of 4-benzyloxy-2-hydroxymethyl-3-methoxypyridine. Beige powder, melting at 68-70oC.
  • Potassium hydroxide in 80 ml of dimethyl sulfoxide is added 2.80 g of benzyl chloride and stirred at 20 ° C for 24 hours.
  • 150 ml of ice water are added, the mixture is acidified to pH 2 with hydrochloric acid, extracted twice with 20 ml of diethyl ether each time, the water phase is adjusted to pH 9 and extracted five times with 50 ml of methylene chloride.
  • 3.1 g (68% of theory) of 5-benzyloxy-4-methoxy-2-methylpyridine are obtained; colorless crystals with a melting point of 69-71 ° C.
  • Example Cd According to the procedure given in Example Cd) is obtained by O-alkylation of 7.7 g of 5-hydroxy-4-methoxy-2,3-dimethylpyridine in 80 ml of dimethyl sulfoxide with 6.7 g of benzyl chloride with the addition of 3.25 g potassium hydroxide 12.0 g (98% of theory) 5-benzyloxy-4-methoxy-2,3-dimethylpyridine, melting point 63-64 ° C; colorless
  • the compounds of the formula I according to the invention and their salts have valuable pharmacological properties which make them commercially usable. They significantly inhibit gastric acid secretion from warm-blooded animals and also have excellent gastric and intestinal protective effects in warm-blooded animals. This gastric and intestinal protective effect is sometimes already observed when doses are administered which are below the acid secretion-inhibiting doses.
  • the compounds according to the invention are distinguished by the absence of significant side effects and a large therapeutic breadth.
  • Another aspect essential to the invention is that the compounds of the formula I have high chemical stability and a significant maximum activity in the pH range desired in each case.
  • stomach and intestinal protection means the prevention and treatment of gastrointestinal diseases, in particular gastrointestinal inflammatory diseases and lesions (such as, for example, ulcer ventriculi, duodenal ulcer, gastritis, hyperacid or drug-induced irritable stomach), which are caused, for example, by microorganisms, bacterial toxins, Medications (e.g. certain anti-inflammatory drugs and anti-rheumatic drugs), chemicals (e.g. ethanol), stomach acid or stressful situations can be caused.
  • gastrointestinal inflammatory diseases and lesions such as, for example, ulcer ventriculi, duodenal ulcer, gastritis, hyperacid or drug-induced irritable stomach
  • Medications e.g. certain anti-inflammatory drugs and anti-rheumatic drugs
  • chemicals e.g. ethanol
  • the compounds according to the invention surprisingly prove to be clearly superior to the compounds known from the prior art.
  • the compounds according to the invention and their pharmacologically acceptable salts are outstandingly suitable for use in human and veterinary medicine, in particular for the treatment and prophylaxis of diseases of the stomach and intestines and of such diseases which are based on excessive gastric acid secretion be applied.
  • the high storage stability of the compounds according to the invention enables their problem-free use in pharmaceutical preparations.
  • the invention further relates to the compounds according to the invention for use in the treatment and prophylaxis of the abovementioned diseases.
  • the invention also includes the use of the compounds according to the invention in the production of medicaments which are used for the treatment and prophylaxis of the abovementioned diseases.
  • the invention further relates to medicaments which contain one or more compounds of the formula I according to the invention and / or their pharmacologically tolerable salts.
  • the pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art.
  • auxiliaries suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
  • solvents yellow flakes, suppository bases, tablet excipients and other active ingredients, antioxidants, dispersants, emulators, defoamers, taste correctors, preservatives, solubilizers, dyes or in particular permeation promoters and complexing agents (e.g. cyclodextrins) can be used.
  • the active ingredients can be administered orally, parenterally or percutaneously.
  • the active ingredient (s) when administered orally in a daily dose of about 0.05 to about 50, preferably 0.25 to 20, in particular 0.5 to 10 mg / kg body weight in the form of several, preferably 1 to 4 individual doses to achieve the desired result.
  • a daily dose of about 0.05 to about 50, preferably 0.25 to 20, in particular 0.5 to 10 mg / kg body weight in the form of several, preferably 1 to 4 individual doses to achieve the desired result.
  • similar or generally lower doses in particular when the active compounds are administered intravenously
  • the determination of the respectively required optimal dosage and type of application of the active ingredients can easily be made by any expert on the basis of his specialist knowledge.
  • the pharmaceutical preparations can also include one or more pharmacologically active constituents of other pharmaceutical groups, such as antacids, for example aluminum hydroxide, magnesium aluminate; Tranquillizers, such as benzodiazepines, for example diazepam; Antispasmodics, such as Bietami verin, camylofin; Anticholinergics such as oxyphencyclimine, phencarbamide; Local anesthetics, such as tetracaine, procaine; optionally also contain ferments, vitamins or amino acids.
  • antacids for example aluminum hydroxide, magnesium aluminate
  • Tranquillizers such as benzodiazepines, for example diazepam
  • Antispasmodics such as Bietami verin, camylofin
  • Anticholinergics such as oxyphencyclimine, phencarbamide
  • Local anesthetics such as tetracaine, procaine
  • the combination of the compounds according to the invention with other drugs which inhibit acid secretion such as H 2 blockers (for example cimetidine, ranitidine), furthermore with so-called peripheral anticholinergics (for example pirenzepin, telenzepin, zolenzepin) and with gastrin antagonists should be emphasized in particular , with the aim of strengthening the main effect in an additive or superadditive sense and / or eliminating or reducing the side effects.
  • H 2 blockers for example cimetidine, ranitidine
  • peripheral anticholinergics for example pirenzepin, telenzepin, zolenzepin
  • gastrin antagonists should be emphasized in particular , with the aim of strengthening the main effect in an additive or superadditive sense and / or eliminating or reducing the side effects.
  • the pharmacological properties of the compounds according to the invention can be demonstrated on various animal models.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Des dérivés de benzoglyoxaline ayant la formule (I), dans laquelle les substituants ont la signification donnée dans la description, et leurs sels, constituent de nouveaux composés à effet gastroprotecteur marqué.
PCT/EP1988/001120 1987-12-11 1988-12-08 Nouveaux derives benzoglyoxaline Ceased WO1989005299A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH484487 1987-12-11
CH4844/87-5 1987-12-11

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WO1989005299A1 true WO1989005299A1 (fr) 1989-06-15

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EP (1) EP0390842A1 (fr)
JP (1) JPH03501609A (fr)
AU (1) AU2817989A (fr)
WO (1) WO1989005299A1 (fr)
ZA (1) ZA889194B (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4965269A (en) * 1989-12-20 1990-10-23 Ab Hassle Therapeutically active chloro substituted benzimidazoles
EP0330329B1 (fr) * 1988-02-16 1992-07-22 Pfizer Inc. Dérivés de pyrimidine anti-ulcères
AP215A (en) * 1990-06-20 1992-09-02 Ab Astra Substituted benzimidazoles, process for their preparation and their pharmaceutical use.
AP253A (en) * 1990-06-20 1993-05-03 Ab Astra Dialkoxy-pyridinyl-benzimidazole derivatives process for their preparation and thei phamaceutical use.
EP0893445A1 (fr) * 1997-07-24 1999-01-27 Bayer Ag Procédé pour la préparation des dérivés de 2-chlorobenzimidazole
US6472412B1 (en) * 1993-07-28 2002-10-29 Aventis Pharma Limited Compounds as PDE IV and TNF inhibitors
US12312326B2 (en) 2016-09-14 2025-05-27 Yufeng Jane Tseng Substituted benzimidazole derivatives as D-amino acid oxidase (DAAO) inhibitors

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5049674A (en) * 1989-12-20 1991-09-17 Aktiebolaget Hassle Therapeutically active fluoro substituted benzimidazoles
NZ244301A (en) * 1991-09-20 1994-08-26 Merck & Co Inc Preparation of 2-pyridylmethylsulphinylbenzimidazole and pyridoimidazole derivatives from the corresponding sulphenyl compounds

Citations (4)

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Publication number Priority date Publication date Assignee Title
EP0166287A1 (fr) * 1984-06-16 1986-01-02 Byk Gulden Lomberg Chemische Fabrik GmbH Dialcoxypyridines, procédé pour leur préparation, leur application et médicaments les contenant
EP0208452A2 (fr) * 1985-07-02 1987-01-14 Takeda Chemical Industries, Ltd. Dérivés de pyridine, leur préparation et utilisation
JPS62201885A (ja) * 1985-02-12 1987-09-05 Banyu Pharmaceut Co Ltd インド−ル誘導体、その製造法及び用途
EP0298440A1 (fr) * 1987-07-10 1989-01-11 Hoechst Aktiengesellschaft Benzimidazoles substitués, procédé pour leur préparation, compositions pharmaceutiques les contenant et leur application

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0166287A1 (fr) * 1984-06-16 1986-01-02 Byk Gulden Lomberg Chemische Fabrik GmbH Dialcoxypyridines, procédé pour leur préparation, leur application et médicaments les contenant
JPS62201885A (ja) * 1985-02-12 1987-09-05 Banyu Pharmaceut Co Ltd インド−ル誘導体、その製造法及び用途
EP0208452A2 (fr) * 1985-07-02 1987-01-14 Takeda Chemical Industries, Ltd. Dérivés de pyridine, leur préparation et utilisation
EP0298440A1 (fr) * 1987-07-10 1989-01-11 Hoechst Aktiengesellschaft Benzimidazoles substitués, procédé pour leur préparation, compositions pharmaceutiques les contenant et leur application

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Patent Abstracts of Japan, Band 12, Nr. 56 (C-477)(2903), 19. Februar 1988; & JP-A-62201885 (BANYU PHARMACEUT. CO. LTD) 5. September 1987 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0330329B1 (fr) * 1988-02-16 1992-07-22 Pfizer Inc. Dérivés de pyrimidine anti-ulcères
US4965269A (en) * 1989-12-20 1990-10-23 Ab Hassle Therapeutically active chloro substituted benzimidazoles
AP215A (en) * 1990-06-20 1992-09-02 Ab Astra Substituted benzimidazoles, process for their preparation and their pharmaceutical use.
AP253A (en) * 1990-06-20 1993-05-03 Ab Astra Dialkoxy-pyridinyl-benzimidazole derivatives process for their preparation and thei phamaceutical use.
US6472412B1 (en) * 1993-07-28 2002-10-29 Aventis Pharma Limited Compounds as PDE IV and TNF inhibitors
US7045660B2 (en) 1993-07-28 2006-05-16 Aventis Pharma Limited Compounds as PDE IV and TNF-inhibitors
US7652144B2 (en) 1993-07-28 2010-01-26 Aventis Pharma Limited Compounds as PDE IV and TNF inhibitors
US6028200A (en) * 1997-07-22 2000-02-22 Bayer Aktiengesellschaft Process for preparing 2-chloro-benzimidazole derivatives
US6054589A (en) * 1997-07-22 2000-04-25 Bayer Aktiengesellschaft Process for preparing 2-chloro-benzimidazole derivatives
EP0893445A1 (fr) * 1997-07-24 1999-01-27 Bayer Ag Procédé pour la préparation des dérivés de 2-chlorobenzimidazole
US12312326B2 (en) 2016-09-14 2025-05-27 Yufeng Jane Tseng Substituted benzimidazole derivatives as D-amino acid oxidase (DAAO) inhibitors
AU2023274172B2 (en) * 2016-09-14 2025-08-07 National Health Research Institutes Novel substituted benzimidazole derivatives as D-amino acid oxidase (DAAO) inhibitors

Also Published As

Publication number Publication date
ZA889194B (en) 1989-08-30
EP0390842A1 (fr) 1990-10-10
AU2817989A (en) 1989-07-05
JPH03501609A (ja) 1991-04-11

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