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EP0232399A1 - Nouvelles amines, leur procede de fabrication, leur utilisation, et medicaments les contenant - Google Patents

Nouvelles amines, leur procede de fabrication, leur utilisation, et medicaments les contenant

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Publication number
EP0232399A1
EP0232399A1 EP19860905269 EP86905269A EP0232399A1 EP 0232399 A1 EP0232399 A1 EP 0232399A1 EP 19860905269 EP19860905269 EP 19860905269 EP 86905269 A EP86905269 A EP 86905269A EP 0232399 A1 EP0232399 A1 EP 0232399A1
Authority
EP
European Patent Office
Prior art keywords
benzimidazole
hydrogen
alkyl
methoxy
dimethylaminophenyl
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
EP19860905269
Other languages
German (de)
English (en)
Inventor
Bernhard Kohl
Richard Riedel
Christian Schudt
Wolfgang A. Simon
Ernst Sturm
Kurt Klemm
Georg Rainer
Hartmann Schaefer
Jörg Senn-Bilfinger
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda GmbH
Original Assignee
Byk Gulden Lomberg Chemische Fabrik GmbH
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 Byk Gulden Lomberg Chemische Fabrik GmbH filed Critical Byk Gulden Lomberg Chemische Fabrik GmbH
Publication of EP0232399A1 publication Critical patent/EP0232399A1/fr
Pending legal-status Critical Current

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Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/28—Sulfur atoms

Definitions

  • New amines Process for their preparation, their application and medicinal products containing them
  • the invention relates to new amines, 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 amines of the formula I.
  • R1, R2, R3 and R4 can be at any position in the benzo part of the benzimidazole and wherein
  • R1 is hydrogen or C 1 -C 6 alkyl
  • R2 is hydrogen, cyano, nitro, halogen, trifluoromethyl, C 1 -C 6 alkyl, C 1 -
  • Hydroxy-C 1 -C 4 alkyl cyano-C 1 -C 4 alkoxy, C 1 -C 4 alkoxy-C 1 -C 4 alkoxy, C 1 -C 6 alkylcarbonyl, C 1 -C 4 - Alkoxycarbonyl, phenyl, phenoxy, phenoxy-C 1 -C 4 -alkyl, phenoxy-C 1 -C 4 -alkoxy, phen-C 1 -C 4 -alkyl, phen-C 1 -C 4 -alkoxy or benzoyl ,
  • R3 is hydrogen, halogen, trifluoromethyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 - C 6 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, in whole or in part
  • R4 is hydrogen, C 1 -C 6 -alkyl, completely or partly substituted by C 1 -C 4 -alkoxy, chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or together with R3 optionally completely or partly substituted by fluorine 1 -C 2 -alkylenedioxy or chlorotrifluoroethylenedio ⁇ y means
  • R5 denotes hydrogen or a group which can easily be split off under physiological conditions
  • R9 is C 1 -C 6 alkyl or phenyl, or together with R10 and the nitrogen atom, to which both are attached, represents a pyrrolidino, piperidino, morpholino, piperazino or NC 1 -C 4 alkylpiperazinorest, R10 C 1 -C 6 alkyl or phenyl, or together with R9 and the nitrogen atom, to which both are bound, represents a pyrrolidino, piperidino, morpholino, piperazino or NC 1 -C 4 alkylpiperazinorest,
  • R12 is hydrogen or C 1 -C 4 alkyl and n is the number 0 or 1, and the salts of these compounds, where R8 is not halogen or trifluoromethyl when R1, R4, R5, R6,
  • R7 and R12 are hydrogen
  • R2 is hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alk- oxy, halogen, trifluoromethyl, C 1 -C 4 alkoxycarbonyl or C 1 -C 6 alkylcarbonyl
  • R3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, trifluoromethyl, C 1 -C 4 -alkoxycarbonyl or C 1 -C 6 -alkylcarbonyl means
  • R9 means C 1 -C 6 -alkyl
  • R10 means C 1 -C 6 -alkyl
  • n represents the number 1.
  • C 1 -C 6 alkyl represents straight-chain or branched alkyl radicals.
  • Straight-chain alkyl radicals are the hexyl, pentyl, butyl, propyl, ethyl and in particular the methyl radical.
  • Branched alkyl radicals are, for example, the neopentyl, i-butyl, sec-butyl, t-butyl and the isopropyl radical.
  • Halogen in the sense of the present invention is bromine, chlorine and fluorine.
  • C 1 -C 6 alkoxy represents 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.
  • C 1 -C 4 alkoxy represents straight-chain or branched alkoxy radicals; Examples include the butoxy, i-butoxy, sec. butoxy, t-butoxy, propoxy, isopropoxy, ethoxy and in particular the methoxy radical.
  • C 1 -C 4 alkyl represents straight-chain or branched alkyl radicals;
  • the butyl, i-butyl, sec-butyl, t-butyl, propyl, isopropyl, ethyl and especially the methyl radical may be mentioned.
  • C 1 -C 4 alkoxy-C 1 -C 4 alkyl represents C 1 -C 4 alkyl which is substituted by C 1 -C 4 alkoxy. Examples include the ethoxymethyl, propoxybutyl, methoxymethyl and especially the methoxyethyl radical.
  • C 1 -C 2 -alkylenedioxy-C 1 -C 4 -alkyl represents C 1 -C 4 -alkyl which is substituted by an alkylenedioxy radical.
  • the ethylenedioxy-methyl radical may be mentioned.
  • Hydroxy-C 1 -C 4 alkyl represents C 1 -C 4 alkyl which is substituted by a hydroxy radical. Examples include the 3-hydroxybutyl, 2-hydroxyisopropyl, 2-hydroxyethyl and especially the hydroxymethyl radical.
  • Cyan-C 1 -C 4 alkoxy stands for C 1 -C 4 alkoxy, which is substituted by a cyan radical is acted upon.
  • the cyanomethoxy radical may be mentioned.
  • C 1 -C 4 alkoxy-C 1 -C 4 alkoxy represents C 1 -C 4 alkoxy which is substituted by C 1 -C 4 alkoxy.
  • Examples include the ethoxyethoxy, hethoxypropoxy, ethoxymethoxy and in particular the methoxyethoxy radical.
  • C 1 -C 6 alkylcarbonyl represents C 1 -C 4 alkyl bonded to a carbonyl group.
  • the propionyl, butyryl, i-butyryl and in particular the cyclopropylcarbonyl and acetyl radicals may be mentioned.
  • C 1 -C 4 alkoxycarbonyl represents a carbonyl group bonded to C 1 -C 4 - Alko ⁇ y.
  • the ethoxycarbonyl and methoxycarbonyl radicals may be mentioned in particular.
  • Phenoxy-C 1 -C 4 alkyl stands for C 1 -C 4 alkyl which is substituted by a phenoxy radical.
  • the phenoxypropyl and the phenoxyethyl radical may be mentioned.
  • Phenoxy-C 1 -C 4 alkoxy stands for C 1 -C 4 alkoxy which is substituted by a phenoxy radical.
  • the phenoxyethoxy and the phenoxypropoxy radical may be mentioned.
  • Phen-C 1 -C 4 alkyl represents C 1 -C 4 alkyl which is substituted by a phenyl radical. Examples include the phenethyl and especially the benzyl radical.
  • Phen-C 1 -C 4 alkoxy stands for C 1 -C 4 alkoxy which is substituted by a phenyl radical.
  • the 2-phenyl-ethoxy and the benzyloxy radical may be mentioned.
  • Examples of the completely or partially substituted by fluorine-substituted C 1 -C 4 alkoxy include 1,1,2-trifluoroethoxy, perfluoropropoxy, perfluoroethoxy and in particular 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy , the 2,2,2-trifluoroethoxy and the difluoromethoxy radical.
  • the C 1 -C 2 -alkylenedioxy which may be mentioned are the ethylenedioxy- (-O-CH 2 -CH 2 -O-) and the methylenedioxy radical (-O-CH 2 -O-).
  • Examples of Ci-Cj-alkylenedioxy which are completely or partially substituted by fluorine include 1,1-difluoroethylene-dioxy- (-O-CF 2 -CH 2 -O-), 1,1,2,2-tetrafluoroethylene-dioxy- (-O- CF 2 -CF 2 -O-) and especially the difluoromethylenedioxy (-O-CF 2 -O-) and the 1,1,2-trifluoroethylene dioxy radical (-O-CF 2 -CHF-O-).
  • a group R5 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 it itself - with the attachment of a hydroxyl group - is converted into a physiologically harmless and in particular pharmacologically compatible compound becomes.
  • All types of substituted carbonyl groups such as the alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl or the optionally substituted carbamoyl group, may be mentioned in particular as the R5 groups which can be removed. Examples include the methoxycarbonyl, t-butoxycarbonyl, benzoyl, phenylcarbamoyl and dimethylcarbamoyl groups.
  • Suitable salts for compounds of the formula I in which n is the number 0 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 preparation 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.
  • water-soluble and water-insoluble acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulfo
  • the preferred salts are basic salts, in particular pharmacologically acceptable salts with inorganic and organic bases commonly used in galenics.
  • Examples of basic salts are lithium, sodium, potassium, calcium, aluminum, magnesium, titanium tan, ammonium or guanidinium salts mentioned.
  • R3 and R4 together are optionally fully or partially substituted by fluorine-substituted C 1 -C 2 -alkylenedioxy or chlorotrifluoroethylene dioxy, the substituents R3 and R4 are in adjacent positions on the benzo part of the benzimidazole ring, and here in particular in positions 5 and 6.
  • One embodiment (embodiment a) of the invention are compounds of the formula I in which R4 is completely or partially substituted by fluorine-substituted C 1 -C 4 -alkoxy, chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or together with R3, if appropriate entirely or C 1 -C 4 -alkylenedioxy or chlorotrifluoroethylenedioxy, partially substituted by fluorine, and R1, R2, R3, R5, R6, R7, R8, R9, R10, R11, R12, m and n have the meanings given above, and their salts , and also those compounds of the formula I in which R4 is hydrogen and R1, R2, R3, R5, R6, R7, R8, R9, R10, R11, R12, m and n have the meanings given above and are selected from the group consisting of 5-benzoyl-2 - [(2-dimethylaminophenyl) methylthio
  • R1 means hydrogen
  • R2 means hydrogen
  • R3 is hydrogen or together with R4 methylenedioxy or difluoromethylenedioxy
  • R4 means difluoromethoxy or together with R3 methylenedioxy or difluoromethylenedioxy
  • R5 means hydrogen
  • R6 represents hydrogen or chlorine
  • R7 means hydrogen
  • R8 represents hydrogen or fluorine
  • R9 is methyl or together with R10 and the nitrogen atom, to which both are bound, represents a pyrrolidino, morpholino or N-methylpiperazio radical,
  • R10 is methyl or together with R9 and the nitrogen atom, to which both are bound, represents a pyrrolidino, morpholino or N-methylpiperazinorest,
  • R12 is hydrogen and n represents the numbers 0 or 1, and their salts, and also those compounds of the formula I in which
  • R1 means hydrogen
  • R2 means methoxy or benzoyl
  • R3 means hydrogen
  • R4 means hydrogen
  • R5 means hydrogen
  • R6 means hydrogen or chlorine
  • R7 means hydrogen
  • R8 means hydrogen
  • R9 is methyl or together with R10 and the nitrogen atom, to which both are bound, a pyrrolidino, morpholino or N-methylpiperazino radical
  • R10 is methyl or together with R9 and the nitrogen atom, to which both are bound, a pyrrolidino, Represents morpholino or N-methyl-piperazino
  • R12 represents hydrogen and n represents the numbers 0 or 1, which are selected from the group consisting of
  • a further embodiment (embodiment b) of the invention are compounds of the formula I in which R4 is wholly or partly substituted by fluorine-substituted C 1 -C 4 -alkoxy, chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or together with R3 if appropriate entirely or partially substituted by fluorine-substituted C 1 -C 2 -alkylenedioxy or chlorotrifluoroethylenedioxy, and R1, R2, R3, R5, R6, R7, R8, R9, R10, R11, R12, m and n have the meanings given above, and Salts of these compounds.
  • connections of configuration b) are such connections of formula I, wherein
  • R1 means hydrogen
  • R2 means hydrogen
  • R3 is hydrogen or together with R4 methylenedioxy or difluoromethylenedioxy
  • R4 means difluoromethoxy or together with R3 methylenedioxy or difluoromethylenedioxy
  • R5 means hydrogen
  • R6 represents hydrogen or chlorine
  • R7 means hydrogen
  • R8 represents hydrogen or fluorine
  • R9 is methyl or together with R10 and the nitrogen atom, to which both are bound, represents a pyrrolidino, morpholino or N-methylpiperazinorest,
  • R10 is methyl or together with R9 and the nitrogen atom, to which both are bound, represents a pyrrolidino, morpholino or N-methylpiperazinorest,
  • R12 means hydrogen and. n represents the numbers 0 or 1, and the salts of these compounds.
  • Examples of compounds of embodiment b according to the invention which may be mentioned are: 5-difluoromethoxy-4,6-dimethyl-2 - [(2-dimethylaminophenyl) methylthio] -1H-benzimidazole, 5-difluoromethoxy-6-methoxy-2 - [(2-dimethylaminophenyl ) methylthio] -1H-benzimidazole, 5- (2-chloro-1,1,2-trifluoroethoxy) -2 - [(2-dimethylaminophenyl) methylthio] -1H-benzimidazole, 2 - [(2-dimethylaminophenyl) methylthio ] -5- (1,1,2,2-tetrafluoroethoxy) -1H-benzimidazole, 2 - [(2-dimethylaminophenyl) methylthio] -5-trifluoromethoxy-1H-benzimidazole, 2 - [(2-d
  • Another object of the invention is a process for the preparation of the compounds of formula I, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 and n have the meanings given above, and their Salts.
  • the process is characterized in that
  • Y, Y ′′, Z ′ and Z ′′ represent suitable leaving groups
  • Y ′ represents a leaving or reactive group
  • M ′ represents the equivalent of a metal atom
  • R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 and n have the meanings given above.
  • the compounds II-XII 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 which it is bound forms a reactive sulfinic acid derivative.
  • suitable leaving groups Y include 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.
  • Y' 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 R5'-Y '(XI) also encompasses those compounds (precursors of the group R5 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 cleavable group R5.
  • 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 'or Z' 'are for example, 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 the 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 the 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, oimethylformamide or acetonitrile) with the addition or exclusion of 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, oimethylformamide or acetonitrile
  • reaction can also be carried out without a proton acceptor, with the acid addition salts optionally being able to be separated off in a particularly pure form, depending on the nature of the starting compounds.
  • the reaction temperature can be between 0 ° and 150 ° C, in the presence of proton acceptors temperatures 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-nitroperoxybenzoic acid, peroxymaleic acid or preferably m-chloroperoxybenzoic acid.
  • the reaction temperature is (depending on the reactivity of the oxidizing agent and degree of dilution) between -70 ° C and the boiling point of the solvent used, but preferably between -40 ° and + 20 ° C.
  • Oxidation with halogens or with hypohalites for example with aqueous sodium hypochlorite solution, which is expediently carried out at temperatures between Q ° and 30 ° C., has also proven to be advantageous.
  • the reaction is conveniently carried out in inert solvents, e.g. B.
  • aromatic or chlorinated hydrocarbons such as benzene, toluene, dichloromethane or chloroform
  • esters or ethers such as ethyl acetate, isopropyl acetate or dioxane.
  • the compounds IX are reacted with the compounds X 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 e) takes place 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).
  • suitable solvents such as tetrahydrofuran or acetonitrile
  • this reaction gives mixtures of isomers which have to be separated by suitable separation processes (e.g. chromatography).
  • Solvolysis according to process variant f) 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 g) 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 a suitable solvent, 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 to which the desired acid or base - if appropriate 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
  • 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 R12, there may be additional chiral centers in the molecule (e.g. if R12 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 prepared by asymmetric synthesis, for example by reacting optically active pure compounds IX or diastereoisomerically pure compounds IX with compounds XCee K.K. Andersen, Tetrahedron Lett., 93 (1962)].
  • 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, XI and XII are either known, or they can be obtained in an analogous manner according to known regulations, starting from known precursors or obtained in a known manner.
  • connections are e.g. starting from known 5-chloro-2-nitrobenzoic acids or those which can be prepared in a known manner by nucleophilic substitution of the chlorine atom (for example in dimethyl sulfoxide with alcoholate or amine in the presence of a base such as potassium carbonate), reduction of the nitro to the amino group (for example with hydrogen / Pd / C), reductive alkylation of the amino to the dialkylamino group (for example with formaldehyde / sodium cyanoborohydride), reduction of the carboxylic acid to the benzyl alcohol (for example with lithium aluminum hydride in ether) and introduction of the leaving group Z '(for example by reaction with thionyl chloride).
  • a base such as potassium carbonate
  • reduction of the nitro to the amino group for example with hydrogen / Pd / C
  • reductive alkylation of the amino to the dialkylamino group for example with formaldehyde / sodium cyanoborohydride
  • 5-chloro-2-nitrobenzaldehyde H
  • R12 alkyl
  • 5-chloro-2-nitro) - phenyl-alkyl-ketones are used.
  • These compounds are, for example, from the 5-alkoxy-2-nitrobenzoic acids or 5-alkoxy-2-nitrobenzaldehydes and (5-alkoxy-2-nitro) phenyl alkyl ketones by chlorination of the alkoxy group (for example using phosphorus pentachloride) and subsequent exchange of the chlorine atoms for fluorine atoms (for example by reaction with antimony trifluoride) and subsequent reaction sequence analogous to point 1).
  • the compounds V, VII and X are e.g. B. accessible from the compounds III in a manner known to those skilled in the art.
  • the water phase is extracted twice with 50 ml of methylene chloride and the combined organic phases are washed twice with 20 ml of 5% sodium carbonate solution. It is dried over magnesium sulfate, filtered from the drying agent, concentrated on a rotary evaporator and the residue is crystallized from acetone / diisopropyl ether. The precipitated solid is filtered off, washed with diisopropyl ether and dried to constant weight. 3.0 g (71.41 of theory) of the title compound are obtained as a colorless solid; Mp 109-110 ° C.
  • dioxolo 1.0 g (2.4 mmol) 2,2-difluoro-6 - ⁇ [2- (4-methylpiperazin-1-yl) phenyl] methylthio ⁇ -5H- [1.3] dioxolo [4.5-f] benzimidazole are dissolved in 20 ml of dioxane and 27.4 ml of 0.1N sodium hydroxide solution; A mixture of 7.5 ml of 1N sodium hydroxide solution and 4.78 mmol of sodium hypochlorite solution is added dropwise within 30 minutes.
  • Example 6b The procedure described in Example 6b is obtained by reacting 2.16 g (10 mmol) of 5-difluoromethoxybenzimidazole-2-thiol with 2.48 g (10 mmol) of 1- (2-chloromethylphenyl) morpholinium chloride in 20 ml of isopropanol Add 11 ml of 2N sodium hydroxide to an oily crude product. Crystallization from diisopropyl ether gives 2.15 g (55% of theory) of 5-difluoromethoxy-2 - [(2-morpholinophenyl) methylthio] -1H-benzimidazole as a colorless, amorphous solid; Mp 108-09 ° C.
  • a solution of 16.5 g (94 mmol) of 2- (pyrrolidin-1-yl) benzaldehyde in 38 is added dropwise to a suspension of 1.27 g (33 mmol) of sodium borohydride in 25 ml of ethanol with cooling within 30 minutes ml of ethanol, stirred for a further 30 minutes, 25 ml of ice water are added dropwise and the mixture is concentrated to 20 ml on a rotary evaporator. After adding 35 ml of water, the mixture is extracted three times with 50 ml of methylene chloride each time; the combined organic phases are washed with water, dried over magnesium sulfate and concentrated.
  • Example Bc The procedure described in Example Bc) is obtained by reacting 8.7 g (55 mmol) of 2-chloro-6-fluorobenzaldehyde with 9.0 ml (110 mmol) of pyrrolidine in 600 ml of dimethyl sulfoxide in the presence of 87 g of powdered potassium carbonate 1 h at 100 ° C 7.8 g (68% of theory) 2-chloro-6- (pyrrolidin-1-yl) benzaldehyde, melting point 77-78 ° C.
  • the compounds of general formula I and their salts have valuable pharmacological properties which make them commercially useful. They clearly inhibit gastric acid secretion in warm-blooded animals and, moreover, have an excellent gastric and intestinal protective effect in warm-blooded animals. This gastric and intestinal protective effect is already observed when doses are administered which are below the acid secretion-inhibiting ooses.
  • the compounds according to the invention are distinguished by the absence of significant side effects and a large therapeutic breadth.
  • 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
  • Another advantage of the compounds according to the invention is their comparatively high chemical stability.
  • the compounds according to the invention surprisingly prove to be clearly superior to the compounds known from the prior art.
  • the compounds of the general formula I and their pharmacologically acceptable salts are outstandingly suitable for use in human and veterinary medicine, in particular for the treatment and / or prophylaxis of diseases of the stomach and intestines and of such diseases which are exaggerated Gastric acid secretion are used.
  • the invention therefore furthermore relates to the compounds according to the invention for use in the treatment and / or prophylaxis of the abovementioned diseases.
  • the invention also includes the use of the compounds according to the invention for the production of medicaments which are used for the treatment and / or prophylaxis of the abovementioned diseases.
  • the invention further relates to medicaments which contain one or more compounds of the general formula I 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 and excipients suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
  • solvents for example antioxidants, dispersants, emulsifiers, defoamers, taste correctors, preservatives, solubilizers, colorants 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 0.01 to about 20, preferably 0.05 to 5, in particular 0.1 to 1.5 mg / kg of body weight , if necessary 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
  • Any specialist can determine the respectively required optimal dosage and type of application of the active ingredients easy to do due to his expertise.
  • the pharmaceutical preparations can also contain one or more pharmacologically active constituents of other groups of medicaments, such as antacids, for example aluminum hydroxide, magnesium aluminate; Tranquilizers, such as benzodiazpines, for example diazepam; Antispasmodics, e.g. Bietamiverin, Camylofin; Anticholinergics such as Oxyphencyclimine, phencarbamide; Local anesthetics, e.g. Tetracaine, procaine; optionally also contain ferments, vitamins or amino acids.
  • antacids for example aluminum hydroxide, magnesium aluminate
  • Tranquilizers such as benzodiazpines, for example diazepam
  • Antispasmodics e.g. Bietamiverin, Camylofin
  • Anticholinergics such as Oxyphencyclimine, phencarbamide
  • Local anesthetics e.g. Tetracaine, pro
  • 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 increasing the main effect in an additive or superadditive sense and / or eliminating or reducing the side effects.
  • the formulation of the active ingredient can e.g. in the following way: a) tablets with 40 mg of active ingredient
  • ED25 or ED50 dose that reduces the lesion index or the HCl secretion (4h) of the rat stomach in the treated group compared to the control group by 25 or 50%.
  • the ulcer provocation is carried out in rats fasted for 24 hours (female, 180-200 g, 4 animals per cage on a high grating) by pylorus ligation (under diethyl ether anesthesia) and oral application of 100 mg / 10 ml / kg acetylsalicylic acid.
  • the substances to be tested are administered orally (10 ml / kg) one hour before the pylorus ligation.
  • the wound is closed using Michel clips. 4 hours later, the animals were killed in ether rush by atlas dislocation and resection of the stomach.
  • the product of the severity (according to the following scale of points) and the number of ulcers serves as an individual lesion index. Score scale: no ulcers 0
  • the ED25 and ED50 denote those doses that reduce the mean lesion index or HCl secretion by 25% and 50% compared to the control.
  • the LD50 of all tested compounds is above 1000 mg / kg [p.o.] in the mouse.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Des nouveaux composés de formule générale (I) où les substituants ont les représentations indiquées dans la description, possèdent un effet protecteur marqué de l'estomac et des intestins.
EP19860905269 1985-08-21 1986-08-19 Nouvelles amines, leur procede de fabrication, leur utilisation, et medicaments les contenant Pending EP0232399A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH361685 1985-08-21
CH3616/85 1985-08-21

Publications (1)

Publication Number Publication Date
EP0232399A1 true EP0232399A1 (fr) 1987-08-19

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Application Number Title Priority Date Filing Date
EP19860905269 Pending EP0232399A1 (fr) 1985-08-21 1986-08-19 Nouvelles amines, leur procede de fabrication, leur utilisation, et medicaments les contenant

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EP (1) EP0232399A1 (fr)
WO (1) WO1987001114A2 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4824856A (en) * 1985-08-14 1989-04-25 Nippon Chemiphar Co., Ltd. Method of protecting gastrointestinal tract
AR243167A1 (es) * 1985-08-24 1993-07-30 Hoechst Ag Procedimiento para la preparacion de toluidinas sustituidas.
EP0251536A1 (fr) * 1986-06-24 1988-01-07 FISONS plc Benzimidazoles, leur préparation, formulation et utilisation comme inhibiteurs de sécrétion d'acide gastrique
AT389107B (de) * 1987-12-03 1989-10-25 Fisons Plc Neue benzimidazole, verfahren zu deren herstellung und sie enthaltende pharmazeutische zusammensetzungen
DE19745692A1 (de) * 1997-07-24 1999-01-28 Bayer Ag Verfahren zur Herstellung von 2-Chlor-benzimidazol-Derivaten

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3585252D1 (de) * 1984-07-06 1992-03-05 Fisons Plc Benzimidazole, und verfahren zu deren herstellung, deren formulierung und verwendung als magensaeuresekretionshemmende verbindungen.
AU4640985A (en) * 1984-08-31 1986-03-06 Nippon Chemiphar Co. Ltd. Benzimidazole derivatives
EP0204215B1 (fr) * 1985-05-24 1993-08-11 G.D. Searle & Co. [(1H-benzimidazol-yl-2-sulfonyl)méthyl]-2-benzèneamines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8701114A2 *

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Publication number Publication date
WO1987001114A2 (fr) 1987-02-26
WO1987001114A3 (fr) 1987-04-23

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