EP0200777A1 - Neue aminoverbindungen, verfahren zu ihrer herstellung, ihre anwendung und sie enthaltende arzneimittel - Google Patents

Neue aminoverbindungen, verfahren zu ihrer herstellung, ihre anwendung und sie enthaltende arzneimittel

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Publication number
EP0200777A1
EP0200777A1 EP85905795A EP85905795A EP0200777A1 EP 0200777 A1 EP0200777 A1 EP 0200777A1 EP 85905795 A EP85905795 A EP 85905795A EP 85905795 A EP85905795 A EP 85905795A EP 0200777 A1 EP0200777 A1 EP 0200777A1
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EP
European Patent Office
Prior art keywords
hydrogen
compounds
formula
alkyl
methyl
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.)
Withdrawn
Application number
EP85905795A
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German (de)
English (en)
French (fr)
Inventor
Jörg Senn-Bilfinger
Volker Figala
Bernhard Kohl
Hartmann Schaefer
Richard Riedel
Georg Rainer
Kurt Klemm
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Takeda GmbH
Original Assignee
Byk Gulden Lomberg Chemische Fabrik GmbH
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Publication of EP0200777A1 publication Critical patent/EP0200777A1/de
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings 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 ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/12—1,4-Dioxanes; Hydrogenated 1,4-dioxanes not condensed with other rings
    • 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
    • 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

  • New amino compounds Process for their preparation, their application and medicinal products containing them
  • the invention relates to new amino compounds, 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.
  • Pyridylsulfinylbenzimidazole described that are said to have gastric acid secretion-inhibiting properties.
  • the European patent application 0 074 3.1 describes the use of a number of benzimidazole derivatives for inhibiting gastric acid secretion.
  • the German Offenlegungsschrift 34 04 610 describes further benzimidazole derivatives as cell-protecting agents for the gastrointestinal tract and as inhibitors for gastric acid secretion in mammals.
  • the invention relates to new amino compounds of the formula I.
  • R1, R2, R3 and R4 can be at any position in the benzo part of the benzimidazole and wherein R1, R2, R3 and R4 can be at any position in the benzo part of the benzimidazole and wherein R1, R2, R3 and R4 can be at any position in the benzo part of the benzimidazole and wherein R1, R2, R3 and R4 can be at any position in the benzo part of the benzimidazole and wherein R1, R2, R3 and R4 can be at any position in the benzo part of the benzimidazole and wherein R1, R2, R3 and R4 can be at any position in the benzo part of the benzimidazole and wherein R1, R2, R3 and R4 can be at any position in the benzo part of the benzimidazole and wherein R1, R2, R3 and R4 can be at any position in the benzo part of the benzimidazole and wherein R1, R2, R3 and R4 can be at any position
  • R1 is hydrogen or C 1 -C 6 alkyl
  • R2 is hydrogen, cyano, nitro, halogen, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxy-C 1 -C 4 alkyl, C 1 -C 2 alkylendloxy -C 1 -C 4 alkyl, 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 means R3 is hydrogen, C 1 -C 6 -alkyl, C 1 -C 6
  • R5 denotes hydrogen or a group which can easily be split off under physiological conditions
  • R6 represents hydrogen or C 1 -C 4 alkyl
  • R7 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or together with R8a is C 2 -C 3 -alkylene,
  • R8a is hydrogen, C 1 -C 4 -alkyl, C 3 -C 4 -alkenyl, together with R7 C 2 -C 3 alkylene, together with R9 C 2 -C 3 -alkylene or together with R8b optionally C 4 - interrupted by oxygen C 6 alkylene means
  • R8b is hydrogen, C 1 -C 4 -alkyl, C 3 -C 4 -alkenyl, C 1 -C 4 -alkylcarbonyl or together with RBa C 4 -C 6 -alkylene optionally interrupted by oxygen,
  • R9 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or together with R8a is C 2 -C 3 -alkylene,
  • R10 represents hydrogen or C 1 -C 4 alkyl and n represents the numbers 0 or 1, and the salts of these compounds.
  • Halogen in the sense of the present invention is bromine, chlorine and fluorine.
  • C 1 -C 6 alkyl represents straight-chain, branched or cyclic alkyl radicals.
  • Straight-chain alkyl radicals are the hexyl, pentyl, butyl, propyl, ethyl, and especially the methyl radical.
  • Branched alkyl radicals are, for example, the neopentyl, 1-butyl, sec-butyl, t-butyl and the isopropyl radical.
  • the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals may be mentioned as cyclic alkyl radicals.
  • C 1 -C 6 alkoxy represents straight-chain or branched alkoxy radicals. Examples include the hexyloxy, neopentyloxy, butoxy, 1-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 in particular 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 ethylenedioxymethyl radical may be mentioned.
  • Hydroxy-C 1 -C 4 alkyl represents C 1 -C 4 alkyl which is substituted by a hydroxy radical.
  • a hydroxy radical For example, the 3-hydroxybutyl, 2-hydroxyisopropyl, 2-hydroxyethyl and especially the hydroxymethyl radical may be mentioned.
  • Cyan-C 1 -C 4 alkoxy stands for C 1 -C 4 alkoxy which is substituted by a cyan radical.
  • the cyanomethoxy radical may be mentioned.
  • C 1 -C 4 alkoxy-C 1 -C 4 alkoxy represents C 1 -C 4 alkoxy, which is replaced by C 1 -C 4 - Alkoxy is substituted.
  • Examples include the ethoxyethoxy, methoxypropoxy, ethoxymethoxy and in particular the methoxyethoxy radical.
  • C 1 -C 6 alkylcarbonyl represents C 1 -C 6 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 - alkoxy. Examples include the ethoxycarbonyl and methoxycarbonyl radicals.
  • 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. Examples include the 2-phenyl-ethoxy and the benzyloxy radical.
  • Examples of 1, 1, 2-trifluoroethoxy, perfluoropropoxy, perfluoroethoxy and, in particular, 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, and the like as completely or predominantly substituted by fluorine are C 1 -C 4 alkoxy. , the 2,2,2-trifluoroethoxy and the Oifluormethoxyrest called.
  • Examples of the completely or partially substituted by fluorine-substituted C 1 -C 2 -alkylenedioxy are 1,1-difluoroethylenedioxy- (-O-CF 2 -CH 2 -O-), 1,1,2,2-tetrafluoroethylenedioxy- (- O-CF 2 -CF 2 -O-) and in particular the difluoromethylene dioxy- (-O-CF 2 -O-) and the 1,1,2-trifluoroethyleneendloxy- rest (-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, if appropriate, enzymatically catalyzed hydrolysis to form an NH bond, whereby it itself - with the attachment of a hydroxyl group - is converted into a physiologically acceptable and in particular pharmacologically compatible compound .
  • All types of substituted carbonyl groups such as the alkylcarbonyl, arylcarbonyl, aralkylcarbonyl,
  • Alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl or the optionally substituted carbamoyl group examples include the methoxycarbonyl, t-butoxycarbonyl, benzoyl, phenylcarbamoyl and dimethylcarbamoyl groups.
  • C 2 -C 3 alkylene which is formed jointly by R8a and R7 or R8a and R9, stands for ethylene or propylene.
  • C 3 -C 4 alkenyl represents the but-2-enyl, the but-3-enyl and in particular the allyl radical.
  • C 4 -C 6 alkylene which may be interrupted by oxygen represents - (CH 2 ) 4 -, - (CH 2 ) 5 -, - (CH 2 ) 6 - or - (CH 2 ) 2 -O- (Ch 2 ) 2 -, so that for the radicals R8a and R8b together with the nitrogen atom to which they are attached there is a pyrrolidlno, piperidino, perhydroazepino or morpholino radical.
  • C 1 -C 4 alkylcarbonyl represents C 1 -C 4 alkyl bonded to a carbonyl group.
  • the proponyl, butyryl and especially the acetyl radical may be mentioned.
  • 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 can initially be obtained as process products, for example in the preparation of the compounds according to the invention, are characterized by Methods known to the person skilled in the art converted into pharmacologically acceptable salts.
  • Suitable as such are, for example, water-soluble and water-insoluble slurry addition salts, such as hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, cltrate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulfosallcylate, 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 slurry addition salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, cltrate, gluconate, benzoate, hibenzate, fend
  • the preferred salts are basic salts, in particular pharmacologically compatible 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.
  • R3 and R4 together mean completely or partially substituted by fluorine-substituted C 1 -C 2 -alkylenedioxy or chlorotrifluoroethylenedloxy, the substituents R3 and R4 are bonded in neighboring positions on the benzo part of the benzimidazole ring.
  • One embodiment (embodiment a) of the invention are compounds of the formula I in which R7 and R9 are hydrogen and R1, R2, R3, R4, R5, R6, R8a, R8b, R10 and n have the meanings given above, and their salts.
  • a further embodiment (embodiment b) of the invention are compounds of the formula I in which R7 is C 1 -C 4 -alkyl, R9 is hydrogen and R1, R2, R3, R4, R5, R6, R8a, R8b, R10 and n the have meanings given above, and their salts.
  • R1 is hydrogen or C 1 -C 4 alkyl
  • R2 is hydrogen, halogen, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxy-C 1 -C 4 alkyl, hydroxy-C 1 -C 4 alkyl, C 1 -C 4 alkoxy-C 1 -C 4 alkoxy, C 1 -C 4 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, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, completely or predominantly substituted by fluorine-substituted C 1 -C 4 -alkoxy, chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or together with R4 C 1 -C 2 -alkylenedioxy or chlorotrifluoroethylenedloxy which is wholly or partly substituted by fluorine,
  • R4 is completely or predominantly substituted by fluorine-substituted C 1 -C 4 -alkoxy, chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or together with R3 completely or partially substituted by fluorine-substituted C 1 -C 2 -alkylene dioxy or chlorotrifluoroethylene doxy ,
  • R5 means hydrogen
  • R6 represents hydrogen or C 1 -C 4 alkyl
  • R8 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or together with R8a is C 2 -C 3 -alkylene,
  • R8a is hydrogen, C 1 -C 4 alkyl, together with R7 is C 2 -C 3 alkylene, together with R9 is C 2 -C 3 alkylene or together with R8b is C 4 -C 6 alkylene which is optionally interrupted by oxygen,
  • R8b is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkylcarbonyl or, together with R8a, C 4 -C 6 alkylene which is optionally interrupted by oxygen,
  • R9 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or together with R8a is C 2 -C 3 -alkylene,
  • R10 represents hydrogen or C 1 -C 4 alkyl and n represents the numbers 0 or 1, and the salts of these compounds.
  • An embodiment (embodiment a ') of the compounds to be emphasized are those of the formula I in which R7 and R9 are hydrogen and R1, R2, R3, R4, R5, R6, R8a, R8b, R10 and n have the meanings given for the compounds to be emphasized , and their salts.
  • a further embodiment (embodiment b ') of the compounds to be emphasized are those of the formula I in which R7 is C 1 -C 4 -alkyl, R9 is hydrogen and R1, R2, R3, R4, R5, R6, R8a, R8b, R10 and n have the meanings given for the compounds to be emphasized, and their salts.
  • Preferred compounds according to the invention are those in which
  • R1 is hydrogen, methyl or ethyl
  • R2 is hydrogen, chlorine, fluorine, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, acetyl, methoxycarbonyl or ethoxycarbonyl
  • R3 is hydrogen, methyl, ethyl, methoxy, ethoxy, 1,1,2,2 -Tetrafluoro-ethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy or together with R4 means difluoromethyleneendloxy, 1,1,2-trifluoroethylene dioxy or 1-chloro-1,2,2-trifluoroethylene dioxy,
  • R4 denotes 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trlfluoroethoxy, difluoromethoxy or together with R3 difluoromethylene-dioxy, 1,1,2-trifluoroethylene-dioxy or 1-chloro-1,2,2-trifluoroethylene-dioxy, R5 Hydrogen means
  • RB means hydrogen, methyl or ethyl
  • R7 is hydrogen, methyl, ethyl, methoxy, ethoxy or together with R8a
  • Ethylene or propylene means R8a is hydrogen, methyl, ethyl, together with R7 ethylene or propylene, together with R9 ethylene or propylene or together with R8b and the nitrogen atom, to which both are bound, pyrrolidino, piperidino or morpholino means R8b hydrogen, Methyl, ethyl, acetyl or together with R8a and the nitrogen atom, to which both are bound, means pyrrolidino, piperidino or morpholino,
  • R9 is hydrogen, methyl, ethyl, methoxy, ethoxy or together with R8a
  • Ethylene or propylene means R10 means hydrogen, methyl or ethyl and n represents the numbers 0 or 1, and the salts of these compounds.
  • An embodiment (embodiment a ′′) of the preferred compounds are those of the formula I in which R7 and R9 are hydrogen and Rl, R2, R3, R4, R5, R6, R8a, R8b, R10 and n are the meanings given for the preferred compounds and their salts.
  • a further embodiment (embodiment b '') of the preferred compounds are those of the formula I in which R7 is methyl or ethyl, R9 is hydrogen and R1, 12, R3, R4, R5, R6, R8a, R8b, R10 and n have the meanings given for the preferred compounds, and their salts.
  • Particularly preferred compounds according to the invention are those in which R1 is hydrogen,
  • R2 means hydrogen
  • R3 is hydrogen or together with R4 difluoromethyleneendloxy
  • R4 denotes 1,1,2,2-tetrafluoroethoxy, Dlfluormethoxy or together with R3 Difluormethylenendloxy, R5 means hydrogen,
  • R6 means hydrogen
  • R7 means hydrogen or methyl
  • R8a is methyl or together with R8b and the nitrogen atom, to which both are bound, means pyrrolidino or morpholino
  • R8b is methyl or together with R8a and the nitrogen atom, to which both are bonded, means pyrrolidino or morpholino
  • R9 means hydrogen
  • R10 represents hydrogen and n represents the numbers 0 or 1, and the salts of these compounds.
  • the substituents R3 and R4 are in particular in the 5- and 6-position of the benzimidazole.
  • 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, R8a, R8b, R9, R10 and n have the meanings given above, and their salts.
  • Y, Y ", Z, Z 'and Z" represent suitable leaving groups
  • Y' represents a leaving or reactive group
  • M stands for an alkali metal atom (Li, Na or K)
  • M ' stands for the equivalent of a metal atom
  • R1, R2, R3, R4, RS, RB, R7, R8a, R8b, R9, R10 and n have the meanings given above.
  • the compounds II-XIV may be used in such or, if appropriate, in the form of their salts.
  • compounds I are prepared from starting compounds II to XII in which R1, R2, R3, R4, R5, R6, R7, R8a, R8b, R9, R10 and n are defined as specified above.
  • a suitable leaving group Y is, for example, a group which, together with the sulfinyl group to which it is attached, forms a reactive sulfinic acid derivative.
  • suitable leaving groups Y are alkoxy, dialkylamino or alkyl mercapto groups.
  • a suitable outlet or Reactive group Y ' is a group which is able to react with a secondary amino group with elimination of HY' or with addition.
  • R5 ' is for example a leaving group which together with the carbonyl group to which it is attached is a reactive carboxylic acid derivative, e.g. an acid halide.
  • the general formula R5'-Y '(XIII) 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 one of ordinary skill in the art for alkylation reactions common group that goes off during the alkylation - for example with dialkyl sulfate, alkyl fluorosulfonate or alkyl iodide.
  • the X equivalent of 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, 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 carbonate or tertiary amines such as pyridine, trlethylamine or ethyldiisopropylamine are suitable as such.
  • 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 preferred in polar, optionally water-containing solvents in the presence of a strong acid, for example hydrochloric acid, in particular at the boiling point of the used Solvent carried out.
  • a strong acid for example hydrochloric acid, in particular at the boiling point of the used Solvent carried out.
  • Suitable oxidizing agents are all reagents commonly used for the oxidation of sulfides to sulfoxides, in particular peroxy acids, e.g. Peroxyacetic acid, trifluoroperoxyacetic acid, 3,5-dinitroperoxybenzoic acid, peroxymaleic acid or preferably m-chloroperoxybenzoic acid.
  • the reaction time 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 -30 ° C and + 20 ° C.
  • Oxidation with halogens or with hypohalites has also been found to be advantageous (eg with aqueous sodium hypochlorite solution), which is expediently carried out at temperatures between 0 ° and 30 ° C.
  • reaction is advantageously carried out in inert solvents, for example aromatic or chlorinated hydrocarbons, such as benzene, toluene, dichloromethane or chloroform, preferably in esters or ethers, such as ethyl acetate, isopropyl acetate or dloxane.
  • aromatic or chlorinated hydrocarbons such as benzene, toluene, dichloromethane or chloroform
  • esters or ethers such as ethyl acetate, isopropyl acetate or dloxane.
  • the reaction of IX with X is preferably carried out in inert solvents, as are usually used for the reaction of enolate ions with alkylating agents.
  • inert solvents such as 8enzene or toluene may be mentioned.
  • the reaction temperature is (depending on the nature of the alkali metal atom M and the leaving group Z) 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 point of benzene 80 ° C.
  • the compounds XI are reacted with the compounds XI I in a manner known per se, as is known to the person skilled in the art for the reaction organorga African connections is common.
  • reaction according to process variant f) is carried out in a manner known to those skilled in the art in suitable solvents such as tetrahydrofuran or acetone tril, 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 acetone tril
  • this reaction gives mixtures of isomers which have to be separated by suitable separation processes (e.g. chromatography).
  • 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 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, e.g. in a chlorinated hydrocarbon such as methylene chloride or chloroform, a low molecular weight aliphatic alcohol (ethanol, isopropanol), an ether
  • the salts are obtained by filtration, reprecipitation, precipitation or by evaporation of the solvent. Salts obtained can be converted into the free compounds by alkalization or acidification, for example with aqueous sodium hydrogen carbonate or with dilute hydrochloric acid, 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 R10, there may be additional chiral centers in the molecule (e.g. if R6 is not hydrogen).
  • the invention therefore encompasses both 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 reaction of optically active pure compounds XI or diastereoisomerically pure compounds XI with compounds XII [see 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, XIII and XIV are either known, or they can be obtained analogously according to known regulations, starting from known or obtainable precursors [see e.g. DE-OS 28 48 531; J. Org. Chem. 44, 2907-2910 (1979); J. Org. Chem. 29, 1-11 (1964); DE-OS 20 29 556; J. Fluorine Chem. 18: 281-91 (1981); Synthesis 1980, 727-8].
  • the compounds III are new and also a subject of the invention. They are made from corresponding pyridines unsubstituted in the 4-position by N-oxidation (e.g. with hydrogen peroxide), nitration in the 4-position (e.g. with fuming nitric acid), exchange of the nitro group for a chlorine atom (e.g. with concentrated hydrochloric acid), reaction with an amine HN (R8a) R8b and corresponding further reactions, as described in EP-A-0 103 553 or EP-A-0 080 602, can be obtained in a manner known to those skilled in the art.
  • the compounds V, VII and XII are e.g. B. from the compounds III in catfish known to those skilled in the art.
  • Compounds X are prepared based on Z. Talik, Roczniki Chem. 35, 475 (1961).
  • Example 1 5.6 g (15 mmol) of 6- [4-dimethylamino-3-methylpyridyl- (2) -methylthiol-2,2-difluoro-5H- [1.3] -dioxolo- [4, 5-f] benzimidazole after chromatographic purification on silica gel (eluent ethyl acetate / ethanol / concentrated ammonia 20: 4: 1) and stirring with dichloromethane / diethyl ether 1.2 g (20% of theory) of the title compound of mp 170-171 ° C (decomposition).
  • Example 1 3.1 g (7.63 mmol) of 5-difluoromethoxy-2- [3-methyl-4-morpholinopyridyl- (2) -methylthio] -1H-benzimidazole are obtained after stirring with dichloromethane to 1 g ( 30% of theory) of the title compound of mp. 149-150 ° C (decomposition).
  • Example 1 1-g (2.5 mmol) of 2,2-difluoro-6- [3-methyl-4-pyrrolidinyl- (1) -pyridyl- (2) -methylthio] -5H- [1,3 ] -dioxolo- [4,5-f] benzimidazole after chromatography on silica gel (eluent: ethyl acetate / ethanol / concentrated ammonia 20: 4: 1) and stirring with water and subsequently ethanol 0.45 g (43% of theory) Title compound of mp 18G-181 ° C (decomposition).
  • Example A1 6.8 g (97% of theory) of 2-chloromethyl-4-methylaminopyridine hydrochloride, mp. 171-173 ° C., are obtained from 5 g (36.2 mmol) of 2-hydroxymethyl-4-methylaminopyridine .
  • Example A1 7.4 g (99% of theory) of colorless 2-chloromethyl-4-dimethylamino-6- is obtained from 5.6 g (33.7 mmol) of 4-dimethylamino-2-hydroxymethyl-6-methylpyridine. methylpyridine hydrochloride, mp. 162-168 ° C.
  • Example A1 4 g (approx. 95% of theory) of the very hygroscopic 4-acetylamino-2-chloromethylpyridine hydrochloride is obtained from 3.17 g (19.1 mmol) of 4-acetylamino-2-hydroxymethylpyridine. 140 ° C.
  • Example A1 3 g (18 mmol) of 4-dimethylamino-2-hydroxymethyl-3-methylpyridine gave 1.9 g (48% of theory) of 2-chloromethyl-4-dimethylamino-3-methylpyridine hydrochloride, mp 197 -199 ° C.
  • Example A1 23.7 g (94% of theory) of 2-chloromethyl-3-methyl-4-morpholinopyridine hydrochloride are obtained from 20 g (96 mmol) of 2-hydroxymethyl-3-methyl-4-morpholinopyridine from mp. 77-80 ° C.
  • Example A1 11 g (57 mmol) of 2-hydroxymethyl-3-methyl-4-pyrrolidinyl- (1) -pyridine gave 3.5 g (25% of theory) of 2-chloromethyl-3-methyl-4 -pyrrolidinyl- (1) -pyridine hydrochloride of mp. 88-90 ° C. The substance is hygroscopic.
  • the substance is isolated by extraction with methylene chloride, washing, drying and evaporation on a rotary evaporator.
  • a solution of 60 g (0.38 mol) of 4-chloro-2,3-dimethylpyridine-N-oxide in 120 ml of methanol and 120 ml of water is mixed with 100 mg of copper (dchloride and 80 ml of olmethylamine) in a laboratory autoclave with a Teflon lining. After sealing, the mixture is stirred for 55 h at 90 ° C.
  • Example B1 Analogously to Example B1, the title compound of mp 305 is obtained in 75% yield by reacting 4-trifluoromethoxy-1,2-phenylenediamine dihydrochloride (cf. CA. 55, 23408d, 1961) with potassium O-ethyldithiocarbonate and sodium hydroxide solution in ethanol -307 ° C (decomposed from toluene).
  • a sample is separated on a silica gel column with cyclohexane / ethyl acetate (4: 1) into two pure isomers with melting points 110, 5-111, 5 ° C and 120-121 ° C, whose NMR spectra on a 60 MHz Device in deuterochloroform are practically identical.
  • the compounds of the formula I according to the invention and their salts have valuable pharmacological properties which make them commercially usable. They clearly inhibit the magnesic acid secretion of warm-blooded animals and also have an excellent gastric and intestinal protective effect 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. Because of these properties, the compounds according to the invention and their pharmacologically tolerated salts are outstandingly suitable for use in human and veterinary medicine, and are used in particular for the treatment and prophylaxis of diseases of the stomach and intestines and of diseases which are based on excessive gastric acid secretion .
  • the high storage stability of the compounds according to the invention enables their problem-free use in pharmaceutical preparations.
  • the invention also relates to the invention bindings for use in the treatment and prophylaxis of the aforementioned diseases.
  • the invention also includes the use of the blindings according to the invention in the manufacture 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 which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
  • solvents for example antioxidants, dispersants, emulsifiers, defoamers, taste correctives, 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 0.05 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.
  • parenteral treatment similar or (especially in the case of intravenous administration of the active compounds) in the gel lower doses are used.
  • the optimum dosage and type of application of the active ingredients required in each case can easily be determined by a specialist based on his specialist knowledge.
  • 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; Tranquillizers, such as benzodiazepines, for example dlazepam; Antispasmodics, e.g. Bietamiverin, Camylofin; Anticholinergics such as Oxyphencyclimine, phencarbamide; Local anesthetics, e.g. Tetracaine, procaine, and possibly also ferment, vitamins or amino acids.
  • antacids for example aluminum hydroxide, magnesium aluminate
  • Tranquillizers such as benzodiazepines, for example dlazepam
  • Antispasmodics e.g. Bietamiverin, Camylofin
  • Anticholinergics such as Oxyphencyclimine, phencarbamide
  • Local anesthetics e.g. Tetracaine
  • H 2 blockers for example cimetidine, ranltidine
  • 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 ulcer provocation takes place in 24 hours fasted rats (female, 180-200 g, 4 animals per cage on a high grating)
  • 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)
EP85905795A 1984-10-31 1985-10-29 Neue aminoverbindungen, verfahren zu ihrer herstellung, ihre anwendung und sie enthaltende arzneimittel Withdrawn EP0200777A1 (de)

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CH522584 1984-10-31
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EP (1) EP0200777A1 (enrdf_load_stackoverflow)
AU (1) AU5092985A (enrdf_load_stackoverflow)
GR (1) GR852630B (enrdf_load_stackoverflow)
IL (1) IL76837A0 (enrdf_load_stackoverflow)
PT (1) PT81397B (enrdf_load_stackoverflow)
WO (1) WO1986002645A1 (enrdf_load_stackoverflow)

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Publication number Priority date Publication date Assignee Title
JO1406B1 (en) * 1984-11-02 1986-11-30 سميث كلاين اند فرينش لابوراتوريز ليمتد Chemical compounds
NZ242756A (en) * 1991-06-03 1994-07-26 Sumitomo Chemical Co Benzimidazole derivatives having a fused ring which contains 1 or 2 o atoms and at least 1 -cf2- unit; use as fungicides; and precursors
SE508669C2 (sv) * 1996-04-26 1998-10-26 Astra Ab Nytt förfarande
DE19745692A1 (de) * 1997-07-24 1999-01-28 Bayer Ag Verfahren zur Herstellung von 2-Chlor-benzimidazol-Derivaten

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Title
See references of WO8602645A1 *

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GR852630B (enrdf_load_stackoverflow) 1986-02-03
PT81397B (de) 1987-08-04
AU5092985A (en) 1986-05-15
PT81397A (de) 1985-11-01
IL76837A0 (en) 1986-02-28

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