EP0415990A1 - New fluoralkoxy compounds - Google Patents

New fluoralkoxy compounds

Info

Publication number
EP0415990A1
EP0415990A1 EP89906099A EP89906099A EP0415990A1 EP 0415990 A1 EP0415990 A1 EP 0415990A1 EP 89906099 A EP89906099 A EP 89906099A EP 89906099 A EP89906099 A EP 89906099A EP 0415990 A1 EP0415990 A1 EP 0415990A1
Authority
EP
European Patent Office
Prior art keywords
hydrogen
compounds
methyl
formula
trifluoroethoxy
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Withdrawn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
EP89906099A
Other languages
German (de)
French (fr)
Inventor
Bernhard Kohl
Ernst Sturm
Richard Riedel
Georg Rainer
Uwe Krüger
Wolfgang-Alexander Simon
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 EP0415990A1 publication Critical patent/EP0415990A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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 fluoroalkoxy 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.
  • the invention relates to new fluoroalkoxy compounds of the formula I.
  • Rl, R2 and R3 can be at any position in the benzo part of the benzimidazole and wherein
  • R1 hydrogen, halogen, trifluoromethyl, 1- ⁇ C-alkyl, 1-6C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-aloxy, phenyl, phenoxy , Phenoxy-1-4C-alkyl, phenoxy-1-4C-alkoxy, phen-1-4C-al yl or phen-1-4C-alkoxy,
  • R2 is hydrogen, 1-6C-alkyl, 1-6C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy, chlorodifluoromethoxy, 2-chloro-1, 1,2-trifluoroethoxy or together with R3 in whole or in part Is fluorine-substituted 1-2C-alkylenedioxy or chlorotrifluoroethylenedioxy,
  • R3 is completely or predominantly fluorine-substituted 1-4C-alkoxy, chlorodifluoromethoxy, 2-chloro-1,2,2-trifluoroethoxy or together with R2 completely or partly fluorine-substituted 1,2-alkylenedioxy or chlorotrifluoroethylenedioxy,
  • 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 hydrogen, 1-6C-alkyl, 1-6C-alkoxy, 2-5C-alkenyloxy, 2-5C-alkynyloxy or 1-4C-alkoxy-1-4C-alkoxy,
  • R8 is completely or predominantly fluorine-substituted 1-4C-alkoxy 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 AI ylreste.
  • 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, see. -Butyl, t-butyl and the isopropyl radical.
  • 1-6C-Alkoxy stands for straight-chain or branched alkoxy radicals. Examples include the hexyl oxy, neopentyl oxy, butoxy, i-butoxy, sec-butoxy, t-butoxy, propoxy, isopropoxy, ethoxy and in particular the methoxy radical.
  • 1-4C-Alkoxy stands for 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-A1kyl represents straight-chain or branched alkyl radicals; For example, the butyl, i-butyl, see.-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.
  • methoxypropoxy, ethoxymethoxy and in particular the ethoxyethoxy and methoxyethoxy radicals 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-l-4C-alkoxy stands for l-4C-alkoxy which is substituted by a phenoxy radical. Examples include phenoxyethoxy and phenoxypropoxy.
  • Phen-1-4C-al yl stands for 1-4C-alkyl which is substituted by a phenyl radical.
  • the phenethyl and especially the benzyl radical may be mentioned.
  • 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.
  • 1,1-difluoroethylenedioxy- (-0-CF 2 -CH 2 -0-), 1,1,2,2-tetra-fluoroethylenedioxy- (as wholly or partly substituted by fluorine substituted by fluorine are -0-CF 2 -CF 2 -0-) and in particular the difluoroethylenedioxy- (_0-CF 2 -0-) and the 1,1,2-trifluoroethylenedioxy radical (-0-CF 2 -CHF-0-).
  • 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 pharmacologically acceptable compound is converted.
  • substituted carbonyl groups such as the AI ylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl or the optionally substituted carbamoyl group, may be mentioned in particular as the R4 groups which can be split off.
  • R4 groups which can be split off. Examples include the methoxycarbonyl, t-butoxycarbonyl, benzoyl, phenylcarbamoyl and the dimethylcarbonyl group.
  • 2-5C-alkenyloxy represents 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.
  • Suitable salts for compounds of the formula I in which n denotes the number 0 (sulfides), preferably alTe acid addition salts, are suitable.
  • Pharmacologically incompatible salts which may initially be obtained as process products in the production 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, carbonate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulfosal cylate, 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, carbonate, gluconate, benzoate, hibenzate, fendizoate, butyrate
  • 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.
  • Rl is hydrogen
  • R2 is hydrogen, methyl, ethyl, methoxy, ethoxy, 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-l, 1,2-tri fluoroethoxy or together with R3 difluoromethylene dioxy , 1,1,2-trifluoroethylene dioxy or l-chloro-l, 2,2-trifluoroethylene dioxy,
  • R3 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-l, l, 2-trifluoroethoxy or together with R2 difluoromethyl methylenedioxy, 1,1,2-trifluoroethylene dioxy or l-chloro-l, 2,2-trifluoroethylene-dioxy means
  • R4 means hydrogen
  • R5 denotes hydrogen, methyl or ethyl
  • R6 denotes hydrogen or 1-4C-A1 kyl
  • R7 is hydrogen, 1-4C-A1kyl or 1-4C-alkoxy
  • R8 denotes 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoromethoxy and n represents the number 0 or 1, and the salts of these compounds.
  • Another noteworthy embodiment of the invention are compounds of the formula Ib
  • Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO and n have the meanings given for the configuration, and their salts.
  • Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO and n have the meanings given for the configuration a, and their salts.
  • Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO 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 and I in those
  • Rl is hydrogen
  • R2 is hydrogen or together with R3 difluoromethylene dioxy
  • R3 is 2,2,2-trifluoroethoxy, difluoromethoxy or together with R3 is difluoromethylene methylene
  • R4 is hydrogen
  • R5 is hydrogen
  • R6 is hydrogen
  • R7 represents hydrogen, methyl or methoxy
  • R8 represents 2,2,2-trifluoroethoxy
  • n represents the number 0 or 1
  • the salts of these compounds
  • Another object of the invention is a process for the preparation of the compounds of formula I, wherein Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO and n have the meanings given above, and their salts.
  • the process to be prepared are product products - that compounds of the formula I in which R4 is hydrogen are reacted with compounds of the formula R4'-Y ' (XIII), in which R4 'is the desired group which can easily be split off under physiological conditions or is a precursor together with Y' i and, if desired, is subsequently converted into the salts, or
  • Y, Y ' 1 , 1, V and 1 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
  • Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO 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 it is attached, 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 R4'-Y '(XIII) also includes those compounds (precursors of the group R4 which can easily be split off under physiological conditions) in which Y 1 represents a reactive group (for example isonitriles) which are involved in the reaction with the secondary amino group, there is no condensation with elimination of HY 'but an addition to form the desired removable group R4.
  • the leaving group Y 11 is a group familiar to the person skilled in the art for alkylation reactions, which goes off during the alkylation - for example with dialkyl sulfate, fluorosulfonic acid alkyl ester or alkyl iodide.
  • Suitable leaving groups Z, V or 1 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 case of 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 case of substitution reactions of organometallic compounds, such as the metals mentioned above.
  • the reaction of II with III is carried out 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, triethylamine or ethyldiisopropylamine, are suitable as such.
  • reaction can also be carried out without a proton acceptor, it being possible, depending on the nature of the starting compounds, first of all to separate off the acid addition salts in a particularly pure form.
  • the reaction temperature can be between 0 and 150 ° C, temperatures in the presence of proton acceptors between 20 and 80 ° C and without proton acceptors between 60 and 120 ° C
  • the boiling point of the solvents used - are preferred.
  • the response times are between 0.5 and 12 hours.
  • the reaction of VI with VII is preferably carried out 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 solvent used.
  • a strong acid for example hydrochloric acid
  • the oxidation of sulfides VIII takes place under the conditions known to the person skilled in the art for the oxidation of sulfides to sulfoxides (see, for example, J. Drabowicz and M. Mikolajczyk, Organic preparations and procedures int. 14 (1-2) , 45-89 (1982) or E. Block in S. Patai, The Chemistry of Functional Groups, Supplement E. Part 1, pp. 539-608, John Wiley and Sons (Interscience Publication), 1980.
  • oxidizing agents reagents commonly used for the oxidation of sulfides to sulfoxides in particular peroxy acids, such as peroxyacetic acid, trifluoroperoxyacetic acid, 3,5-dinitroperoxybenzoic acid, peroxymaleic acid, magnesium monoperoxiphthalate or preferably m-chloroperoxybenzoic acid.
  • the reaction temperature (depending on the reactivity of the oxidizing agent and degree of dilution) is between -70 C and the boiling temperature of the solvent used, but preferably between -30 and +20 C. Also advantageous is the oxidation with halogens or with hypohalites (eg with aqueous sodium hypochlorite solution), which is expediently carried out at temperatures between 0 and 50 ° C.
  • the reaction is conveniently carried out in inert solvents, e.g. B. aromatic or chlorinated hydrocarbons, such as benzene, toluene, dichloromethane or chloroform, preferably in esters or ethers, such as ethyl acetate, isopropyl acetate or dioxane.
  • 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.
  • aromatic solvents such as benzene or toluene may be mentioned.
  • the reaction temperature is (depending on the type of Al alimeo o tallatoms M and the leaving group Z) generally between 0 and 120 C, the boiling point of the solvent used is preferred.
  • M represents Li (lithium) and Z Cl (chlorine) and the reaction is carried out in benzene o] the boiling point 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 also without base addition (if Y 'represents a reactive group).
  • suitable solvents such as tetrahydrofuran or acetonitrile
  • Y 'represents a leaving group or also without base addition (if Y 'represents a reactive group).
  • this reaction gives isomeric mixtures which have to be separated by suitable separation processes (for example 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 alkylation according to process variant h) is carried out - if appropriate after prior deprotonation - in a manner familiar to the person 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, e.g. 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 contains 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 converted into the free compounds by alkalization or acidification, for example with aqueous sodium bicarbonate 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 sulfox de invention are optically active compounds. Depending on the nature of the substituents Rl to R8, there may be additional chiral centers in the molecule (eg if R5 is not hydrogen). The invention therefore includes both the enantiomers and d astereomers and their mixtures and racemates.
  • the enantiomers can be separated in a manner known per se (for example by producing and separating corresponding diastereoisomeric compounds).
  • the enantiomers can also be obtained by asymmetric synthesis, for example by enantioselective oxidation of the sulfides, for example using tert-butyl hydroperoxide with the addition of optically pure tartaric acid, or for example by reacting optically active pure compounds XI or diastereoisomerically pure compounds XI with compounds XII are produced [see KK 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.
  • Compounds II, IV, VI, IX and XI are e.g. known from W086 / 02646, EP 134400 or EP 127763.
  • the compounds III are known from EP 174726 and EP 208452, or they can be prepared in an analogous manner.
  • 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 1 The procedure described in Example 1 is obtained by reacting 0.66 g of 5-difluoromethoxy-2-mercapto-1H-benzimiazole with 0.78 g of 2-chloromethyI-4- (2,2,2-trifluoroethoxy ) -3-methylpy ⁇ d ⁇ nium chloride with the addition of 3.1 ml of 2N sodium hydroxide solution in ethanol / water after crystallization from methylene chloride / di-isopropyl ether 1.18 g (80% of theory) of the title compound as a colorless powder of mp 148 -149 C.
  • 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 gastric acid secretion from warm-blooded animals and, moreover, 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” in this context means the prevention and treatment of gastrointestinal diseases, in particular gastrointestinal inflammatory diseases and lesions (such as, for example, ulcer ventriculi, duodenal ulcer, gastrititis, hyperacid or drug-induced irritable stomach), which are caused, for example, by microorganisms, bacterial toxins , Drugs (eg certain anti-inflammatory drugs and anti-rheumatic drugs), chemicals (eg ethanol), stomach acid or stressful situations can be caused.
  • gastrointestinal inflammatory diseases and lesions such as, for example, ulcer ventriculi, duodenal ulcer, gastrititis, hyperacid or drug-induced irritable stomach
  • Drugs eg certain anti-inflammatory drugs and anti-rheumatic drugs
  • chemicals eg ethanol
  • stomach acid or stressful situations can be caused.
  • the compounds according to the invention surprisingly prove to be significantly superior to the compounds known from the prior art.
  • the compounds according to the invention and their pharmacologically tolerable salts are outstandingly suitable for use in human and veterinary medicine, in particular for the treatment and prophylaxis of diseases of the stomach and intestine and those diseases which are exaggerated Gastric acid secretion are based, be used ver.
  • 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 manufacture of medicinal products 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 medicaments are produced according to known processes known 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 correctors, preservatives, solubilizers, dyes or in particular performance 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 of body weight ⁇ if necessary 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 of body weight ⁇ if necessary in the form of several, preferably 1 to 4 individual doses to achieve the desired result.
  • parenteral treatment similar or (in particular in the case of intravenous administration of the active substances) generally lower doses can be used. Any person skilled in the art can easily determine the optimum dosage and mode of application of the active ingredients required on the basis of his or her specialist knowledge.
  • the pharmaceutically preparations also include one or more pharmacologically active constituents of other groups of medicaments, such as antacids, for example aluminum hydroxide, magnesium aluminate; Tranquilizers, such as benzodiazepines, for example diazepam; Antispasmodics such as Bietamiverin, Camylofin; Anticholi ergica, such as, for example, Oxyphencycli in, phencarbamide; Local anesthetics, such as tetracaine, procaine; Antibiotics such as penicillins, tetracyeline, etc .; optionally also contain ferments, vitamins or amino acids.
  • antacids for example aluminum hydroxide, magnesium aluminate
  • Tranquilizers such as benzodiazepines, for example diazepam
  • Antispasmodics such as Bietamiverin, Camylofin
  • Anticholi ergica such as, for example, Oxyphencycl
  • H 2 blockers for example cimetidine, ranitidine
  • peripheral anticholinergics for example pirenzepin, telenzepin, zolenzepin
  • gastrin antagonists with the aim of increasing the main effect in an additive or superadditive sense and / or eliminating or reducing the side effects, or further with antibacterially active substances (such as cephalosporins, tetracyclines, nalidixic acid, penicillins etc .) to combat Ca pylobacter pyloridis.
  • the excellent stomach protection effect and the gastric secretion-inhibiting effect of the compounds according to the invention can be demonstrated in studies on models of animal experiments.
  • the compounds according to the invention investigated in the models listed below have been given numbers which correspond to the example numbers.
  • Table 1 below shows the influence of the compounds according to the invention after oral (p. O.) Administration on lesion formation and acid excretion in the modified Shay rat.
  • ED50 dose (interpolated) that reduces the lesion index or the HCl secretion of the rat stomach in the treated group compared to the control group by 50%.
  • the ulcer provocation is carried out on 24 hours fasting rats (female, 180-200 g, 4 animals per cage on a high grating) by pyloric acid (under diethyl ether anesthesia) and oral application of 100 mg / lOml / kg acetylsalicylic acid.
  • the substances to be tested are administered orally (10 ml / kg) one hour before the pylorus ligature.
  • the wound is closed using Miehe! lammer made. 4 hours later, the animals were killed in etheric intoxication by atlas displacement and gastric resection.
  • the stomach is opened along the large curvature and stretched out on a cork plate after the amount of the secreted gastric juice (volume) and later its HCl content (titration with sodium hydroxide solution) is determined.
  • the product of the severity (according to the following scale of points) and the number of ulcers serves as an individual lesion index.
  • the ED50 is the dose that reduces the mean lesion index or HCl secretion by 50% compared to the control.
  • Table 2 shows the influence of the compounds according to the invention after intravenous administration on the acid secretion of the perfused rat stomach stimulated by pentagastrin in vivo.
  • ED50 Dosi s (interpolated), which causes a maximum inhibition of the HCl secretion IO ⁇ u 50%.
  • anesthetized rats (CD rat, female, 200-250 g; 1.5 g / kg in urethane) were opened by a median upper abdominal incision and a PVC catheter transorally in the esophagus and another via The pylorus was fixed in such a way that the ends of the tube were just protruding into the gastric lumen.
  • the catheter leading out of the pylorus led outwards through a lateral opening in the right abdominal wall.
  • the stomach was continuously flowed through with 37 C warm physiological NaCl solution (0.5 ml / min, pH 6.8-6.9; Braun-Unita I).
  • p 7 Dosimat 655 Metrohm
  • the maximum decrease in acid excretion (15 min fractions) of each treated group compared to that of the untreated control group ( 100%) served as a measure of the secretion-inhibiting effect.
  • the ED50 denotes the dose that causes a maximum inhibition of HCl secretion by 50%.

Landscapes

  • 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)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Des composés fluorés d'alkoxyde ayant la formule (I), dans laquelle les substituants et les symboles ont la signification donnée dans la description, sont de nouveaux composés qui présentent des propriétés anti-ulcérogènes.Fluorinated alkoxide compounds of the formula (I), in which the substituents and symbols have the meaning given in the description, are new compounds which exhibit anti-ulcerogenic properties.

Description

Neue Fluoralkoxyverbindungen New fluoroalkoxy compounds
Anwendungsgebiet der ErfindungField of application of the invention
Die Erfindung betrifft neue Fluoralkoxyverbindungen, Verfahren zu ihrer Her¬ stellung, ihre Anwendung und sie enthaltende Arzneimittel. Die erfindungsge¬ mäßen Verbindungen werden in der pharmazeutischen Industrie als Zwischenprodu te und zur Herstellung von Medikamenten verwendet.The invention relates to new fluoroalkoxy 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.
Stand der TechnikState of the art
In einer Vielzahl von Patentanmeldungen und Patenten werden 2-(2-Pyridylmethy sulfinyl)-lH-benzimidazolderivate beschrieben, die magensäuresekretionshemmen und ulcusprotektive Eigenschaften besitzen sollen. - Unter anderem werden in den Europäischen Patentanmeldungen 174 726, 208 452 und 237 200 2-(2-Pyridylm thylsulfinyl)-lH-benzimidazolderivate beschrieben, die - neben Wasserstoff¬ atomen und/oder Alkyl- oder Alkoxygruppen - als wesentliches Strukturelement einen fluorierten Alkoxysubstituenten im 2-Pyridylring besitzen. - Überra¬ schenderweise wurde nun gefunden, daß die unten näher beschriebenen neuen Fluoralkoxyverbindungen, die als wesentliches Strukturelement neben einem fluorierten Alkoxyrest im Pyridinring einen fluorierten Alkoxyrest im Benzimi dazolring tragen, interessante und unerwartete Eigenschaften aufweisen, durch die sie sich in vorteilhafter Weise von den bekannten Verbindungen unterschei den.A large number of patent applications and patents describe 2- (2-pyridylmethysulfinyl) -IH-benzimidazole derivatives which are said to have gastric acid secretion inhibitors and ulcer protective properties. - Among other things, European patent applications 174 726, 208 452 and 237 200 describe 2- (2-pyridylmethylsulfinyl) 1H-benzimidazole derivatives which, in addition to hydrogen atoms and / or alkyl or alkoxy groups, have a fluorinated alkoxy substituent as an essential structural element possess in the 2-pyridyl ring. Surprisingly, it has now been found that the new fluoroalkoxy compounds described in more detail below, which, as an essential structural element in addition to a fluorinated alkoxy radical in the pyridine ring, also contain a fluorinated alkoxy radical in the benzimi ring, have interesting and unexpected properties which advantageously distinguish them from the known ones Differentiate the connections.
Beschreibung der ErfindungDescription of the invention
Gegenstand der Erfindung sind neue Fluoralkoxyverbindungen der Formel IThe invention relates to new fluoroalkoxy compounds of the formula I.
(I)(I)
worin Rl, R2 und R3 an beliebigen Positionen im Benzoteil des Benzimidazols stehen können und worin wherein Rl, R2 and R3 can be at any position in the benzo part of the benzimidazole and wherein
Rl Wasserstoff, Halogen, Trifluormethyl, 1-βC-Alkyl, l-6C-Alkoxy, 1-4C-Alk- oxy-l-4C-alkyl , l-4C-Al oxy-l-4C-al oxy, Phenyl , Phenoxy, Phenoxy-l-4C-al- kyl , Phenoxy-l-4C-alkoxy, Phen-l-4C-al yl oder Phen-l-4C-alkoxy bedeutet,R1 hydrogen, halogen, trifluoromethyl, 1-βC-alkyl, 1-6C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-aloxy, phenyl, phenoxy , Phenoxy-1-4C-alkyl, phenoxy-1-4C-alkoxy, phen-1-4C-al yl or phen-1-4C-alkoxy,
R2 Wasserstoff, 1-6C-Alkyl, l-6C-Alkoxy, ganz oder überwiegend durch Fluor substituiertes l-4C-Alkoxy, Chlordifluormethoxy, 2-Chlor-l,l,2-trifluor- ethoxy oder gemeinsam mit R3 ganz oder teilweise durch Fluor substituier¬ tes l-2C-Alkylendioxy oder Chlortrifluorethylendioxy bedeutet,R2 is hydrogen, 1-6C-alkyl, 1-6C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy, chlorodifluoromethoxy, 2-chloro-1, 1,2-trifluoroethoxy or together with R3 in whole or in part Is fluorine-substituted 1-2C-alkylenedioxy or chlorotrifluoroethylenedioxy,
R3 ganz oder überwiegend durch Fluor substituiertes l-4C-Alkoxy, Chlordi¬ fluormethoxy, 2-Chlor-l,l,2-trifluorethoxy oder gemeinsam mit R2 ganz oder teilweise durch Fluor substituiertes l-2C-Alkylendioxy oder Chlortrifluor¬ ethylendioxy bedeutet,R3 is completely or predominantly fluorine-substituted 1-4C-alkoxy, chlorodifluoromethoxy, 2-chloro-1,2,2-trifluoroethoxy or together with R2 completely or partly fluorine-substituted 1,2-alkylenedioxy or chlorotrifluoroethylenedioxy,
R4 Wasserstoff oder eine unter physiologischen Bedingungen leicht abspaltbare Gruppe bedeutet,R4 denotes hydrogen or a group which can easily be split off under physiological conditions,
R5 Wasserstoff oder 1-6C-Alkyl bedeutet,R5 denotes hydrogen or 1-6C-alkyl,
R6 Wasserstoff oder 1-6C-Alkyl bedeutet,R6 represents hydrogen or 1-6C-alkyl,
R7 Wasserstoff, 1-6C-Alkyl, l-6C-Alkoxy, 2-5C-Alkenyloxy, 2-5C-Alkinyloxy oder l-4C-Alkoxy-l-4C-alkoxy bedeutet,R7 denotes hydrogen, 1-6C-alkyl, 1-6C-alkoxy, 2-5C-alkenyloxy, 2-5C-alkynyloxy or 1-4C-alkoxy-1-4C-alkoxy,
R8 ganz oder überwiegend durch Fluor substituiertes l-4C-Alkoxy bedeutet und n die Zahl 0 oder 1 darstellt, und die Salze dieser Verbindungen.R8 is completely or predominantly fluorine-substituted 1-4C-alkoxy and n represents the number 0 or 1, and the salts of these compounds.
Halogen im Sinne der vorliegenden Erfindung ist Brom, Chlor und Fluor.Halogen in the sense of the present invention is bromine, chlorine and fluorine.
1-6C-Alkyl steht für geradkettige und verzweigte AI ylreste. Geradkettige Al- kylreste sind der Hexyl-, Pentyl-, Butyl-, Propyl-, Ethyl- und insbesondere der Methyl rest. Verzweigte AI kylreste sind beispielsweise der Neopentyl-, i -Butyl-, see. -Butyl-, t-Butyl- und der Isopropylrest.1-6C-Alkyl stands for straight-chain and branched AI ylreste. 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, see. -Butyl, t-butyl and the isopropyl radical.
l-6C-Alkoxy steht für geradkettige oder verzweigte Alkoxyreste. Beispielsweise seien genannt der Hexyl oxy-, Neopentyl oxy-, Butoxy-, i-Butoxy-, sec.-Butoxy-, t-Butoxy-, Propoxy-, Isopropoxy-, Ethoxy- und insbesondere der Methoxyrest.1-6C-Alkoxy stands for straight-chain or branched alkoxy radicals. Examples include the hexyl oxy, neopentyl oxy, butoxy, i-butoxy, sec-butoxy, t-butoxy, propoxy, isopropoxy, ethoxy and in particular the methoxy radical.
l-4C-Alkoxy steht für geradkettige oder verzweigte Alkoxyreste; beispielsweise seien genannt der Butoxy-, i-Butoxy-, sec.-Butoxy-, t-Butoxy-, Propoxy-, Iso¬ propoxy-, Ethoxy- und insbesondere der Methoxyrest. 1-4C-A1kyl steht für geradkettige oder verzweigte AIkylreste; beispielsweise seien der Butyl-, i-Butyl-, see.-Butyl-, t-Butyl-, Propyl-, Isopropyl-, Ethyl und insbesondere der Methylrest genannt.1-4C-Alkoxy stands for 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-A1kyl represents straight-chain or branched alkyl radicals; For example, the butyl, i-butyl, see.-butyl, t-butyl, propyl, isopropyl, ethyl and especially the methyl radical may be mentioned.
l-4C-Alkoxy-l-4C-alkyl steht für 1-4C-A1kyl , das durch l-4C-Alkoxy substituie ist. Beispielsweise seien der Ethoxymethyl-, Propoxybutyl-, Methoxymethyl- un insbesondere der Methoxyethyl- und der Ethoxyethylrest genannt.1-4C-Alkoxy-1-4C-alkyl represents 1-4C-alkyl which is substituted by 1-4C-alkoxy. For example, the ethoxymethyl, propoxybutyl, methoxymethyl and especially the methoxyethyl and ethoxyethyl radicals may be mentioned.
l-4C-Alkoxy-l-4C-alkoxy steht für l-4C-Alkoxy, das durch l-4C-Alkoxy substitu iert ist. Beispielsweise seien der Methoxypropoxy-, Ethoxymethoxy- und insbe¬ sondere der Ethoxyethoxy- und der Methoxyethoxyrest genannt.1-4C-Alkoxy-1-4C-alkoxy stands for 1-4C-alkoxy which is substituted by 1-4C-alkoxy. For example, the methoxypropoxy, ethoxymethoxy and in particular the ethoxyethoxy and methoxyethoxy radicals may be mentioned.
Phenoxy-l-4C-alkyl steht für 1-4C-A1kyl , das durch einen Phenoxyrest substitu iert ist. Beispielsweise seien der Phenoxypropyl- und der Phenoxyethylrest ge nannt.Phenoxy-1-4C-alkyl stands for 1-4C-alkyl which is substituted by a phenoxy radical. For example, the phenoxypropyl and the phenoxyethyl radical may be mentioned.
Phenoxy-l-4C-alkoxy steht für l-4C-Alkoxy, das durch einen Phenoxyrest substi tuiert ist. Beispielsweise seien der Phenoxyethoxy- und der Phenoxypropoxyres genannt.Phenoxy-l-4C-alkoxy stands for l-4C-alkoxy which is substituted by a phenoxy radical. Examples include phenoxyethoxy and phenoxypropoxy.
Phen-l-4C-al yl steht für 1-4C-Alkyl, das durch einen Phenylrest substituiert ist. Beispielsweise seien der Phenethyl und insbesondere der Benzylrest ge¬ nannt.Phen-1-4C-al yl stands for 1-4C-alkyl which is substituted by a phenyl radical. For example, the phenethyl and especially the benzyl radical may be mentioned.
Phen-l-4C-alkoxy steht für l-4C-Alkoxy, das durch einen Phenylrest substituie ist. Beispielsweise seien der 2-Phenyl-ethoxy- und der Benzyloxyrest genannt.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.
Als ganz oder überwiegend durch Fluor substituiertes l-4C-Alkoxy seien bei¬ spielsweise der 1,2,2-Trifluorethoxy-, der 2,2,3,3,3-Pentafluorpropoxy-, der Perfluorethoxy- und insbesondere der 1,1,2,2-Tetrafluorethoxy-, der Trifluor- methoxy-, der 2,2,2-Trifluorethoxy- und der Difluormethoxyrest genannt.Examples of 1,2-trifluoroethoxy-, 2,2,3,3,3-pentafluoropropoxy-, perfluoroethoxy- and in particular 1,1- 2,2-tetrafluoroethoxy, the trifluoromethoxy, the 2,2,2-trifluoroethoxy and the difluoromethoxy radical.
Als ganz oder teilweise durch Fluor substituiertes l-2C-Alkylendioxy seien bei spielsweise der 1,1-Difluorethylendioxy- (-0-CF2-CH2-0-) , der 1,1,2,2-Tetra- fluorethylendioxy- (-0-CF2-CF2-0-) und insbesondere der Difluor ethylendioxy- (_0-CF2-0-) und der 1,1,2-Trifluorethylendioxyrest (-0-CF2-CHF-0-) genannt. Eine unter physiologischen Bedingungen leicht abspaltbare Gruppe R4 ist ein Substituent, der durch - gegebenenfalls enzy at sch katalysierte - Hydrolyse vom Stickstoffatom unter Ausbildung einer N-H-Bindung abgetrennt wird, wobei er selbst - unter Anbindung einer Hydroxylgruppe - in eine physiologisch unbedenk¬ liche und insbesondere pharmakologisch verträgliche Verbindung umgewandelt wird. Als abspaltbare Gruppen R4 seien insbesondere alle Arten von substitu¬ ierten Carbonylgruppen genannt, wie die AI ylcarbonyl-, Arylcarbonyl-, Aralkyl- carbonyl-, Alkoxycarbonyl-, Aryloxycarbonyl-, Aralkoxycarbonyl- oder die gege¬ benenfalls substituierte Carbamoylgruppe. Beispielswe se seien die Methoxycar- bonyl-, t-Butoxycarbonyl-, Benzoyl-, Phenylcarbamoyl- und die Dimethylcar¬ bamoylgruppe genannt.Examples of 1,1-difluoroethylenedioxy- (-0-CF 2 -CH 2 -0-), 1,1,2,2-tetra-fluoroethylenedioxy- (as wholly or partly substituted by fluorine substituted by fluorine are -0-CF 2 -CF 2 -0-) and in particular the difluoroethylenedioxy- (_0-CF 2 -0-) and the 1,1,2-trifluoroethylenedioxy radical (-0-CF 2 -CHF-0-). 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 pharmacologically acceptable compound is converted. All types of substituted carbonyl groups, such as the AI ylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl or the optionally substituted carbamoyl group, may be mentioned in particular as the R4 groups which can be split off. Examples include the methoxycarbonyl, t-butoxycarbonyl, benzoyl, phenylcarbamoyl and the dimethylcarbonyl group.
2-5C-Alkenyloxy steht für Alkenyloxyreste wie den Pent-2-enyloxy-, den But-1- enyloxy- und insbesondere den Allyloxyrest.2-5C-alkenyloxy represents alkenyloxy radicals such as the pent-2-enyloxy, but-1-enyloxy and in particular the allyloxy radical.
2-5C-Alkinyloxy steht für Alkinyloxyreste wie den Ethinyloxy- und insbesondere den Prop-2-inyloxyrest.2-5C-alkynyloxy represents alkynyloxy radicals such as the ethynyloxy and in particular the prop-2-ynyloxy radical.
Als Salze kommen für Verbindungen der Formel I, in denen n die Zahl 0 bedeutet (Sulfide), bevorzugt alTe Säureadditionssalze in Betracht. Besonders erwähnt seien die pharmakologisch verträglichen Salze der in der Galenik üblicherweise verwendeten anorganischen und organischen Säuren. Pharmakologisch unverträgli¬ che Salze, die beispielsweise bei der Herstellung der erfindungsgemäßen Verbin¬ dungen im industriellen Maßstab als Verfahrensprodukte zunächst anfallen kön¬ nen, werden durch dem Fachmann bekannte Verfahren in pharmakologisch verträg¬ liche Salze übergeführt. Als solche eignen sich beispielsweise wasserlösliche und wasserunlösl che Säureadditionssalze, wie das Hydrochlorid, Hydrobromid, Hydroiodid, Phosphat, Nitrat, Sulfat, Acetat, C trat, Gluconat, Benzoat, Hi- benzat, Fendizoat, Butyrat, Sulfosal cylat, Maleat, Laurat, Malat, Fumarat, Succinat, Oxalat, Tartrat, Amsonat, Embonat, Metembonat, Stearat, Tosilat, 2-Hydroxy-3-naphthoat, 3-Hydroxy-2-naphthoat oder Mesilat.Suitable salts for compounds of the formula I in which n denotes the number 0 (sulfides), preferably alTe acid addition salts, are suitable. 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 production 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, carbonate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulfosal cylate, maleate, laurate, malate , Fumarate, succinate, oxalate, tartrate, amsonate, embonate, metembonate, stearate, tosilate, 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate or mesilate.
Für Verbindungen der Formel I, in denen n die Zahl 1 bedeutet (Sulfoxide), kom¬ men als Salze bevorzugt basische Salze in Betracht, insbesondere pharmakolo¬ gisch verträgliche Salze mit in der Galenik üblicherweise verwendeten anorgani¬ schen und organischen Basen. Als Beispiele für basische Salze seien Lithium-, Natrium-, Kalium-, Calcium-, Aluminium-, Magnesium-, Titan-, Ammonium- oder Guanidiniumsalze erwähnt. Wenn R2 und R3 gemeinsam ganz oder teilweise durch Fluor substituiertes 1-2C Alkylendioxy oder Chlortrifluorethylendioxy bedeuten, so sind die Substituen R2 und R3 in Nachbarpositionen am Benzoteil des Benzimidazolringes gebunden.For compounds of the formula I in which n is 1 (sulfoxides), 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. If R2 and R3 together mean completely or partially fluorine-substituted 1-2C alkylenedioxy or chlorotrifluoroethylenedioxy, the substituents R2 and R3 are bound in adjacent positions on the benzo part of the benzimidazole ring.
Eine erwähnenswerte Ausgestaltung der Erfindung (Ausgestaltung a) sind Verbi dungen der Formel Ia,A noteworthy embodiment of the invention (embodiment a) are compounds of the formula Ia,
worinwherein
Rl Wasserstoff bedeutet,Rl is hydrogen,
R2 Wasserstoff, Methyl, Ethyl, Methoxy, Ethoxy, 1,1,2,2-Tetrafluorethoxy, Trifluormethoxy, 2,2,2-Trifluorethoxy, Difluormethoxy, 2-Chlor-l, 1,2-tri fluorethoxy oder gemeinsam mit R3 Difluormethylendioxy, 1,1,2-Trifluor- ethylendioxy oder l-Chlor-l,2,2-trifluorethylendioxy bedeutet,R2 is hydrogen, methyl, ethyl, methoxy, ethoxy, 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-l, 1,2-tri fluoroethoxy or together with R3 difluoromethylene dioxy , 1,1,2-trifluoroethylene dioxy or l-chloro-l, 2,2-trifluoroethylene dioxy,
R3 1,1,2,2-Tetrafluorethoxy, Trifluormethoxy, 2,2,2-Trifluorethoxy, Difluor methoxy, 2-Chlor-l,l,2-trifluorethoxy oder gemeinsam mit R2 Difluormethy lendioxy, 1,1,2-Trifluorethylendioxy oder l-Chlor-l,2,2-trifluorethylen- dioxy bedeutet,R3 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-l, l, 2-trifluoroethoxy or together with R2 difluoromethyl methylenedioxy, 1,1,2-trifluoroethylene dioxy or l-chloro-l, 2,2-trifluoroethylene-dioxy means
R4 Wasserstoff bedeutet,R4 means hydrogen,
R5 Wasserstoff, Methyl oder Ethyl bedeutet,R5 denotes hydrogen, methyl or ethyl,
R6 Wasserstoff oder 1-4C-A1 kyl bedeutet,R6 denotes hydrogen or 1-4C-A1 kyl,
R7 Wasserstoff, 1-4C-A1 kyl oder l-4C-Alkoxy bedeutet,R7 is hydrogen, 1-4C-A1kyl or 1-4C-alkoxy,
R8 1,1,2,2-Tetrafluorethoxy, Trifluormethoxy, 2,2,2-Trifluorethoxy oder Di¬ fluormethoxy bedeutet und n die Zahl 0 oder 1 darstellt, und die Salze dieser Verbindungen. Eine weitere erwähnenswerte Ausgestaltung der Erfindung (Ausgestaltung b) sind Verbindungen der Formel IbR8 denotes 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoromethoxy and n represents the number 0 or 1, and the salts of these compounds. Another noteworthy embodiment of the invention (embodiment b) are compounds of the formula Ib
worin Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO und n die für die Ausgestaltung angegebenen Bedeutungen haben, und ihre Salze.wherein Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO and n have the meanings given for the configuration, and their salts.
Eine weitere erwähnenswerte Ausgestaltung der Erfindung (Ausgestaltung c) sind Verbindungen der Formel 1cA further noteworthy embodiment of the invention (embodiment c) are compounds of the formula 1c
worin Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO und n die für die Ausgestaltung a angegebenen Bedeutungen haben, und ihre Salze.wherein Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO and n have the meanings given for the configuration a, and their salts.
Eine weitere erwähnenswerte Ausgestaltung der Erfindung (Ausgestaltung d) sind Verbindungen der Formel IdA further noteworthy embodiment of the invention (embodiment d) are compounds of the formula Id
worin Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO und n die für die Ausgestaltung a angegebenen Bedeutungen haben, und ihre Salze. Bevorzugte erfindungsgemäße Verbindungen sind solche der Formeln I, Ia, und I in denenwherein Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO 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 and I in those
Rl Wasserstoff bedeutet,Rl is hydrogen,
R2 Wasserstoff oder gemeinsam mit R3 Difluormethylendioxy bedeutet, R3 2,2,2-Trifluorethoxy, Difluormethoxy oder gemeinsam mit R3 Difluormethy¬ lendioxy bedeutet, R4 Wasserstoff bedeutet, R5 Wasserstoff bedeutet, R6 Wasserstoff bedeutet,R2 is hydrogen or together with R3 difluoromethylene dioxy, R3 is 2,2,2-trifluoroethoxy, difluoromethoxy or together with R3 is difluoromethylene methylene, R4 is hydrogen, R5 is hydrogen, R6 is hydrogen,
R7 Wasserstoff, Methyl oder Methoxy bedeutet, R8 2,2,2-Trifluorethoxy bedeutet und n die Zahl 0 oder 1 darstellt, und die Salze dieser Verbindungen.R7 represents hydrogen, methyl or methoxy, R8 represents 2,2,2-trifluoroethoxy and n represents the number 0 or 1, and the salts of these compounds.
Als erfindungsgemäße Verbindungen seien beispielsweise genannt:The following compounds may be mentioned as examples:
2-{[3-Methoxy-4-(2,2,2-trifluorethoxy)-2-pyridyl]methylsulfinyl}-5-trifluor- methoxy-lH-benzimidazol ,2 - {[3-methoxy-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl} -5-trifluoro-methoxy-1H-benzimidazole,
2- { [3-Methoxy-4- (2 ,2,2-tri f 1 uorethoxy) -2-pyri dyl] methyl thi o} -5-tri f 1 uormethox lH-benzimidazol ,2- {[3-methoxy-4- (2, 2,2-tri f 1 uorethoxy) -2-pyridyl] methyl thi o} -5-tri f 1 uormethox lH-benzimidazole,
2- {[3-Methoxy-4- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] methyl sulfinyl} -5- (1,1, 2, 2- tetraf 1 uorethoxy) -lH-benzi i dazol ,2- {[3-methoxy-4- (2, 2, 2-trifl uorethoxy) -2-pyridyl] methyl sulfinyl} -5- (1,1, 2, 2-tetraf 1 uorethoxy) -lH-benzi i dazol,
2- {[3-Methoxy-4- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] methyl thi o} -5- (1,1,2, 2-tetra- fluorethoxy)-lH-benzimi dazol ,2- {[3-methoxy-4- (2, 2, 2-trifluoroethoxy) -2-pyridyl] methyl thi o} -5- (1,1,2, 2-tetrafluoroethoxy) -IH-benzimi dazol,
2- {[3-Methoxy-4- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] methyl sulfinyl } -5- (2,2, 2-tri- fluorethoxy)-lH-benzimi dazol ,2- {[3-methoxy-4- (2, 2, 2-trifluoroethoxy) -2-pyridyl] methyl sulfinyl} -5- (2,2, 2-trifluoroethoxy) -lH-benzimi dazol,
2- {[3-Methoxy-4- (2, 2, 2-trifl uorethoxy) -2-pyridyl]methyl thi o} -5- (2, 2, 2-trifl uor ethoxy)-lH-benzimi dazol ,2- {[3-methoxy-4- (2, 2, 2-trifl uorethoxy) -2-pyridyl] methylthio} -5- (2, 2, 2-trifl uor ethoxy) -lH-benzimi dazol,
5-Di f 1 uormethoxy-2- { [3-methoxy-4- (2,2,2-tri f 1 uorethoxy) -2-pyri dyl] methyl sul - finyl}-lH-benzimi dazol ,5-di f 1 uormethoxy-2- {[3-methoxy-4- (2,2,2-tri f 1 uorethoxy) -2-pyridyl] methyl sul - finyl} -lH-benzimi dazol,
5-Di fluormethoxy-2-{[3-methoxy-4- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] methyl thi o}- lH-benzi idazol ,5-di fluoromethoxy-2 - {[3-methoxy-4- (2, 2, 2-trifl uorethoxy) -2-pyridyl] methylthi o} - 1H-benzide idazole,
5-Chl ordifl uormethoxy-2-{[3-methoxy-4- (2, 2, 2-trifl uorethoxy )-2-pyri dyl] methyl - sulfinyl}-lH-benzimidazol ,5-chl ordifl uormethoxy-2 - {[3-methoxy-4- (2, 2, 2-trifl uorethoxy) -2-pyridyl] methyl-sulfinyl} -lH-benzimidazole,
5-Chl ordi f 1 uormethoxy-2- { [3-methoxy-4- (2,2 , 2-tri f 1 uorethoxy) -2-pyri dyl ] methyl - thio}-lH-benzimidazol , 5,6-Bi s (d f 1 uormethoxy) -2- { [3-methoxy-4-(2, 2,2-tri f 1 uorethoxy) -2-pyri dyl ] - methyl sul f i nyl } -lH-benzimi dazol ,5-chloro ordi f 1 uormethoxy-2- {[3-methoxy-4- (2,2, 2-tri f 1 uorethoxy) -2-pyridyl] methyl-thio} -lH-benzimidazole, 5,6-Bi s (df 1 uormethoxy) -2- {[3-methoxy-4- (2, 2,2-tri f 1 uorethoxy) -2-pyridyl] - methyl sul fi nyl} -lH-benzimi dazol,
5 , 6-Bi s (di f 1 uormethoxy) -2- { [3-methoxy-4- (2,2, 2-tri f 1 uorethoxy) -2-pyri dyl ] - methyl thi o} -IH-benzimi dazol5, 6-Bi s (di f 1 uormethoxy) -2- {[3-methoxy-4- (2,2, 2-tri f 1 uorethoxy) -2-pyridyl] methyl thi o} -IH-benzimi dazol
5-Di fl uormethoxy-6-methoxy-2-{ [3-methoxy-4- (2, 2, 2-tri f 1 uorethoxy) -2-pyri dyl] - methyl sul f i nyl } -lH-benzimi dazol ,5-difluoromethoxy-6-methoxy-2- {[3-methoxy-4- (2, 2, 2-tri f 1 uorethoxy) -2-pyridyl] methyl sulfinyl} -lH-benzimi dazol,
5-Di f 1 uormethoxy-6-methoxy-2- { [3-methoxy-4- (2, 2, 2-tri f 1 uorethoxy) -2-pyri dyl ] - methyl thi o} -lH-benzimi dazol ,5-di f 1 uormethoxy-6-methoxy-2- {[3-methoxy-4- (2, 2, 2-tri f 1 uorethoxy) -2-pyridyl] methyl thi o} -lH-benzimi dazol,
2, 2-Difluor-6-{ [3-methoxy-4- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] methyl thi o} -5H- [1, 3] -dioxolo [4, 5-f] benzimi dazol,2,2-difluoro-6- {[3-methoxy-4- (2,2,2-2-trifluoroethoxy) -2-pyridyl] methyl thi o} -5H- [1,3] dioxolo [4,5 -f] benzimi dazol,
2,2-Di f 1 uor-6- { [3-methoxy-4- (2, 2, 2-tri f 1 uorethoxy) -2-pyri dyl] methyl sul f i nyl } - 5H- [1 , 3] -di oxol o- [4, 5-f ] benzi mi dazol ,2,2-di f 1 uor-6- {[3-methoxy-4- (2, 2, 2-tri f 1 uorethoxy) -2-pyridyl] methyl sul fi nyl} - 5H- [1, 3] -di oxol o- [4, 5-f] benzi mi dazol,
2- {[3-Methoxy-4- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] methyl thi o} -6,6, 7-trifl uor- 6, 7-di hydro-lH- [1,4] dioxino [2, 3-f] benzimi dazol ,2- {[3-methoxy-4- (2, 2, 2-trifl uorethoxy) -2-pyridyl] methyl thi o} -6,6,7-trifl uor- 6,7-di hydro-lH- [ 1,4] dioxino [2, 3-f] benzimi dazol,
2- {[3-Methoxy-4- (2, 2, 2-trifl uorethoxy) -2-pyr dyl] ethyl sulfinyl } -6, 6, 7-tri¬ fl uor-6,7-dihydro-lH- [1,4] -dioxino [2, 3-f]benzimi dazol, 6, 6-Difluor-6, 7-di hydro-2-{[3-methoxy-4- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] - methylthio}-lH[l,4]-dioxino[2,3-f]benzim dazol,2- {[3-methoxy-4- (2, 2, 2-trifluoroethoxy) -2-pyridyl] ethyl sulfinyl} -6, 6, 7-trifluor-6,7-dihydro-lH- [ 1,4] -dioxino [2, 3-f] benzimi dazol, 6, 6-difluoro-6, 7-di hydro-2 - {[3-methoxy-4- (2, 2, 2-trifl uorethoxy) - 2-pyridyl] -methylthio} -lH [1,4] -dioxino [2,3-f] benzim azole,
6 , 6-Di f 1 uor-6 , 7-di hydro-2- { [3-methoxy-4- (2 , 2, 2-tri f 1 uorethoxy) -2-pyri dyl ] me¬ thyl sul f i nyl } -1H- [1 , 4] -di oxi no [2, 3-f ] benzimi dazol ,6, 6-Di f 1 uor-6, 7-di hydro-2- {[3-methoxy-4- (2, 2, 2-tri f 1 uorethoxy) -2-pyridyl] methyl sul fi nyl } -1H- [1, 4] -di oxi no [2, 3-f] benzimi dazol,
2- {[3-Methoxy-4- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] methyl thi o} -6,6,7, 7-tetra- fluor-6, 7-di hydro-lH- [1,4] -dioxino [2, 3-f] benzimi dazol ,2- {[3-methoxy-4- (2, 2, 2-trifluoroethoxy) -2-pyridyl] methyl thi o} -6,6,7,7-tetrafluoro-6,7-di hydro- 1H- [1,4] dioxino [2, 3-f] benzimi dazol,
2- {[3-Methoxy-4- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] methyl sulfinyl } -6,6,7, 7-tetra- f 1 uor-6 , 7-di hydro-lH- [1,4] -di oxi no [2, 3-f ] benzimi dazol ,2- {[3-methoxy-4- (2, 2, 2-trifluoroethoxy) -2-pyridyl] methyl sulfinyl} -6,6,7,7-tetra-f 1 uor-6,7-di hydro -lH- [1,4] -di oxi no [2, 3-f] benzimi dazol,
6-Chlor-6, 7, 7-trifl uor-6, 7-di hydro-2-{[3-methoxy-4- (2, 2, 2-trifl uorethoxy) -2-py- ri dyl ] methyl sul f i nyl } -1H- [1 , 4] -di oxi no [2 , 3-f ] benzimi dazol , 6-Chl or-6, 7, 7-trifl uor-6, 7-di hydro-2-{[3-methoxy-4- (2, 2, 2-trifl uorethoxy) -2-py- r dyl] methyl thi o}-lH- [1,4] -dioxino [2, 3-f] benzimi dazol,6-chloro-6, 7, 7-trifl uor-6, 7-di hydro-2 - {[3-methoxy-4- (2, 2, 2-trifl uorethoxy) -2-pyridyl] methyl sul fi nyl} -1H- [1, 4] -di oxi no [2, 3-f] benzimi dazol, 6-chloro-6, 7, 7-trifl uor-6, 7-di hydro-2 - {[ 3-methoxy-4- (2, 2, 2-trifl uorethoxy) -2-py- dyl] methyl thio} -lH- [1,4] -dioxino [2, 3-f] benzimi dazol,
2- { [4-Methoxy-3- (2,2, 2-tri f uorethoxy) -2-pyri dyl ] methyl sul f i nyl } -5-tri f 1 uor- methoxy-lH-benzim dazol ,2- {[4-methoxy-3- (2,2, 2-tri f uorethoxy) -2-pyridyl] methyl sul f i nyl} -5-tri f 1 uor- methoxy-lH-benzim dazol,
2- {[4-Methoxy-3-(2, 2, 2-trifl uorethoxy) -2-pyri dyl] ethyl thi o} -5-tri fl uor¬ methoxy- lH-benzimi dazol,2- {[4-methoxy-3- (2, 2, 2-trifl uorethoxy) -2-pyridyl] ethyl thi o} -5-trifluoromethoxy-lH-benzimi dazol,
2- {[4-Methoxy-3- (2, 2,2-tri fl uorethoxy) -2-pyri dyl] methyl sulfinyl } -5- (1,1, 2,2- tetraf 1 uorethoxy) -lH-benzimi dazol ,2- {[4-Methoxy-3- (2, 2,2-trifluorethoxy) -2-pyridyl] methyl sulfinyl} -5- (1,1, 2,2-tetraf 1 uorethoxy) -IH-benzimi dazol,
2- {[4-Methoxy-3- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] methyl thi o} -5- (1,1,2, 2-tetra- f 1 uorethoxy) -lH-benzimi dazol ,2- {[4-methoxy-3- (2, 2, 2-trifl uorethoxy) -2-pyridyl] methyl thi o} -5- (1,1,2, 2-tetra-f 1 uorethoxy) -lH -benzimi dazol,
2- {[4-Methoxy-3- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] methyl sulfinyl } -5- (2, 2, 2-tri¬ fl uorethoxy) -lH-benzimi dazol , 2- {[4-Methoxy-3- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] methyl thi 0} -5- (2, 2, 2-trifl uor ethoxy) -lH-benzi idazol ,2- {[4-methoxy-3- (2, 2, 2-trifl uorethoxy) -2-pyridyl] methyl sulfinyl} -5- (2, 2, 2-trifl uorethoxy) -lH-benzimi dazol, 2- {[4-methoxy-3- (2, 2, 2-trifl uorethoxy) -2-pyridyl] methyl thi 0} -5- (2, 2, 2-trifl uor ethoxy) -lH-benzidazole,
5-Di f 1 uormethoxy-2- { [4-methoxy-3- (2, 2, 2-tri f 1 uorethoxy) -2-pyri dyl ] methyl sul - finyl}-lH-benzimi dazol ,5-di f 1 uormethoxy-2- {[4-methoxy-3- (2, 2, 2-tri f 1 uorethoxy) -2-pyridyl] methyl sul - finyl} -lH-benzimi dazol,
5-Di f 1 uormethoxy-2- { [4-methoxy-3- ( ,2 , 2-tri f 1 uorethoxy) -2-pyri dyl ] ethyl thi 0} - lH-benzimi dazol ,5-di f 1 uormethoxy-2- {[4-methoxy-3- (, 2, 2-tri f 1 uorethoxy) -2-pyridyl] ethyl thi 0} - 1H-benzimi dazol,
5-Chl ordifl uormethoxy-2-{[4-methoxy-3- (2, 2, 2-trifl uorethoxy )-2-pyri dyl] methyl - sul fi nyl }-lH-benzimi dazol ,5-chloro-ordomethoxy-2 - {[4-methoxy-3- (2, 2, 2-trifluoro-ethoxy) -2-pyridyl] methyl - sul fi nyl} -lH-benzimi dazol,
5-Chl ordi f 1 uormethoxy-2- { [4-methoxy-3- (2 , 2 , -tri f 1 uorethoxy) -2-pyri dyl ] methyl - thio}-lH-benzimi dazol ,5-chloro ordi f 1 uormethoxy-2- {[4-methoxy-3- (2, 2, -tri f 1 uorethoxy) -2-pyridyl] methyl - thio} -lH-benzimi dazol,
5, 6-Bis(difl uormethoxy) -2- {[4-methoxy-3- (2, 2, 2-trifl uorethoxy )-2-pyri dyl] - methyl sul f i nyl } -lH-benzimi dazol ,5, 6-bis (difl uormethoxy) -2- {[4-methoxy-3- (2, 2, 2-trifl uorethoxy) -2-pyridyl] - methyl sul f i nyl} -lH-benzimi dazol,
5, 6-Bi s (di fl uormethoxy) -2- {[4-methoxy-3- (2, , 2-trifl uorethoxy )-2-pyri dyl] - methyl thi o}-lH-benzimi dazol5, 6-Bi s (di fl uomethoxy) -2- {[4-methoxy-3- (2,, 2-trifl uorethoxy) -2-pyridyl] - methyl thi o} -lH-benzimi dazol
5-Di fluormethoxy-6-methoxy-2-{[4-methoxy-3- (2, 2, 2-trifl uorethoxy )-2-pyri dyl] - methyl sul fi nyl }-lH-benzimi dazol,5-di fluoromethoxy-6-methoxy-2 - {[4-methoxy-3- (2, 2, 2-trifluoroethoxy) -2-pyridyl] - methyl sul fi nyl} -lH-benzimi dazol,
5-Di f 1 uormethoxy-6-methoxy-2- { [4-methoxy-3- (2, 2, 2-tri f 1 uorethoxy) -2-pyri dyl] - methylthio}-lH-benzimidazol,5-di f 1 uormethoxy-6-methoxy-2- {[4-methoxy-3- (2, 2, 2-tri f 1 uorethoxy) -2-pyridyl] -methylthio} -lH-benzimidazole,
2, 2-Difluor-6-{ [4-methoxy-3- (2, 2, 2-trifl uorethoxy) -2-pyr dyl] methyl thi o}-5H- [1,3] -dioxolo[4, 5-f] benzimi dazol ,2,2-difluoro-6- {[4-methoxy-3- (2,2,2-2-trifluoroethoxy) -2-pyridyl] methylthio} -5H- [1,3] dioxolo [4,5 -f] benzimi dazol,
2, 2-Difluor-6-{ [4-methoxy-3- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] methyl sulfinyl } - 5H- [1,3] -dioxolo- [4, 5-f] benzimi dazol ,2,2-difluoro-6- {[4-methoxy-3- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl sulfinyl} - 5H- [1,3] -dioxolo- [4,5 -f] benzimi dazol,
2- {[4-Methoxy-3- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] methyl thi 0} -6, 6, 7-trifl uor- 6, 7-di hydro-lH- [1,4] dioxino [2, 3-f] benzimi dazol ,2- {[4-methoxy-3- (2, 2, 2-trifl uorethoxy) -2-pyridyl] methyl thi 0} -6, 6, 7-trifl uor- 6, 7-di hydro-lH- [ 1,4] dioxino [2, 3-f] benzimi dazol,
2- { [4-Methoxy-3- (2, 2, 2-tri f 1 uorethoxy) -2-pyri dyl ] methyl sul f i nyl } -6 , 6 , 7-tri - f luor-6, 7 -dihydro-lH- [1,4] -dioxino [2, 3-f] benzim dazol ,2- {[4-methoxy-3- (2, 2, 2-tri f 1 uorethoxy) -2-pyridyl] methyl sul fi nyl} -6, 6, 7-tri-f luor-6, 7 -dihydro -lH- [1,4] dioxino [2,3-f] benzim dazol,
6, 6-Difluor-6, 7-di hydro-2-{ [4-methoxy-3- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] - methyl thi o}-lH [1,4] -dioxino [2, 3-f] benzimi dazol ,6, 6-difluoro-6, 7-di hydro-2- {[4-methoxy-3- (2, 2, 2-trifluoroethoxy) -2-pyridyl] methyl thi o} -lH [1.4 ] -dioxino [2, 3-f] benzimi dazol,
6, 6-Difluor-6, 7-di hydro-2-{ [4-methoxy-3- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] me¬ thyl sulfinyl }-lH- [1,4] -dioxino [2, 3-f] benzimi dazol ,6, 6-difluoro-6, 7-di hydro-2- {[4-methoxy-3- (2, 2, 2-trifl uorethoxy) -2-pyridyl] methyl sulfinyl} -lH- [1, 4] -dioxino [2, 3-f] benzimi dazol,
2- {[4-Methoxy-3- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] methyl thi 0} -6,6,7, 7-tetra- f luor-6, 7-di hydro-lH- [1,4] -dioxino [2, 3-f] benzimi dazol ,2- {[4-methoxy-3- (2, 2, 2-trifluoroethoxy) -2-pyridyl] methyl thi 0} -6,6,7,7-tetrafluoro-6,7-di hydro -lH- [1,4] -dioxino [2, 3-f] benzimi dazol,
2- {[4-Methoxy-3- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] methyl sulfinyl } -6,6,7, 7-tetra f luor-6, 7-di hydro-lH- [1,4] -dioxino [2, 3-f] benzimi dazol ,2- {[4-methoxy-3- (2, 2, 2-trifluoroethoxy) -2-pyridyl] methyl sulfinyl} -6,6,7,7-tetrafluor-6,7-dihydro-1H - [1,4] -dioxino [2, 3-f] benzimi dazol,
6-Chl or-6, 7, 7-tri fluor-6, 7-di hydro-2-{[4-methoxy-3- (2, 2, 2-trifl uorethoxy) -2-py ri dyl ] methyl sul fi nyl }-lH- [1,4] -dioxino [2, 3-f] benzimi dazol ,6-chloro-6, 7, 7-tri fluoro-6, 7-di hydro-2 - {[4-methoxy-3- (2, 2, 2-trifl uorethoxy) -2-pyridyl] methyl sul fi nyl} -lH- [1,4] -dioxino [2, 3-f] benzimi dazol,
6-Chl or-6, 7, 7-tri fluor-6, 7-di hydro-2-{[4-methoxy-3- (2, 2, 2-trifl uorethoxy) -2-py ri dy 1 ] ethyl thi o}-lH- [1,4] -dioxino [2, 3-f] benzimi dazol , 2- { [3-Methyl -4- (2, 2, 2-tri f 1 uorethoxy) -2-pyri dyl ] methyl sul f i nyl } -5-tri f 1 uor- ethoxy-lH-benzi i dazol ,6-Chloro-6, 7, 7-tri fluoro-6, 7-di hydro-2 - {[4-methoxy-3- (2, 2, 2-trifl uorethoxy) -2-pyridia 1] ethyl thi o} -lH- [1,4] -dioxino [2, 3-f] benzimi dazol, 2- {[3-methyl -4- (2, 2, 2-tri f 1 uorethoxy) -2-pyridyl] methyl sul fi nyl} -5-tri f 1 uor-ethoxy-lH-benzi i dazol,
2- { [3-Methyl -4- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] methyl thi o} -5-tri fl uormethoxy- lH-benzi i dazol ,2- {[3-methyl -4- (2, 2, 2-trifl uorethoxy) -2-pyridyl] methyl thi o} -5-trifluoromethoxy-lH-benzi i dazol,
2- { [3-Methyl -4- (2, 2, 2-trifl uorethoxy) -2-pyr dyl] methyl sulfinyl } -5- (1, 1, 2,2- tetraf 1 uorethoxy) -lH-benzimi dazol ,2- {[3-Methyl -4- (2, 2, 2-trifl uorethoxy) -2-pyrdyl] methyl sulfinyl} -5- (1, 1, 2,2-tetraf 1 uorethoxy) -lH-benzimi dazol ,
2-{ [3-Methyl-4-(2, 2, 2-trifl uorethoxy) -2-pyri dyl] methyl thio} -5- (1, 1 ,2, 2-tetra- f 1 uorethoxy) -lH-benzimi dazol ,2- {[3-methyl-4- (2, 2, 2-trifl uorethoxy) -2-pyridyl] methyl thio} -5- (1, 1, 2, 2-tetra-f 1 uorethoxy) -lH- benzimi dazol,
2- { [3-Methyl -4- (2, 2,2-tr fl uorethoxy) -2-pyri dyl] methyl sul fi nyl } -5- (2, 2, 2-tri ¬ fl uorethoxy) -lH-benzimi dazol ,2- {[3-Methyl -4- (2, 2,2-tr-fluoroethoxy) -2-pyridyl] methyl sul fi nyl} -5- (2, 2, 2-tri-fluoroethoxy) -lH- benzimi dazol,
2-{ [3-Methyl -4- (2, 2, 2-tri fl uorethoxy) -2-pyri dyl] methyl thio} -5- (2, 2, 2-tri fl uor¬ ethoxy) -lH-benzimi dazol ,2- {[3-Methyl -4- (2, 2, 2-tri-fluoroethoxy) -2-pyridyl] methyl thio} -5- (2, 2, 2-tri-fluoroethoxy) -IH-benzimi dazol,
5-Di f 1 uormethoxy-2- { [3-methyl -4- (2 , 2, 2-tri f 1 uorethoxy) -2-pyri dyl ] methyl sul - finyl } -lH-benzimidazol ,5-di f 1 uormethoxy-2- {[3-methyl -4- (2, 2, 2-tri f 1 uorethoxy) -2-pyridyl] methyl sul - finyl} -lH-benzimidazole,
5-Di f 1 uormethoxy-2- { [3-methyl -4- (2, 2, 2-tri f 1 uorethoxy) -2-pyri dyl ] methyl thi o} - IH-benzimidazol ,5-di f 1 uormethoxy-2- {[3-methyl -4- (2, 2, 2-tri f 1 uorethoxy) -2-pyridyl] methyl thi o} - IH-benzimidazole,
5-Chl ordi f 1 uormethoxy-2- { [3-methyl -4- (2 , 2 , 2-tri f 1 uorethoxy) -2-pyri dyl ] methyl - sul fi nyl }-lH-benzimidazol ,5-chloro ordi f 1 uormethoxy-2- {[3-methyl -4- (2, 2, 2-tri f 1 uorethoxy) -2-pyridyl] methyl-sul fi nyl} -lH-benzimidazole,
5-Chl ordi f 1 uormethoxy-2- { [3-methyl -4- (2, 2, 2-tri f 1 uorethoxy) -2-pyri dyl] methyl - thi o} -lH-benzimi dazol ,5-chloro ordi f 1 uormethoxy-2- {[3-methyl -4- (2, 2, 2-tri f 1 uorethoxy) -2-pyridyl] methyl-thi o} -lH-benzimi dazol,
5,6-Bi s (di f 1 uormethoxy) -2- { [3-methyl -4- (2, 2, 2-tri f 1 orethoxy) -2-pyri dyl] ethyl - sul fi nyl } -lH-benzimi dazol ,5,6-Bi s (di f 1 uormethoxy) -2- {[3-methyl -4- (2, 2, 2-tri f 1 orethoxy) -2-pyridyl] ethyl - sul fi nyl} -lH- benzimi dazol,
5,6-Bi s (dif 1 uormethoxy) -2- { [3-methyl -4- (2,2, 2-tri f 1 uorethoxy) -2-pyri dyl]methyl - thi o} -lH-benzi mi dazol5,6-Bi s (dif 1 uormethoxy) -2- {[3-methyl -4- (2,2, 2-tri f 1 uorethoxy) -2-pyridyl] methyl - thi o} -lH-benzi mi dazol
5-Di f 1 uormethoxy-6-methoxy-2-{ [3-methyl -4- (2, 2, 2-tri fl uorethoxy) -2-pyri dyl] - methyl sul f i nyl } -lH-benzimi dazol ,5-di f 1 uormethoxy-6-methoxy-2- {[3-methyl -4- (2, 2, 2-trifluoroethoxy) -2-pyridyl] - methyl sul f i nyl} -lH-benzimi dazol,
5-Di f 1 uormethoxy-6-methoxy-2-{ [3-methyl -4- (2, 2, 2-tri f 1 uorethoxy) -2-pyri dyl] - methyl thi o} -lH-benzimi dazol ,5-di f 1 uormethoxy-6-methoxy-2- {[3-methyl -4- (2, 2, 2-tri f 1 uorethoxy) -2-pyridyl] - methyl thi o} -lH-benzimi dazol,
2, 2-Di f 1 uor-6- { [3-methyl -4- (2 , 2, 2-tri f 1 uorethoxy) -2-pyri dyl ] methyl thi o} -5H- [1,3] -di oxol o [4, 5-f] benzimi dazol ,2, 2-Di f 1 uor-6- {[3-methyl -4- (2, 2, 2-tri f 1 uorethoxy) -2-pyridyl] methyl thi o} -5H- [1,3] - di oxol o [4, 5-f] benzimi dazol,
2 , 2-Di f 1 uor-6- { [3-methyl -4- (2 , 2 , 2-tri f 1 uorethoxy) -2-pyri dyl ] methyl sul f i nyl } -5H- [1,3] -dioxolo- [4, 5-f] benzimi dazol ,2, 2-Di f 1 uor-6- {[3-methyl -4- (2, 2, 2-tri f 1 uorethoxy) -2-pyridyl] methyl sul fi nyl} -5H- [1,3] -dioxolo- [4, 5-f] benzimi dazol,
2- { [3-Methyl -4-(2, 2, 2-trifl uorethoxy) -2-pyri dyl] methyl thio} -6, 6, 7-tri fl uor-6, 7- di hydro-lH- [1,4] dioxino [2, 3-f] benzimi dazol ,2- {[3-methyl -4- (2, 2, 2-trifl uorethoxy) -2-pyridyl] methyl thio} -6, 6, 7-trifl uor-6, 7- di hydro-lH- [ 1,4] dioxino [2, 3-f] benzimi dazol,
2- { [3-Methyl -4- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] methyl sul fi nyl } -6, 6, 7-tri fl uor- 6 , 7-d hydro-lH- [1 ,4] -di ox no [2, 3-f] benzimi dazol ,2- {[3-methyl -4- (2, 2, 2-trifluoroethoxy) -2-pyridyl] methyl sul fi nyl} -6, 6, 7-trifluor u-6, 7-d hydro-lH - [1, 4] -di ox no [2, 3-f] benzimi dazol,
6 , 6-Di f 1 uor-6 , 7-d hydro-2- { [3-methyl -4- (2 , 2, 2-tri f 1 uorethoxy) -2-pyri dyl ] methyl - thi o} -1H [1,4] -di oxi no [2, 3-f] benzimi dazol , 6, 6-Difluor-6, 7-di hydro-2-{ [3-methyl -4- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] methyl sul fi nyl }-lH- [1,4] -dioxino [2, 3-f] benzimi dazol,6, 6-di f 1 uor-6, 7-d hydro-2- {[3-methyl -4- (2, 2, 2-tri f 1 uorethoxy) -2-pyridyl] methyl - thi o} - 1H [1,4] -di oxi no [2, 3-f] benzimi dazol, 6, 6-difluoro-6, 7-di hydro-2- {[3-methyl -4- (2, 2, 2-trifluoroethoxy) -2-pyridyl] methyl sul fi nyl} -lH- [1, 4] -dioxino [2, 3-f] benzimi dazol,
2- {[3-Methyl -4- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] ethyl thio} -6,6,7, 7-tetrafl uor 6, 7-di hydro-lH- [1,4] -dioxino [2, 3-f] benzimi dazol ,2- {[3-methyl -4- (2, 2, 2-trifluoroethoxy) -2-pyridyl] ethyl thio} -6,6,7,7-tetrafluoro 6,7-di hydro-lH- [ 1,4] -dioxino [2, 3-f] benzimi dazol,
2- {[3-Methyl -4- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] methyl sulfinyl } -6, 6, 7, 7-tetra¬ fl uor-6, 7-di hydro-lH- [1,4] -dioxino [2, 3-f] benzimi dazol ,2- {[3-methyl -4- (2, 2, 2-trifluoroethoxy) -2-pyridyl] methyl sulfinyl} -6, 6, 7, 7-tetrafluor-6, 7-di hydro- 1H- [1,4] dioxino [2, 3-f] benzimi dazol,
6-Chl or-6, 7, 7-tri fluor-6, 7-di hydro-2-{ [3-methyl -4- (2, 2, 2-trifl uorethoxy) -2-py- ri dyl ] ethy 1 sul fi nyl }-lH- [1,4] -dioxino [2, 3-f] benzimi dazol , 6-Chl or-6, 7, 7-tri fluor-6, 7-di hydro-2-{ [3-methyl -4- (2, 2, 2-trifl orethoxy) -2-py- ri dy 1 ] methyl thi o}-lH- [1,4] -dioxino [2, 3-f] benzimi dazol , und die Salze dieser Verbindungen.6-chloro-6, 7, 7-tri fluoro-6, 7-di hydro-2- {[3-methyl -4- (2, 2, 2-trifluoroethoxy) -2-pyridyl] ethyl 1 sul fi nyl} -lH- [1,4] -dioxino [2, 3-f] benzimi dazol, 6-chloro-6, 7, 7-tri fluoro-6, 7-di hydro-2- {[ 3-methyl -4- (2, 2, 2-trifl orethoxy) -2-pyridy 1] methylthi o} -lH- [1,4] -dioxino [2, 3-f] benzimi dazol, and the salts of these compounds.
Bedingt durch die Tautomerie im I i dazol ring ist die 5-Substitution im Benz¬ imi dazol mit der 6-Substitution identisch. Entsprechend ist bei den Verbindun¬ gen, in denen R2 und R3 gemeinsam einen substituierten Ethylendioxyrest dar¬ stellen, die 6-Position im [l,4]-Dioxino[2,3-f]benzimidazolteil mit der 7-Po- sition identisch.Due to the tautomerism in the I i dazol ring, the 5 substitution in the Benz¬ imi dazol 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.
Ein weiterer Gegenstand der Erfindung ist ein Verfahren zur Herstellung der Verbindungen der Formel I, worin Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO und n die oben angegebenen Bedeutungen haben, und ihrer Salze.Another object of the invention is a process for the preparation of the compounds of formula I, wherein Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO and n have the meanings given above, and their salts.
Das Verfahren ist dadurch gekennzeichnet, daß manThe process is characterized in that
a) Mercaptobenzi idazole der Formel II mit Picolinderivaten III,a) mercaptobenzi idazoles of the formula II with picolin derivatives III,
oder b) Benzimidazole der Formel IV mit Mercaptopicolinen Vor b) Benzimidazoles of the formula IV with mercaptopicolins V
(IV), (V),(IV), (V),
oder c) o-Phenylendiamine der Formel VI mit Ameisensäurederivaten VIIor c) o-phenylenediamines of the formula VI with formic acid derivatives VII
umsetzt und (falls Verbindungen der Formel I mit n=l die gewünschten Endproduk¬ te sind) anschließend die nach a) , b) oder c) erhaltenen 2-Benzimidazolyl-2-py- ri dyl methyl -su fide der Formel VIII (Verbindungen der Formel I mit n=0)and (if compounds of the formula I with n = 1 are the desired end products) then the 2-benzimidazolyl-2-pyridyl methyl sulfides of the formula VIII (compounds.) obtained according to a), b) or c) of formula I with n = 0)
oxidiert und/oder gewünschtenfalls in die Salze überführt, oder daß man d) Benzimidazole der Formel IX mit Pyridinderivaten Xoxidized and / or, if desired, converted into the salts, or that d) benzimidazoles of the formula IX with pyridine derivatives X
oder e) Sul fi nyl deri vate der Formel XI mi t 2-Pi col i nderi vaten XI Ior e) Sul fi nyl derivatives of the formula XI with 2-Pi col i nderi vates XI I
umsetzt und gewünschtenfalls anschließend in die Salze überführt, oderimplemented and, if desired, subsequently converted into the salts, or
f) - falls Verbindungen der Formel I, worin R4 eine unter physiologischen Be¬ dingungen leicht abspaltbare Gruppe darstellt, die herzustellenden Verfahrens prodükte sind - daß man Verbindungen der Formel I, worin R4 Wasserstoff bedeu tet, mit Verbindungen der Formel R4'-Y' (XIII), worin R4' die gewünschte, unt physiologischen Bedingungen leicht abspaltbare Gruppe oder gemeinsam mit Y' i Vorläufer ist, umsetzt und gewünschtenfalls anschließend in die Salze über¬ führt, oderf) - if compounds of the formula I in which R4 is a group which can easily be split off under physiological conditions, the process to be prepared are product products - that compounds of the formula I in which R4 is hydrogen are reacted with compounds of the formula R4'-Y ' (XIII), in which R4 'is the desired group which can easily be split off under physiological conditions or is a precursor together with Y' i and, if desired, is subsequently converted into the salts, or
g) - falls Verbindungen der Formel I, worin R4 Wasserstoff bedeutet, die herz stellenden Verfahrensprodukte sind - daß man Verbindungen der Formel I, worin R4 eine unter physiologischen Bedingungen leicht abspaltbare Gruppe darstellt solvolysiert, und die erhaltenen Produkte gewünschtenfalls in die Salze über¬ führt, oder h) - falls Verbindungen der Formel I, worin R51-6C-A1kyl bedeutet, die herzu¬ stellenden Verfahrensprodukte sind - daß man Verbindungen der Formel I, worin R5 Wasserstoff bedeutet, mit Verbindungen der Formel R5-Y1' (XIV), worin R5 1-6C-A1kyl bedeutet, alkyliert und gewünschtenfalls anschließend in die Salze überführt,g) - if compounds of the formula I in which R4 is hydrogen are the heart of the process products - that compounds of the formula I in which R4 is a group which can easily be split off under physiological conditions are solvolysed and, if desired, the products obtained are converted into the salts , or h) - if compounds of the formula I in which R51-6C-alkyl is the process products to be prepared - that compounds of the formula I in which R5 is hydrogen with compounds of the formula R5-Y 1 '(XIV) in which R5 denotes 1-6C-A1kyl, alkylated and, if desired, subsequently converted into the salts,
wobei Y, Y'1, 1, V und 1 " geeignete Abgangsgruppen darstellen, Y' eine Ab¬ gangs- bzw. Reaktivgruppe darstellt, M für ein Alkalimetallatom (Li , Na oder K) steht, M' für das Äquivalent eines Metallatoms steht und Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO und n (sofern nicht anders definiert) die oben angegebenen Bedeutungen haben.where Y, Y ' 1 , 1, V and 1 "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 and Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO and n (unless otherwise defined) have the meanings given above.
Bei den vorstehend aufgeführten Umsetzungen können die Verbindungen II-XIV als solche oder gegebenenfalls in Form ihrer Salze eingesetzt werden.In the reactions listed above, the compounds II-XIV can be used as such or, if appropriate, in the form of their salts.
Die Herstellungsverfahren a) , b) und c) führen zu den erfindungsgemäßen Sulfi¬ den, die Oxidation der Verbindungen VIII und die Verfahren d) und e) liefern die erfindungsgemäßen Sulfoxide, die Verfahren f) , g) und h) führen zu beiden Produktklassen.The production processes a), b) and c) lead to the sulfides according to the invention, the oxidation of the compounds VIII and processes d) and e) give the sulfoxides according to the invention, the processes f), g) and h) lead to both product classes .
Welche Abgangsgruppen Y, Y', Y1', Z, Z1 bzw. Z' ' geeignet sind, ist dem Fach¬ mann aufgrund seines Fachwissens geläufig. Eine geeignete Abgangsgruppe Y ist beispielsweise eine Gruppe, die zusammen mit der Sulfinylgruppe, an die sie gebunden ist, ein reaktives Sulfinsäurederivat bildet. Als geeignete Abgangs¬ gruppe Y seien beispielsweise Alkoxy-, Dialkylamino- oder Alkylmercaptogruppen genannt. Eine geeignete Abgangs bzw. Reaktivgruppe Y' ist eine Gruppe, die mit einer sekundären Aminogruppe unter Abspaltung von HY' oder unter Anlagerung zu reagieren in der Lage ist. Bei Verbindungen der Formel XIII, in denen R4' ins¬ besondere eine substituierte Carbonylgruppe darstellt, ist Y' beispielsweise eine Abgangsgruppe, die zusammen mit der Carbonylgruppe, an die sie gebunden ist, ein reaktives Carbonsäurederivat, z.B. ein Säurehaiogenid, bildet. Erfin¬ dungsgemäß sind durch die allgemeine Formel R4'-Y' (XIII) auch solche Verbin¬ dungen (Vorläufer der unter physiologischen Bedingungen leicht abspaltbaren Gruppe R4) umfaßt, bei denen Y1 eine Reaktivgruppe darstellt (z.B. Isonitrile), die bei der Reaktion mit der sekundären Aminogruppe keine Kondensation unter Abspaltung von HY' sondern eine Addition unter Bildung der gewünschten abspalt¬ baren Gruppe R4 durchlaufen. Die Abgangsgruppe Y11 ist eine dem Fachmann für Alkylierungsreaktionen geläufi ge Gruppe, die bei der Alkylierung - z.B. mit Dialkylsulfat, Fluorsulfonsäure alkylester oder Alkyliodid - abgeht.The person skilled in the art is familiar with the leaving groups Y, Y ', Y 1 ', Z, Z 1 and Z '' which are suitable. 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. Examples of 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. In the case of compounds of the formula XIII, in which R4 'in particular represents a substituted carbonyl group, 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. According to the invention, the general formula R4'-Y '(XIII) also includes those compounds (precursors of the group R4 which can easily be split off under physiological conditions) in which Y 1 represents a reactive group (for example isonitriles) which are involved in the reaction with the secondary amino group, there is no condensation with elimination of HY 'but an addition to form the desired removable group R4. The leaving group Y 11 is a group familiar to the person skilled in the art for alkylation reactions, which goes off during the alkylation - for example with dialkyl sulfate, fluorosulfonic acid alkyl ester or alkyl iodide.
Als geeignete Abgangsgruppen Z, V bzw. 1 " seien beispielsweise Halogenatome, insbesondere Chloratome, oder durch Veresterung (z.B. mit p-Toluolsulfonsäure) aktivierte Hydroxylgruppen genannt.Suitable leaving groups Z, V or 1 "are, for example, halogen atoms, in particular chlorine atoms, or hydroxyl groups activated by esterification (e.g. with p-toluenesulfonic acid).
Das Äquivalent eines Metallatoms M' ist beispielsweise ein Alkalimetall- (Li, Na oder K) , oder ein Erdalkalimetallatom (z.B. Mg), das durch ein Halogenatom (z.B. Br, Grignard-Reagenz) substituiert ist, oder irgendein anderes, gegebe¬ nenfalls substituiertes Metallatom, von dem bekannt ist, daß es bei Substitu¬ tionsreaktionen metallorganischer Verbindungen wie die obenerwähnten Metalle reagiert.The 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 case of substitution reactions of organometallic compounds, such as the metals mentioned above.
Die Umsetzung von II mit III erfolgt in geeigneten, vorzugsweise polaren pro¬ tischen oder aprotischen Lösungsmitteln (wie Methanol, Isopropanol , Dimethyl- sulfoxid, Aceton, Dimethylformamid oder Acetonitril) unter Zusatz oder unter Ausschluß von Wasser. Sie wird beispielsweise in Gegenwart eines Protonenakzep tors durchgeführt. Als solche eignen sich Alkalimetallhydroxide, wie Natrium¬ hydroxid, Alkali etallcarbonate, wie Kaliumcarbonat, oder tertiäre Amine, wie Pyridin, Triethylamin oder Ethyldiisopropylamin. Alternativ kann die Umsetzung auch ohne Protonenakzeptor durchgeführt werden, wobei - je nach Art der Aus¬ gangsverbindungen - gegebenenfalls zunächst die Säureadditionssalze in beson¬ ders reiner Form abgetrennt werden können. Die Reaktionstemperatur kann zwi- o o sehen 0 und 150 C liegen, wobei in Gegenwart von Protonenakzeptoren Tempera- o o o o turen zwischen 20 und 80 C und ohne Protonenakzeptoren zwischen 60 und 120 CThe reaction of II with III is carried out 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. Alkali metal hydroxides, such as sodium hydroxide, alkali metal carbonates, such as potassium carbonate, or tertiary amines, such as pyridine, triethylamine or ethyldiisopropylamine, are suitable as such. Alternatively, the reaction can also be carried out without a proton acceptor, it being possible, depending on the nature of the starting compounds, first of all to separate off the acid addition salts in a particularly pure form. The reaction temperature can be between 0 and 150 ° C, temperatures in the presence of proton acceptors between 20 and 80 ° C and without proton acceptors between 60 and 120 ° C
- insbesondere die Siedetemperatur der verwendeten Lösungsmittel - bevorzugt sind. Die Reaktionszeiten liegen zwischen 0,5 und 12 Stunden.- In particular the boiling point of the solvents used - are preferred. The response times are between 0.5 and 12 hours.
Bei der Umsetzung von IV mit V, die in an sich bekannter Weise erfolgt, kommen ähnliche Reaktionsbedingungen wie bei der Umsetzung von II mit III zur Anwen¬ dung.In the reaction of IV with V, which is carried out in a manner known per se, similar reaction conditions are used as in the reaction of II with III.
Die Reaktion von VI mit VII wird bevorzugt in polaren, gegebenenfalls wasser¬ haltigen Lösungsmitteln in Gegenwart einer starken Säure, z.B. Salzsäure, ins¬ besondere bei der Siedetemperatur des verwendeten Lösungsmittels durchgeführt. Die Ox dation der Sulfide VIII erfolgt unter den Bedingungen, wie sie dem Fach¬ mann für die Oxidation von Sulfiden zu Sulfoxiden geläufig sind (siehe hierzu z.B. J. Drabowicz und M. Mikolajczyk, Organic preparations and procedures int. 14(1-2), 45-89(1982) oder E. Block in S. Patai , The Chemistry of Functioπal Groups, Supplement E. Part 1, S. 539-608, John Wiley and Sons (Interscience Publication), 1980}. Als Oxidationsmittel kommen alle für die Oxidation von Sulfiden zu Sulfoxiden üblicherweise verwendeten Reagenzien in Frage, insbeson¬ dere Peroxysäuren, wie z.B. Peroxyessigsäure, Trifluorperoxyessigsäure, 3,5- Dinitroperoxybenzoesäure, Peroxymaleinsäure, Magnesiummonoperoxiphthalat oder bevorzugt m-Chlorperoxybenzoesäure.The reaction of VI with VII is preferably carried out 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 solvent used. The oxidation of sulfides VIII takes place under the conditions known to the person skilled in the art for the oxidation of sulfides to sulfoxides (see, for example, J. Drabowicz and M. Mikolajczyk, Organic preparations and procedures int. 14 (1-2) , 45-89 (1982) or E. Block in S. Patai, The Chemistry of Functional Groups, Supplement E. Part 1, pp. 539-608, John Wiley and Sons (Interscience Publication), 1980. All come as oxidizing agents reagents commonly used for the oxidation of sulfides to sulfoxides, in particular peroxy acids, such as peroxyacetic acid, trifluoroperoxyacetic acid, 3,5-dinitroperoxybenzoic acid, peroxymaleic acid, magnesium monoperoxiphthalate or preferably m-chloroperoxybenzoic acid.
Die Reaktionstemperatur liegt (je nach Reaktivität des Ox dationsmittels und o Verdünnungsgrad) zwischen -70 C und der Siedetemperatur des verwendeten Lö- o o sungs ittels, bevorzugt jedoch zwischen -30 und +20 C. Als vorteilhaft hat sich auch die Oxidation mit Halogenen bzw. mit Hypohalogeniten (z.B. mit wäßri¬ ger Natriumhypochloritlösung) erwiesen, die zweckmäßigerweise bei Temperaturen o o zwischen 0 und 50 C durchgeführt wird. Die Reaktion wird zweckmäßigerweise in inerten Lösungsmitteln, z. B. aromatischen oder chlorierten Kohlenwasserstof¬ fen, wie Benzol, Toluol, Dichlormethan oder Chloroform, vorzugsweise in Estern oder Ethern, wie Essigsäureethylester, Essigsäureisopropylester oder Dioxan durchgeführt.The reaction temperature (depending on the reactivity of the oxidizing agent and degree of dilution) is between -70 C and the boiling temperature of the solvent used, but preferably between -30 and +20 C. Also advantageous is the oxidation with halogens or with hypohalites (eg with aqueous sodium hypochlorite solution), which is expediently carried out at temperatures between 0 and 50 ° C. The reaction is conveniently carried out in inert solvents, e.g. B. aromatic or chlorinated hydrocarbons, such as benzene, toluene, dichloromethane or chloroform, preferably in esters or ethers, such as ethyl acetate, isopropyl acetate or dioxane.
Die Umsetzung von IX mit X erfolgt bevorzugt in inerten Lösungsmitteln, wie sie auch für die Reaktion von Enolationen mit Alkylierungsmitteln üblicherweise verwendet werden. Beispielsweise seien aromatische Lösungsmittel wie Benzol oder Toluol genannt. Die Reaktionstemperatur liegt (je nach Art des Al alime- o o tallatoms M und der Abgangsgruppe Z) in der Regel zwischen 0 und 120 C, wobei die Siedetemperatur des verwendeten Lösungsmittels bevorzugt ist. Beispielswei¬ se [wenn M Li (Lithium) und Z Cl (Chlor) darstellt und die Umsetzung in Benzol o durchgeführt wird] ist die Siedetemperatur von Benzol (80 C) bevorzugt.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. For example, aromatic solvents such as benzene or toluene may be mentioned. The reaction temperature is (depending on the type of Al alimeo o tallatoms M and the leaving group Z) generally between 0 and 120 C, the boiling point of the solvent used is preferred. For example [when M represents Li (lithium) and Z Cl (chlorine) and the reaction is carried out in benzene o] the boiling point of benzene (80 ° C.) is preferred.
Die Verbindungen XI werden mit den Verbindungen XII in an sich bekannter Weise umgesetzt, wie sie dem Fachmann für die Reaktion metallorganischer Verbindungen geläufig ist.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.
Die Umsetzung gemäß Verfahrensvariante f) erfolgt in dem Fachmann bekannter Weise in geeigneten Lösungsmitteln wie Tetrahydrofuran oder Acetonitril, gege¬ benenfalls unter Zusatz einer Base (falls Y' eine Abgangsgruppe darstellt) oder auch ohne Basenzusatz (falls Y' eine Reaktivgruppe darstellt). Bei unsymmetri scher Verteilung der Substituenten Rl, R2 und R3 liefert diese Reaktion Isome rengemische, die durch geeignete Trennverfahren (z.B. Chromatographie) aufge¬ trennt werden müssen.The 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 also without base addition (if Y 'represents a reactive group). In the case of asymmetrical distribution of the substituents R1, R2 and R3, this reaction gives isomeric mixtures which have to be separated by suitable separation processes (for example chromatography).
Die Solvolyse gemäß Verfahrensvariante g) erfolgt in dem Fachmann bekannter Weise in geeigneten, Wasser enthaltenden oder Wasser abspaltenden alkalischen oder sauren Lösungen, bei Raumtemperatur oder gewünschtenfalls unter Erwärmen bis zur Siedetemperatur des eingesetzten Lösungsmittels.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.
Die Alkylierung gemäß Verfahrensvariante h) erfolgt - gegebenenfalls nach vor¬ heriger Deprotonierung - in dem Fachmann geläufiger Weise in geeigneten inerte Lösungsmitteln.The alkylation according to process variant h) is carried out - if appropriate after prior deprotonation - in a manner familiar to the person skilled in the art in suitable inert solvents.
Je nach Art der Ausgangsverbindungen, die gegebenenfalls auch in Form ihrer Salze eingesetzt werden können, und in Abhängigkeit von den Reaktionsbedingun¬ gen werden die erfindungsgemäßen Verbindungen zunächst entweder als solche ode in Form ihrer Salze gewonnen.Depending on the nature of the starting compounds, which can optionally also be used in the form of their salts, and depending on the reaction conditions, the compounds according to the invention are initially obtained either as such or in the form of their salts.
Im übrigen erhält man die Salze durch Auflösen der freien Verbindungen in eine geeigneten Lösungsmittel, z.B. in einem chlorierten Kohlenwasserstoff, wie Methylenchlorid oder Chloroform, einem niedermolekularen aliphatisehen Alkohol (Ethanol, Isopropanol) , einem Ether (Diisopropylether), einem Keton (Aceton) oder Wasser, das die gewünschte Säure bzw. Base enthält, oder dem die gewünsch te Säure bzw. Base - gegebenenfalls in der genau berechneten stöchiometrisehen Menge - anschließend zugegeben wird.Otherwise, 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 (diisopropyl ether), a ketone (acetone) or water, which contains the desired acid or base, or which contains the desired acid or Base - optionally in the precisely calculated stoichiometric amount - is then added.
Die Salze werden durch Filtrieren, Umfallen, Ausfällen oder durch Verdampfen des Lösungsmittels gewonnen.The salts are obtained by filtration, reprecipitation, precipitation or by evaporation of the solvent.
Erhaltene Salze können durch Alkalisieren bzw. Ansäuern, z.B. mit wäßrigem Na- triu hydrogencarbonat bzw. mit verdünnter Salzsäure, in die freien Verbindunge umgewandelt werden, welche wiederum in die Salze übergeführt werden können. Au diese Weise lassen sich die Verbindungen reinigen, oder es lassen sich pharma¬ kologisch nicht verträgliche Salze in pharmakologisch verträgliche Salze um¬ wandeln. Die erfindungsgemäßen Sulfox de sind optisch aktive Verbindungen. Je nach Art der Substituenten Rl bis R8 können noch weitere Chiralitätszentren im Molekül sein (z.B. wenn R5 kein Wasserstoff ist). Die Erfindung umfaßt daher sowohl die Enantiomeren und D astereomeren als auch ihre Mischungen und Racemate. Die Enantiomeren können in an sich bekannter Weise (beispielsweise durch Herstel¬ lung und Trennung entsprechender diastereoisomerer Verbindungen) separiert wer¬ den. Die Enantiomeren können aber auch durch asymmetrische Synthese, beispiels¬ weise durch enantioselektive Oxidation der Sulfide, z.B. mit tert.-Butylhydro- peroxid unter Zusatz von optisch reiner Weinsäure, oder beispielsweise durch Reaktion optisch aktiver reiner Verbindungen XI oder diastereoisomer reiner Verbindungen XI mit Verbindungen XII hergestellt werden [siehe hierzu K.K. Andersen, Tetrahedron Lett., 93 (1962)].Salts obtained can be converted into the free compounds by alkalization or acidification, for example with aqueous sodium bicarbonate 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 sulfox de invention are optically active compounds. Depending on the nature of the substituents Rl to R8, there may be additional chiral centers in the molecule (eg if R5 is not hydrogen). The invention therefore includes both the enantiomers and d astereomers and their mixtures and racemates. The enantiomers can be separated in a manner known per se (for example by producing and separating corresponding diastereoisomeric compounds). However, the enantiomers can also be obtained by asymmetric synthesis, for example by enantioselective oxidation of the sulfides, for example using tert-butyl hydroperoxide with the addition of optically pure tartaric acid, or for example by reacting optically active pure compounds XI or diastereoisomerically pure compounds XI with compounds XII are produced [see KK Andersen, Tetrahedron Lett., 93 (1962)].
Die erfindungsgemäßen Verbindungen werden bevorzugt durch Umsetzung von II mit III und gegebenenfalls anschließende Oxidation des entstandenen Sulfids VIII synthetisiert.The compounds according to the invention are preferably synthesized by reacting II with III and, if appropriate, subsequent oxidation of the sulfide VIII formed.
Die Verbindungen II, IV, VI, IX und XI sind z.B. aus der W086/02646, der EP 134400 oder der EP 127763 bekannt. Die Verbindungen III sind aus der EP 174726 bzw. der EP 208452 bekannt, oder sie können in analoger Weise her¬ gestellt werden.Compounds II, IV, VI, IX and XI are e.g. known from W086 / 02646, EP 134400 or EP 127763. The compounds III are known from EP 174726 and EP 208452, or they can be prepared in an analogous manner.
Die Verbindungen V, VII und XII werden beispielsweise ausgehend von den Verbin¬ dungen III auf für den Fachmann bekannten Wegen hergestellt.The compounds V, VII and XII are prepared, for example, starting from the compounds III in ways known to those skilled in the art.
Die folgenden Beispiele erläutern die Erfindung näher, ohne sie einzuschränken. Die in den Beispielen namentlich aufgeführten Verbindungen der Formel I sowie Salze dieser Verbindungen sind bevorzugter Gegenstand der Erfindung. In den Beispielen bedeutet F. Schmelzpunkt, Zers. steht für Zersetzung, Sdp. steht für Siedepunkt. Bei spi el eThe following examples illustrate the invention without restricting it. The compounds of the formula I mentioned by name in the examples and salts of these compounds are a preferred subject of the invention. In the examples, F. means melting point, decomp. stands for decomposition, Sdp stands for boiling point. At game e
1. 5-Difluormethoxy-2-f[3-methoxy-4-(2,2,2-trif uorethoxy)-2-pyridyl]methyl thio}-lH-benzi idazol1. 5-Difluoromethoxy-2-f [3-methoxy-4- (2,2,2-trif uorethoxy) -2-pyridyl] methyl thio} -lH-benzide idazole
Zu einer Lösung von 1,12 g (5,2 mMol) 5-Difluormethoxy-2-mercapto-lH-benzimid zol in 5,5 ml 2N Natronlauge und 7 ml Ethanol gibt man 1,46 g (5,0 mMol) 2-1.46 g (5.0 mmol) 2 are added to a solution of 1.12 g (5.2 mmol) of 5-difluoromethoxy-2-mercapto-1H-benzimide zol in 5.5 ml of 2N sodium hydroxide solution and 7 ml of ethanol -
Chlormethyl-4-(2,2,2-trifluorethoxy)-3-methoxypyridiniumchlorid unter Rühren o und erwärmt anschließend drei Stunden auf 50 C. Nach Zugabe von 50 ml Wasser und Abdestillieren des Ethanols am Rotavapor im Wasserstrahlvakuum extrahiert man dreimal mit je 30 ml Methylenchlorid, wäscht die vereinigten organischen Phasen zweimal mit je 5 ml IN Natronlauge, trocknet über Magnesiumsulfat und engt vollständig ein. Der ölige Rückstand wird aus Ethanol/Wasser kristalli¬ siert. Man erhält 1,95 g (90 % d. Theorie) der Titelverbindung als farblosen Feststoff; F. 134-136 C.Chloromethyl-4- (2,2,2-trifluoroethoxy) -3-methoxypyridinium chloride with stirring o and then warmed to 50 C for three hours. After adding 50 ml of water and distilling off the ethanol on a Rotavapor in a water jet vacuum, the mixture was extracted three times with 30 ml each Methylene chloride, washes the combined organic phases twice with 5 ml IN sodium hydroxide solution, dries over magnesium sulfate and completely evaporates. The oily residue is crystallized from ethanol / water. 1.95 g (90% of theory) of the title compound are obtained as a colorless solid; F. 134-136 C.
2. 5-Difluormethoxy-2-{[3-methoxy-4-(2,2,2-trifluorethoxy)-2-pyridyl]methyl sulfinyl}-lH-benzimidazol2. 5-Difluoromethoxy-2 - {[3-methoxy-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl sulfinyl} -IH-benzimidazole
1,31 g (3 mMol) 5-Difluormethoxy-2-{[3-methoxy-4-(2,2,2-trifluorethoxy)-2-pyri o dyl]methylthio}-lH-benzimidazol gelöst in Methylenchlorid werden bei -30 C innerhalb einer Stunde mit 1,03 Äquivalenten einer Lösung von m-Chlorperoxi- benzόesäure in Methylenchlorid versetzt und weitere 30 Minuten bei der angege benen Temperatur gerührt. Nach Zugabe von 0,5 ml Triethylamin wird die kalte Reaktionsmischung in 10 ml 5 %-ige Natriumthiosulfatlösung und 10 ml 5 %-ige Natriumcarbonatiösung eingerührt. Nach Phasentrennung wird noch dreimal mit j 10 ml Methylenchlorid extrahiert. Die vereinigten organischen Phasen werden zweimal mit je 5 ml einer 5 %-igen Natriumthiosulfatlösung gewaschen, getrock¬ net, vom Trockenmittel (Magnesiumsulfat) filtriert und eingeengt. Der ölige1.31 g (3 mmol) of 5-difluoromethoxy-2 - {[3-methoxy-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio} -lH-benzimidazole dissolved in methylene chloride are dissolved in - 30 C within one hour with 1.03 equivalents of a solution of m-chloroperoxybenzoic acid in methylene chloride and stirred for a further 30 minutes at the specified temperature. After adding 0.5 ml of triethylamine, the cold reaction mixture is stirred into 10 ml of 5% sodium thiosulfate solution and 10 ml of 5% sodium carbonate solution. After phase separation, 10 ml of methylene chloride are extracted three times with j. The combined organic phases are washed twice with 5 ml of a 5% sodium thiosulfate solution, dried, filtered from the drying agent (magnesium sulfate) and concentrated. The oily
Rückstand wird aus Methylenchlorid/Diisopropylether kristallisiert. Man erhält o 1,07 g (81 % d. Theorie) der Titelverbindung vom F. 106-109 C (Zers.). 3. 5-Di f 1 uormethoxy-2- { [3-methyl -4- (2, 2, 2-tri f 1 uorethoxy) -pyri dyl ] methyl - thi o} -lH-benzimi dazolThe residue is crystallized from methylene chloride / diisopropyl ether. 1.07 g (81% of theory) of the title compound of mp 106-109 C (dec.) Is obtained. 3. 5-Di f 1 uormethoxy-2- {[3-methyl -4- (2, 2, 2-tri f 1 uorethoxy) pyridyl] methyl-thi o} -lH-benzimi dazol
Nach der in Beispiel 1 beschriebenen Arbeitsweise erhält man durch Umsetzung von 0,66 g 5-Di fluormethoxy-2-mercapto-lH-benzimi dazol mit 0,78 g 2-Chlorme- thyI-4-(2,2,2-trifluorethoxy)-3-methylpyπdιniumchlorid unter Zusatz von 3,1 ml 2N Natronlauge in Ethanol /Wasser nach Kristallisation aus Methyl enchlorid/Di - isopropylether 1,18 g (80 % d. Theorie) der Titel Verbindung als farbloses Pul¬ ver vom F. 148-149 C.The procedure described in Example 1 is obtained by reacting 0.66 g of 5-difluoromethoxy-2-mercapto-1H-benzimiazole with 0.78 g of 2-chloromethyI-4- (2,2,2-trifluoroethoxy ) -3-methylpyπdιnium chloride with the addition of 3.1 ml of 2N sodium hydroxide solution in ethanol / water after crystallization from methylene chloride / di-isopropyl ether 1.18 g (80% of theory) of the title compound as a colorless powder of mp 148 -149 C.
4. 5-Di f 1 uormethoxy-2- ( [3-methyl -4- (2,2, 2-tri f 1 uorethoxy) -pyri dyl ] methyl sul - f i nyl } -lH-benzimi dazol4. 5-Di f 1 uormethoxy-2- ([3-methyl -4- (2,2, 2-tri f 1 uorethoxy) pyridyl] methyl sul - fi nyl} -lH-benzimi dazol
Nach der in Beispiel 2 angegebenen Arbeitsweise erhält man durch Oxidation vonAccording to the procedure given in Example 2, oxidation of
0,4 g 5-Di f 1 uormethoxy-2- { [3-methyl -4- (2,2, 2-tr f 1 uorethoxy) -pyri dy 1 ] methyl - thi o}-lH-benzimi dazol in 20 ml Methylenchlorid mit 1,05 Äquivalenten m-Chlor- o peroxibenzoesäure bei -30 C 0,40 g (97 % d. Theorie) der Titel Verbindung als o farbloses Kristall pul ver vom F. 152-153 C (Zers.).0.4 g of 5-di f 1 uormethoxy-2- {[3-methyl -4- (2,2, 2-tr f 1 uorethoxy) -pyridy 1] methyl-thi o} -lH-benzimi dazol in 20 ml methylene chloride with 1.05 equivalents of m-chloro-o peroxibenzoic acid at -30 C 0.40 g (97% of theory) of the title compound as o colorless crystal powder of F. 152-153 C (dec.).
5. 2-{ [3-Methyl-4-(2, 2, 2-trifl uorethoxy) -2-pyri dyl] ethyl thio} -5- (2, 2, 2-tri¬ fl uorethoxy) -lH-benzimi dazol5. 2- {[3-Methyl-4- (2, 2, 2-trifluoroethoxy) -2-pyridyl] ethyl thio} -5- (2, 2, 2-trifluoroethoxy) -lH-benzimi dazol
Nach der in Beispiel 1 beschriebenen Arbeitsweise erhält man durch Umsetzung von 0,69 g 2-Mercapto-5- (2,2,2-trifl uorethoxy) -lH-benzimi dazol mit 0,83 g 2-According to the procedure described in Example 1, reaction of 0.69 g of 2-mercapto-5- (2,2,2-trifluoroethoxy) -lH-benzimiazole with 0.83 g of 2-
Chlormethyl-4-(2,2,2-trifluorethoxy)-3-methylpyridiniumchlorid unter Zusatz vo o 8 ml IN Natronl uge in 50 ml Ethanol bei 60 C 1,04 g gelben amorphen Rückstand.Chloromethyl-4- (2,2,2-trifluoroethoxy) -3-methylpyridinium chloride with the addition of 8 ml IN sodium hydroxide solution in 50 ml ethanol at 60 C 1.04 g yellow amorphous residue.
Kristallisation aus Methyl enchlorid/Di isopropylether (1:5) liefert 0,86 g (68 d. Theorie) der Titel Verbindung als blaßgelbes, mikrokristallines Pulver vom FCrystallization from methylene chloride / diisopropyl ether (1: 5) yields 0.86 g (68 d. Theory) of the title compound as a pale yellow, microcrystalline powder of F.
107-110°C. 6. 2- {[3-Methyl -4- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] methyl sulfinyl }-5- (2, 2,2 tri f 1 uorethoxy) -lH-benzimi dazol107-110 ° C. 6. 2- {[3-methyl -4- (2, 2, 2-trifl uorethoxy) -2-pyridyl] methyl sulfinyl} -5- (2, 2.2 tri f 1 uorethoxy) -lH-benzimi dazol
Nach der in Beispiel 2 angegebenen Arbeitsweise erhält man durch Oxidation voAccording to the procedure given in Example 2, oxidation of vo
0,6 g 2- {[3-Methyl -4- (2, 2, 2-trifl uorethoxy) -2-pyr dyl] methyl thio} -5- (2, 2, 2-tr fluorethoxy)-lH-benzimidazol mit 1,03 Äquivalenten m-Chlorperoxibenzoesäure i o 30 ml Methylenchlorid bei -35 C 0,43 g (69 % d. Theorie) der Titelverbindung o als farbloses Kristallpulver vom F. 164 C (Zers.).0.6 g of 2- {[3-methyl -4- (2, 2, 2-trifluoroethoxy) -2-pyrdyl] methyl thio} -5- (2, 2, 2-tr fluoroethoxy) -IH-benzimidazole with 1.03 equivalents of m-chloroperoxibenzoic acid io 30 ml methylene chloride at -35 C 0.43 g (69% of theory) of the title compound o as a colorless crystal powder of F. 164 C (dec.).
7. 2, 2-Di fluor-6-f [3-methyl -4- (2, 2,2-tri fl uorethoxy) -2-pyri dyl] methyl thio} - 5H- [1,3] -di oxol o [4, 5-f] benz mi dazol7. 2,2-Di fluoro-6-f [3-methyl -4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl thio} - 5H- [1,3] -di oxole o [4, 5-f] benz mi dazol
1,0 g (4,3 mMol) 2,2-Difluor-5H-[l,3]-dioxolo[4,5-f]benzimidazol-6-thiol werd unter Rühren zusammen mit 1,3 g (4,3 mMol) 2-Chlormethyl-4-(2,2,2-trifluor- ethoxy)-3-methylpyridiniumchlorid in 50 ml Isopropanol fünf Stunden unter Rüc o fluß zum Sieden erhitzt. Nach Abkühlung auf 20 C filtriert man vom gebildeten1.0 g (4.3 mmol) of 2,2-difluoro-5H- [1,3] dioxolo [4,5-f] benzimidazole-6-thiol is stirred together with 1.3 g (4.3 mmol) of 2-chloromethyl-4- (2,2,2-trifluoroethoxy) -3-methylpyridinium chloride in 50 ml of isopropanol heated to boiling under reflux for five hours. After cooling to 20 C, the resulting product is filtered off
Feststoff, kocht nochmals mit 30 ml Isopropanol aus, filtriert und wäscht mitSolid, boil again with 30 ml isopropanol, filter and wash with
Isopropanol nach. Man erhält 2,0 g des Dihydrochlorids der Titelverbindung al farbloses Kristal lisat vom F. 234-236 C (Zers.).Isopropanol after. 2.0 g of the dihydrochloride of the title compound are obtained as a colorless crystal lisate of mp 234-236 C (dec.).
8. 2, 2-Di f1uor-6-{ [3-methyl -4- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] methyl sul¬ finyl }-5H- [1,3] -dioxolo [4, 5-f] benzimi dazol8. 2, 2-Di f1uor-6- {[3-methyl -4- (2, 2, 2-trifluoroethoxy) -2-pyridyl] methyl sulfinyl} -5H- [1,3] dioxolo [4, 5-f] benzimi dazol
1,5 g 2, 2-Di fluor-6-{ [3-methyl -4- (2, 2, 2-trifl uorethoxy) -2-pyri dyl] methylthio} 5H-[l,3]-dioxolo[4,5-f]benzimidazol-dihydrochlorid werden in 50 ml Methylen¬ chlorid suspendiert und zweimal mit je 10 ml 0,5 N Natronlauge gewaschen. Die organische Phase wird über Magnesiumsulfat getrocknet. Nach Filtration des o Trockenmittels kühlt man auf -35 C und oxidiert mit 1,0 Äquivalenten m-Chlor- peroxibenzoesäure. Aufarbeitung nach der in Beispiel 2 angegebenen Arbeitsweis liefert einen gelben, öligen Rückstand. Nach Kristallisation mit Di isopropyl¬ ether und nachfolgender Umkri stall isation aus Methyl enchlorid/Di isopropylether erhält man 0,65 g (50 % d. Theorie) der Titelverbindung in Form eines hei 1 - o beigen Kristall pul vers vom F. 188 C (Zers.). Gewerbliche Anwendbarkeit1.5 g 2,2-di fluoro-6- {[3-methyl -4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio} 5H- [1,3] dioxolo [4th , 5-f] benzimidazole dihydrochloride are suspended in 50 ml of methylene chloride and washed twice with 10 ml of 0.5 N sodium hydroxide solution. The organic phase is dried over magnesium sulfate. After filtration of the drying agent, the mixture is cooled to -35 ° C. and oxidized with 1.0 equivalent of m-chloroperoxibenzoic acid. Working up according to the procedure given in Example 2 gives a yellow, oily residue. After crystallization with diisopropyl ether and subsequent recrystallization from methylene chloride / diisopropyl ether, 0.65 g (50% of theory) of the title compound is obtained in the form of a hot 1 - o beige crystal powder of F. 188 C ( Dec.). Industrial applicability
Die erfindungsgemäßen Verbindungen der Formel I und ihre Salze besitzen wert¬ volle pharmakologische Eigenschaften, die sie gewerblich verwertbar machen. Si hemmen deutlich die Magensäuresekretion von Warmblütern und weisen darüberhi¬ naus eine ausgezeichnete Magen- und Darmschutzwirkung bei Warmblütern auf. Die se Magen- und Darmschutzwirkung wird teilweise bereits bei der Verabreichung von Dosen beobachtet, die unterhalb der säuresekretionshemmenden Dosen liegen. Darüberh naus zeichnen sich die erfindungsgemäßen Verbindungen durch das Fehle wesentlicher Nebenwirkungen und eine große therapeutische Breite aus. Ein wei¬ terer erfindungswesentlicher Aspekt besteht darin, daß die Verbindungen der Formel I im jeweils erwünschten pH-Bereich eine hohe chemische Stabilität und ein signifikantes Wirkungsmaximum aufweisen.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 gastric acid secretion from warm-blooded animals and, moreover, 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. In addition, 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.
Unter "Magen- und Darmschutz" wird in diesem Zusammenhang die Verhütung und Behandlung gastrointestinaler Krankheiten, insbesondere gastrointestinaler ent zündlicher Krankheiten und Läsionen (wie z.B. Ulcus ventriculi, Ulcus duodeni, Gastritits, hyperazider oder medikamentös bedingter Reizmagen) verstanden, die beispielsweise durch Mikroorganismen, Bakterientoxine, Medikamente (z.B. be¬ stimmte Antiphlogistika und Antirheumatika), Chemikalien (z.B. Ethanol), Magen säure oder Streßsituationen verursacht werden können."Stomach and intestinal protection" in this context means the prevention and treatment of gastrointestinal diseases, in particular gastrointestinal inflammatory diseases and lesions (such as, for example, ulcer ventriculi, duodenal ulcer, gastrititis, hyperacid or drug-induced irritable stomach), which are caused, for example, by microorganisms, bacterial toxins , Drugs (eg certain anti-inflammatory drugs and anti-rheumatic drugs), chemicals (eg ethanol), stomach acid or stressful situations can be caused.
In ihren ausgezeichneten Eigenschaften erweisen sich die erfindungsgemäßen Ver bindungen überraschenderweise den aus dem Stand der Technik bekannten Verbin¬ dungen deutlich überlegen. Aufgrund dieser Eigenschaften sind die erfindungs¬ gemäßen Verbindungen und ihre pharmakologisch verträglichen Salze für den Ein¬ satz in der Human- und Veterinärmedizin hervorragend geeignet, wobei sie insbe sondere zur Behandlung und Prophylaxe von Krankheiten des Magens und Darms und solcher Krankheiten, die auf einer überhöhten Magensäuresekretion beruhen, ver wendet werden. Die hohe Lagerstabilität der erfindungsgemäßen Verbindungen er¬ möglicht dabei ihren problemlosen Einsatz in pharmazeutischen Zubereitungen.In their excellent properties, the compounds according to the invention surprisingly prove to be significantly superior to the compounds known from the prior art. On the basis of these properties, the compounds according to the invention and their pharmacologically tolerable salts are outstandingly suitable for use in human and veterinary medicine, in particular for the treatment and prophylaxis of diseases of the stomach and intestine and those diseases which are exaggerated Gastric acid secretion are based, be used ver. The high storage stability of the compounds according to the invention enables their problem-free use in pharmaceutical preparations.
Ein weiterer Gegenstand der Erfindung sind die erfindungsgemäßen Verbindungen zur Anwendung bei der Behandlung und Prophylaxe der vorstehend genannten Krank heiten.The invention further relates to the compounds according to the invention for use in the treatment and prophylaxis of the abovementioned diseases.
Ebenso umfaßt die Erfindung die Verwendung der erfindungsgemäßen Verbindungen bei der Herstellung von Arzneimitteln, die zur Behandlung und Prophylaxe der vorstehend genannten Krankheiten eingesetzt werden.The invention also includes the use of the compounds according to the invention in the manufacture of medicinal products which are used for the treatment and prophylaxis of the abovementioned diseases.
Ein weiterer Gegenstand der Erfindung sind Arzneimittel, die ein oder mehrere erfindungsgemäße Verbindungen der Formel I und/oder ihre pharmakologisch ver¬ träglichen Salze enthalten.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.
Die Arzneimittel werden nach an sich bekannten, dem Fachmann geläufigen Verfah ren hergestellt. Als Arzneimittel werden die erfindungsgemäßen pharmakologisch wirksamen Verbindungen (= Wirkstoffe) entweder als solche, oder vorzugsweise i Kombination mit geeigneten pharmazeutischen Hilfsstoffen in Form von Tabletten Dragees, Kapseln, Suppositorien, Pflastern (z.B. als TTS), Emulsionen, Suspen¬ sionen oder Lösungen eingesetzt, wobei der Wirkstoffgehalt vorteilhafterweise zwischen 0,1 und 95 % beträgt.The medicaments are produced according to known processes known to the person skilled in the art. The pharmacologically active compounds (= active ingredients) according to the invention are used as medicinal products either as such, or preferably in combination with suitable pharmaceutical auxiliaries in the form of tablets, coated tablets, capsules, suppositories, plasters (for example as TTS), emulsions, suspensions or solutions, the active substance content advantageously being between 0.1 and 95%.
Welche Hilfsstoffe für die gewünschten Arzneimittelformulierungen geeignet sind, ist dem Fachmann aufgrund seines Fachwissens geläufig. Neben Lösemitteln Gelbildnern, Suppositoriengrundlagen, Tabletten-Hilfsstoffen und anderen Wirk¬ stoffträgem können beispielsweise Antioxidantien, Dispergiermittel, Emulato¬ ren, Entschäumer, Geschmackskorrigentien, Konservierungsmittel, Lösungsvermitt ler, Farbstoffe oder insbesondere Per eationspromotoren und Komplexbildner (z.B. Cyclodextrine) verwendet werden.The person skilled in the art is familiar with the auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge. In addition to solvents, gel formers, suppository bases, tablet adjuvants and other active substance carriers, for example antioxidants, dispersants, emulsifiers, defoamers, taste correctors, preservatives, solubilizers, dyes or in particular performance promoters and complexing agents (e.g. cyclodextrins) can be used.
Die Wirkstoffe können oral, parenteral oder percutan appliziert werden.The active ingredients can be administered orally, parenterally or percutaneously.
Im allgemeinen hat es sich in der Humanmedizin als vorteilhaft erwiesen, den oder die Wirkstoffe bei oraler Gabe in einer Tagesdosis von etwa 0,05 bis etwa 50, vorzugsweise 0,25 bis 20, insbesondere 0,5 bis 10 mg/kg Körpergewicht, ge¬ gebenenfalls in Form mehrerer, vorzugsweise 1 bis 4 Einzelgaben zur Erzielung des gewünschten Ergebnisses zu verabreichen. Bei einer parenteralen Behandlung können ähnliche bzw. (insbesondere bei der intravenösen Verabreichung der Wirk stoffe) in der Regel niedrigere Dosierungen zur Anwendung kommen. Die Festle¬ gung der jeweils erforderlichen optimalen Dosierung und Applikationsart der Wirkstoffe kann durch jeden Fachmann aufgrund seines Fachwissens leicht erfol¬ gen.In general, it has proven advantageous in human medicine to give 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 of body weight ¬ if necessary in the form of several, preferably 1 to 4 individual doses to achieve the desired result. In the case of parenteral treatment, similar or (in particular in the case of intravenous administration of the active substances) generally lower doses can be used. Any person skilled in the art can easily determine the optimum dosage and mode of application of the active ingredients required on the basis of his or her specialist knowledge.
Sollen die erfindungsgemäßen Verbindungen und/oder ihre Salze zur Behandlung der oben genannten Krankheiten eingesetzt werden, so können die phar azeuti- schen Zubereitungen auch einen oder mehrere pharmakologisch aktive Bestandteil anderer Arzneimittelgruppen, wie Antacida, beispielsweise Aluminiumhydroxid, Magnesiumaluminat; Tranqu ll zer, wie Benzodiazepine, beispielsweise Diazepam; Spasmolytika, wie z.B. Bietamiverin, Camylofin; Anticholi ergica, wie z.B. Oxyphencycli in, Phencarbamid; Lokalanaesthetika, wie z.B. Tetracain, Procain; Antibiotika, wie Penicilline, Tetracyeline, etc.; gegebenenfalls auch Fermente, Vitamine oder Aminosäuren enthalten.If the compounds according to the invention and / or their salts are to be used for the treatment of the abovementioned diseases, the pharmaceutically preparations also include one or more pharmacologically active constituents of other groups of medicaments, such as antacids, for example aluminum hydroxide, magnesium aluminate; Tranquilizers, such as benzodiazepines, for example diazepam; Antispasmodics such as Bietamiverin, Camylofin; Anticholi ergica, such as, for example, Oxyphencycli in, phencarbamide; Local anesthetics, such as tetracaine, procaine; Antibiotics such as penicillins, tetracyeline, etc .; optionally also contain ferments, vitamins or amino acids.
Hervorzuheben ist in diesem Zusammenhang insbesondere die Kombination der er¬ findungsgemäßen Verbindungen mit anderen, die Säuresekretion hemmenden Pharma- ka, wie beispielsweise H2-Blockern (z.B. Cimetidin, Ranitidin), ferner mit so¬ genannten peripheren Anticholinergika (z.B. Pirenzepin, Telenzepin, Zolenzepin) sowie mit Gastrin-Antagonisten, mit dem Ziel, die Hauptwirkung in additivem oder überadditivem Sinn zu verstärken und/oder die Nebenwirkungen zu eliminie¬ ren oder zu verringern, oder ferner mit antibakteriell wirksamen Substanzen (wie z.B. Cephalosporinen, Tetracyclinen, Nalidixinsäure, Penicillinen etc.) zur Bekämpfung von Ca pylobacter pyloridis. In this context, the combination of the compounds according to the invention with other pharmaceuticals which inhibit acid secretion, such as, for example, H 2 blockers (for example cimetidine, ranitidine), and also with so-called peripheral anticholinergics (for example pirenzepin, telenzepin, zolenzepin) should be emphasized in particular ) as well as with gastrin antagonists, with the aim of increasing the main effect in an additive or superadditive sense and / or eliminating or reducing the side effects, or further with antibacterially active substances (such as cephalosporins, tetracyclines, nalidixic acid, penicillins etc .) to combat Ca pylobacter pyloridis.
Pharmakologiepharmacology
Die ausgezeichnete Magenschutzwi kung und die magensekretionshemmende Wirkung der erfindungsgemäßen Verbindungen kann in Untersuchungen an tierexperimentel¬ len Modellen nachgewiesen werden. Die in den nachstehend aufgeführten Modellen untersuchten erfindungsgemäßen Verbindungen sind mit Nummern versehen worden, die den Beispielnummern entsprechen.The excellent stomach protection effect and the gastric secretion-inhibiting effect of the compounds according to the invention can be demonstrated in studies on models of animal experiments. The compounds according to the invention investigated in the models listed below have been given numbers which correspond to the example numbers.
1. Prüfung der antiulcerogenen und sekretionshemmenden Wirkung an der modifi zierten Shay-Ratte1. Testing the antiulcerogenic and secretion-inhibiting effect on the modified Shay rat
In der folgenden Tabelle 1 ist der Einfluß der erfindungsgemäßen Verbindungen nach oraler (p. o.) Gabe auf die Läsionsbildung sowie die Säureausscheidung bei der modifizierten Shay-Ratte dargestellt.Table 1 below shows the influence of the compounds according to the invention after oral (p. O.) Administration on lesion formation and acid excretion in the modified Shay rat.
Tabelle 1Table 1
+) ED50 = Dosis (interpoliert), die den Läsionsindex bzw. die HCl-Sekretion des Rattenmagens bei der behandelten Gruppe gegenüber der Kontrollgruppe um 50 % mindert. Methodi k+) ED50 = dose (interpolated) that reduces the lesion index or the HCl secretion of the rat stomach in the treated group compared to the control group by 50%. Methodology
Die Ulcusprovokation erfolgt an 24 Stunden nüchternen Ratten (weiblich, 180-200 g, 4 Tiere je Käfig auf hohem Gitterrost) durch Pylorusl gatur (unter Diethylethernarkose) und orale Applikation von 100 mg/lOml/kg Acetylsalicylsäu¬ re. Die zu prüfenden Substanzen werden oral (10 ml/kg) eine Stunde vor Pylorus¬ ligatur verabreicht. Der Wundverschluß wird mittels Miehe! lammern vorgenommen. 4 Stunden danach erfolgt die Tötung der Tiere im Etherrausch durch Atlas-Dis¬ lokation und die Resektion des Magens. Der Magen wird längs der großen Kurvatur eröffnet und auf einer Korkplatte aufgespannt, nachdem zuvor die Menge des se- zernierten Magensaftes (Volumen) und später sein HCl-Gehalt (Titration mit Na¬ tronlauge) bestimmt wird. Mit einem Stereomikroskop werden bei 10-facher Ver¬ größerung Anzahl und Größe (=Durchmesser) vorhandener Ulcera ermittelt. Das Produkt aus Schweregrad (gemäß nachfolgender Punkteskala) und Anzahl der Ulcera dient als individueller Läsionsindex.The ulcer provocation is carried out on 24 hours fasting rats (female, 180-200 g, 4 animals per cage on a high grating) by pyloric acid (under diethyl ether anesthesia) and oral application of 100 mg / lOml / kg acetylsalicylic acid. The substances to be tested are administered orally (10 ml / kg) one hour before the pylorus ligature. The wound is closed using Miehe! lammer made. 4 hours later, the animals were killed in etheric intoxication by atlas displacement and gastric resection. The stomach is opened along the large curvature and stretched out on a cork plate after the amount of the secreted gastric juice (volume) and later its HCl content (titration with sodium hydroxide solution) is determined. The number and size (= diameter) of existing ulcers are determined with a stereomicroscope at a 10-fold magnification. The product of the severity (according to the following scale of points) and the number of ulcers serves as an individual lesion index.
Punkteskala: keine Ulcera 0Score scale: no ulcers 0
Ulcusdurchmesser 0,1 - 1,4 mm 1Ulcer diameter 0.1 - 1.4 mm 1
1,5 - 2,4 mm 21.5 - 2.4 mm 2
2,5 - 3,4 mm 32.5 - 3.4 mm 3
3,5 - 4,4 mm 43.5 - 4.4 mm 4
4,5 - 5,4 mm 54.5 - 5.4 mm 5
> 5,5 mm 6> 5.5 mm 6
Als Maß für den antiulcerogenen Effekt dient die Minderung des mittleren Lä¬ sionsindex jeder behandelten Gruppe gegenüber dem der Kontrollgruppe (=100 %) . Die ED50 bezeichnet diejenige Dosis, die den mittleren Läsionsindex bzw. die HCl-Sekretion gegenüber der Kontrolle um 50 % mindert.The measure of the antiulcerogenic effect is the reduction in the mean lesion index of each treated group compared to that of the control group (= 100%). The ED50 is the dose that reduces the mean lesion index or HCl secretion by 50% compared to the control.
2. Prüfung der sekretionshemmenden Wirkung am perfundierten Rattenmagen2. Testing the secretion-inhibiting effect on the perfused rat stomach
In der folgenden Tabelle 2 ist der Einfluß der erfindungsgemäßen Verbindungen nach intravenöser Gabe auf die durch Pentagastrin stimulierte Säuresekretion des perfundierten Rattenmagens in vivo dargestellt. Tabel l e 2Table 2 below shows the influence of the compounds according to the invention after intravenous administration on the acid secretion of the perfused rat stomach stimulated by pentagastrin in vivo. Table 2
+) ED50 = Dosi s (i nterpol i ert) , di e ei ne maxi mal e Hemmung der HCl -Sekret IOΠ u 50 % bewi rkt.+) ED50 = Dosi s (interpolated), which causes a maximum inhibition of the HCl secretion IOΠ u 50%.
MethodiMethodi
Narkotisierten Ratten (CD-Ratte, weiblich, 200-250 g; 1,5 g/kg i .m. Urethan) wurde nach Tracheotomie das Abdomen durch einen medianen Oberbauchschnitt er¬ öffnet und ein PVC-Katheter transoral im Ösophagus sowie ein weiterer via Py- lorus derart fixiert, daß die Schlauchenden eben noch in das Magenlumen hinei ragten. Der aus dem Pylorus führende Katheter führte über eine seitliche Öff¬ nung in der rechten Bauchwand nach außen. o Nach gründlicher Spülung (ca.50-100 ml) wurde der Magen mit 37 C warmer physio logischer NaCl-Lösung kontinuierlich durchströmt (0,5 ml/min, pH 6,8-6,9; Braun-Unita I). In dem jeweils im 15 min-Abstand aufgefangenen (25 ml Meßzylin der) Effluat wurde der pH-Wert (pH-Meter 632, Glaselektrode EA 147; = 5 mm, Metrohm) sowie durch Titration mit einer frisch zubereiteten 0,01 N NaOH bis p 7 (Dosimat 655 Metrohm) die sezernierte HCl bestimmt.After tracheotomy, anesthetized rats (CD rat, female, 200-250 g; 1.5 g / kg in urethane) were opened by a median upper abdominal incision and a PVC catheter transorally in the esophagus and another via The pylorus was fixed in such a way that the ends of the tube were just protruding into the gastric lumen. The catheter leading out of the pylorus led outwards through a lateral opening in the right abdominal wall. o After thorough rinsing (approx. 50-100 ml), the stomach was continuously flowed through with 37 C warm physiological NaCl solution (0.5 ml / min, pH 6.8-6.9; Braun-Unita I). The pH value (pH meter 632, glass electrode EA 147; = 5 mm, Metrohm) as well as by titration with a freshly prepared 0.01 N NaOH bis in the effluate collected in 15 min intervals (25 ml measuring cylinder) p 7 (Dosimat 655 Metrohm) determines the secreted HCl.
Die Stimulation der Magensekretion erfolgte durch Dauerinfusion von lμg/kg (=1,65 ml/h) i.v. Pentagastrin (V. fern, sin.) ca 30 min nach Operationsende (d.h. nach Bestimmung von 2 Vorfraktionen). Die zu prüfenden Substanzen wurden intravenös (V. jugularis sin.) in 1 ml/kg Flüssigkeitsvolumen 60 min nach Be¬ ginn der Pentagastrin-Dauerinfusion verabreicht. Die Körpertemperatur der Tiere wurde durch Infrarot-Bestrahlung und Heizkissen (automatische, stufenlose Regelung über rektalen Temperaturfühler) auf konstant 37,8 - 38 C gehalten.Gastric secretion was stimulated by continuous infusion of lμg / kg (= 1.65 ml / h) iv pentagastrin (V. fern, sin.) Approx. 30 min after the end of the operation (ie after determination of 2 pre-fractions). The substances to be tested were administered intravenously (V. jugularis sin.) In 1 ml / kg liquid volume 60 min after the start of the continuous pentagastrin infusion. The body temperature of the animals was kept constant at 37.8 - 38 C by infrared radiation and heating pads (automatic, stepless regulation via rectal temperature sensor).
Als Maß für die sekretionshemmende Wirkung diente die maximale Abnahme der Säu¬ reausscheidung (15 min-Fraktionen) jeder behandelten Gruppe gegenüber derjeni¬ gen der unbehandelten Kontrollgruppe (=100 %) . Die ED50 bezeichnet diejenige Dosis, die eine maximale Hemmung der HCl-Sekretion um 50 % bewirkt. The maximum decrease in acid excretion (15 min fractions) of each treated group compared to that of the untreated control group (= 100%) served as a measure of the secretion-inhibiting effect. The ED50 denotes the dose that causes a maximum inhibition of HCl secretion by 50%.

Claims

Patentansprüche Claims
1. Fluoralkoxyverbindungen der Formel I1. Fluoroalkoxy compounds of the formula I.
worin Rl, R2 und R3 an beliebigen Positionen im Benzoteil des Benzimidazols stehen können und worinwherein Rl, R2 and R3 can be at any position in the benzo part of the benzimidazole and wherein
Rl Wasserstoff, Halogen, Trifluormethyl , 1-6C-Alkyl, l-6C-Alkoxy, 1-4C-Alk- oxy-l-4C-alkyl, l-4C-Alkoxy-l-4C-alkoxy, Phenyl , Phenoxy, Phenoxy-l-4C-al- kyl, Phenoxy-l-4C-alkoxy, Phen-l-4C-alkyl oder Phen-l-4C-alkoxy bedeutet,R1 hydrogen, halogen, trifluoromethyl, 1-6C-alkyl, 1-6C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy, phenyl, phenoxy, phenoxy -l-4C-alkyl, phenoxy-1-4C-alkoxy, phen-1-4C-alkyl or phen-1-4C-alkoxy,
R2 Wasserstoff, 1-6C-A1kyl , l-6C-Alkoxy, ganz oder überwiegend durch Fluor substituiertes l-4C-Alkoxy, Chlordifluormethoxy, 2-Chlor-l,l,2-trifluor- ethoxy oder gemeinsam mit R3 ganz oder teilweise durch Fluor substituier¬ tes l-2C-Alkylendioxy oder Chlortrifluorethylendioxy bedeutet,R2 is hydrogen, 1-6C-A1kyl, 1-6C-alkoxy, completely or predominantly substituted by fluorine-1-4C-alkoxy, chlorodifluoromethoxy, 2-chloro-l, 1,2-trifluoroethoxy or together with R3 in whole or in part Is fluorine-substituted 1-2C-alkylenedioxy or chlorotrifluoroethylenedioxy,
R3 ganz oder überwiegend durch Fluor substituiertes l-4C-Alkoxy, Chlordi- fluormethoxy, 2-Chlor-l,l,2-trifluorethoxy oder gemeinsam mit R2 ganz oder teilweise durch Fluor substituiertes l-2C-Al ylendioxy oder Chlortrifluor¬ ethylendioxy bedeutet,R3 is completely or predominantly fluorine-substituted l-4C-alkoxy, chlorodifluoromethoxy, 2-chloro-l, l, 2-trifluoroethoxy or together with R2 completely or partly fluorine-substituted l-2C-al ylenedioxy or chlorotrifluoroethylenedioxy,
R4 Wasserstoff oder eine unter physiologischen Bedingungen leicht abspaltbare Gruppe bedeutet,R4 denotes hydrogen or a group which can easily be split off under physiological conditions,
R5 Wasserstoff oder 1-6C-A1kyl bedeutet,R5 denotes hydrogen or 1-6C-A1kyl,
R6 Wasserstoff oder 1-6C-A1kyl bedeutet,R6 represents hydrogen or 1-6C-A1kyl,
R7 Wasserstoff, 1-6C-Alkyl, l-6C-Alkoxy, 2-5C-Alkenyloxy, 2-5C-Alkinyloxy oder l-4C-Alkoxy-l-4C-alkoxy bedeutet,R7 denotes hydrogen, 1-6C-alkyl, 1-6C-alkoxy, 2-5C-alkenyloxy, 2-5C-alkynyloxy or 1-4C-alkoxy-1-4C-alkoxy,
R8 ganz oder überwiegend durch Fluor substituiertes l-4C-Alkoxy bedeutet und n die Zahl 0 oder 1 darstellt, und die Salze dieser Verbindungen. 2. Verbindungen nach Anspruch 1 gekennzeichnet durch die Formel Ia,R8 is completely or predominantly fluorine-substituted 1-4C-alkoxy and n represents the number 0 or 1, and the salts of these compounds. 2. Compounds according to claim 1, characterized by the formula Ia,
worinwherein
Rl ' Wasserstoff bedeutet,Rl ' means hydrogen
R2 Wasserstoff, Methyl, Ethyl, Methoxy, Ethoxy, 1, 1, 2, 2-Tetrafl uorethoxy,R2 is hydrogen, methyl, ethyl, methoxy, ethoxy, 1, 1, 2, 2-tetrafluoroethoxy,
Trifluormethoxy, 2, 2, 2-Trifl uorethoxy, Di fl uormethoxy, 2-Chlor-l,l, 2-tri¬ fl uorethoxy oder gemeinsam mit R3 D fluormethylendioxy, 1,1,2-Trifluor- ethylendioxy oder l-Chlor-l,2,2-trifluorethylendioxy bedeutet,Trifluoromethoxy, 2, 2, 2-trifluoroethoxy, di fl uormethoxy, 2-chloro-l, l, 2-tri fl uorethoxy or together with R3 D fluoromethylene dioxy, 1,1,2-trifluoroethylene dioxy or l-chloro 1,2,2-trifluoroethylene dioxy means
R3 1,1, 2, 2-Tetrafl uorethoxy, Trifluormethoxy, 2,2,2-Trifl uorethoxy, Di fl uor¬ methoxy, 2-Chlor-l,l,2-trifluorethoxy oder gemeinsam mit R2 Difluormethy¬ lendioxy, 1,1,2-Trifluorethylendioxy oder l-Chlor-l,2,2-trifluorethylen- d oxy bedeutet,R3 1,1, 2, 2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, di fl uoromethoxy, 2-chloro-l, l, 2-trifluoroethoxy or together with R2 difluoromethyl methylene, 1, 1,2-trifluoroethylene dioxy or l-chloro-l, 2,2-trifluoroethylene-d oxy,
R4 Wasserstoff bedeutet,R4 means hydrogen,
R5 Wasserstoff, Methyl oder Ethyl bedeutet,R5 denotes hydrogen, methyl or ethyl,
R6 Wasserstoff oder 1-4C-Alkyl bedeutet,R6 represents hydrogen or 1-4C-alkyl,
R7 Wasserstoff, 1-4C-Alkyl oder l-4C-Alkoxy bedeutet,R7 denotes hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
R8 1,1, 2, 2-Tetrafl uorethoxy, Trifluormethoxy, 2,2,R8 1,1, 2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,
2-Trifluorethoxy oder Di- fl uormethoxy bedeutet und n die Zahl 0 oder 1 darstellt, und die Salze dieser Verbindungen.2-Trifluoroethoxy or difluoromethoxy means and n represents the number 0 or 1, and the salts of these compounds.
3. Verbindungen nach Anspruch 1 gekennzeichnet durch die Formel Ib,3. Compounds according to claim 1 characterized by the formula Ib,
worin Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO und n die in Anspruch 2 angege¬ benen Bedeutungen haben, und ihre Salze. wherein Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO and n have the meanings given in claim 2, and their salts.
4. Verbindungen der Formel I nach Anspruch 1, in denen Rl Wasserstoff bedeutet,4. Compounds of formula I according to claim 1, in which Rl is hydrogen,
R2 Wasserstoff oder gemeinsam mit R3 Difluormethylendioxy bedeutet, R3 2,2,2-Trifluorethoxy, Difluormethoxy oder gemeinsam mit R3 Difluormethy¬ lendioxy bedeutet, R4 Wasserstoff bedeutet, R5 Wasserstoff bedeutet, R6 Wasserstoff bedeutet,R2 is hydrogen or together with R3 difluoromethylene dioxy, R3 is 2,2,2-trifluoroethoxy, difluoromethoxy or together with R3 is difluoromethylene methylene, R4 is hydrogen, R5 is hydrogen, R6 is hydrogen,
R7 Wasserstoff, Methyl oder Methoxy bedeutet, R8 2,2,2-Trifluorethoxy bedeutet und n die Zahl 0 oder 1 darstellt, und die Salze dieser Verbindungen.R7 represents hydrogen, methyl or methoxy, R8 represents 2,2,2-trifluoroethoxy and n represents the number 0 or 1, and the salts of these compounds.
5. Verbindungen der Formel Ia nach Anspruch 2, in denen Rl Wasserstoff bedeutet,5. Compounds of the formula Ia according to claim 2, in which Rl is hydrogen,
R2 Wasserstoff oder gemeinsam mit R3 Difluormethylendioxy bedeutet, R3 2,2,2-Trifluorethoxy, Difluormethoxy oder gemeinsam mit R3 Difluormethy¬ lendioxy bedeutet, R4 Wasserstoff bedeutet, R5 Wasserstoff bedeutet, R6 Wasserstoff bedeutet,R2 is hydrogen or together with R3 difluoromethylene dioxy, R3 is 2,2,2-trifluoroethoxy, difluoromethoxy or together with R3 is difluoromethylene methylene, R4 is hydrogen, R5 is hydrogen, R6 is hydrogen,
R7 Wasserstoff, Methyl oder Methoxy bedeutet, R8 2,2, -Trifluorethoxy bedeutet und n die Zahl 0 oder 1 darstellt, und die Salze dieser Verbindungen.R7 represents hydrogen, methyl or methoxy, R8 represents 2,2 -trifluoroethoxy and n represents the number 0 or 1, and the salts of these compounds.
6. Verbindungen der Formel Ib nach Anspruch 3, in denen6. Compounds of formula Ib according to claim 3, in which
Rl Wasserstoff bedeutet,Rl is hydrogen,
R2 Wasserstoff oder gemeinsam mit R3 Difluormethylendioxy bedeutet,R2 is hydrogen or together with R3 difluoromethylene dioxy,
R3 2, ,2-Trifluorethoxy, Difluormethoxy oder gemeinsam mit R3 Difluormethy¬ lendioxy bedeutet,R3 denotes 2,, 2-trifluoroethoxy, difluoromethoxy or together with R3 difluoromethylenedioxy,
R4 Wasserstoff bedeutet,R4 means hydrogen,
R5 Wasserstoff bedeutet,R5 means hydrogen
R6 Wasserstoff bedeutet, R7 Wasserstoff, Methyl oder Methoxy bedeutet, R8 2, 2, 2-Trifl uorethoxy bedeutet und n die Zahl 0 oder 1 darstellt, und die Salze dieser Verbindungen.R6 means hydrogen, R7 represents hydrogen, methyl or methoxy, R8 represents 2, 2, 2-trifluoroethoxy and n represents the number 0 or 1, and the salts of these compounds.
7. Verbindung ausgewählt aus der Gruppe bestehend aus7. Connection selected from the group consisting of
5-Di f 1 uormethoxy-2- [ [3-methoxy-4- (2,2, 2-tr f 1 uorethoxy) -2-pyri dyl] ethyl thi o} - lH-benzimi dazol5-Di f 1 uormethoxy-2- [[3-methoxy-4- (2,2, 2-tr f 1 uorethoxy) -2-pyridyl] ethyl thi o} - 1H-benzimi dazol
5-Di f 1 uormethoxy-2-{ [3-methoxy-4- (2,2, 2-tri f 1 uorethoxy) -2-pyri dyl ] methyl sul - fi nyl }-lH-benzimi dazol5-Di f 1 uormethoxy-2- {[3-methoxy-4- (2,2, 2-tri f 1 uorethoxy) -2-pyridyl] methyl sul-fi nyl} -lH-benzimi dazol
5-Di f 1 uormethoxy-2-{ [3-methyl -4- (2, 2, 2-tri f 1 uorethoxy) -pyri dyl ] methyl thi o} -1H- benzimi dazol5-Di f 1 uormethoxy-2- {[3-methyl -4- (2, 2, 2-tri f 1 uorethoxy) pyridyl] methyl thi o} -1H-benzimi dazol
5-Di f 1 uormethoxy-2- { [3-methyl -4- (2, 2, 2-tri f 1 uorethoxy) -pyri dyl ] methyl sul f i - nyl } -lH-benzimi dazol5-Di f 1 uormethoxy-2- {[3-methyl -4- (2, 2, 2-tri f 1 uorethoxy) pyridyl] methyl sul f i - nyl} -lH-benzimi dazol
2-{[3-Methyl-4-(2, 2, 2-trifl uorethoxy) -2-pyri dyl] methyl thio} -5-(2,2, 2-trifl uor¬ ethoxy) -lH-benzimi dazol2 - {[3-Methyl-4- (2, 2, 2-trifl uorethoxy) -2-pyridyl] methyl thio} -5- (2,2, 2-trifl uor¬ ethoxy) -lH-benzimi dazol
2-{[3-Methyl-4-(2,2, 2-trifl uorethoxy) -2-pyri dyl] methyl sulfinyl }-5-(2, 2, 2-tri¬ fl uorethoxy) -lH-benziππ" dazol2 - {[3-Methyl-4- (2,2, 2-trifluoroethoxy) -2-pyridyl] methyl sulfinyl} -5- (2, 2, 2-trifluoroethoxy) -IH-benziππ " dazol
2, 2-Di f 1 uor-6- { [3-methyl -4- (2,2, 2-tri f 1 uorethoxy) -S-pyri dyl ] methyl thi o} -5H- [1 , 3] -di oxol o [4, 5-f] benzi mi dazol2, 2-Di f 1 uor-6- {[3-methyl -4- (2,2, 2-tri f 1 uorethoxy) -S-pyridyl] methyl thi o} -5H- [1, 3] - di oxol o [4, 5-f] benzi mi dazol
2 , 2-Di f 1 uor-6- { [3-methyl -4- (2,2, 2-tri f 1 uorethoxy) -2-pyri dyl ] methyl sul f i nyl } - 5H- [1,3] -dioxolo [4, 5-f] benzimi dazol und ihren Salzen.2, 2-Di f 1 uor-6- {[3-methyl -4- (2,2, 2-tri f 1 uorethoxy) -2-pyridyl] methyl sul fi nyl} - 5H- [1,3] -dioxolo [4, 5-f] benzimi dazol and their salts.
8. Verfahren zur Herstellung der Verbindungen der Formel I nach Anspruch 1, worin Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO und n die in Anspruch 1 angege¬ benen Bedeutungen haben, und ihrer Salze,8. A process for the preparation of the compounds of the formula I as claimed in claim 1, in which Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO and n have the meanings given in claim 1, and their salts,
dadurch gekennzeichnet, daß man a) Mercaptobenzimidazole der Formel II mit Picolinderivaten III,characterized in that one a) mercaptobenzimidazoles of the formula II with picolin derivatives III,
oder b) Benzimidazole der Formel IV mit MereaptopiColinen V,or b) benzimidazoles of the formula IV with MereaptopiColinen V,
oder c) o-Phenylendiamine der Formel VI mit Ameisensäurederivaten VII or c) o-phenylenediamines of the formula VI with formic acid derivatives VII
umsetzt und (falls Verbindungen der Formel I mit n=l die gewünschten Endproduk¬ te sind) anschließend die nach a), b) oder c) erhaltenen 2-Benzimidazolyl-2-py- ndylmethyl -sulf de der Formel VIII (Verbindungen der Formel I mit n=0) and (if compounds of the formula I with n = 1 are the desired end products) then the 2-benzimidazolyl-2-pyndylmethylsulphide of the formula VIII (compounds of the formula I with n = 0)
oxidiert und/oder gewünschtenfalls in die Salze überführt,oxidized and / or, if desired, converted into the salts,
oder daß man d) Benzimidazole der Formel IX mit Pyridinderivaten Xor that d) benzimidazoles of the formula IX with pyridine derivatives X
oder e) Sulf nylderivate der Formel XI mit 2-Picolinderivaten XIIor e) sulfyl derivatives of the formula XI with 2-picoline derivatives XII
umsetzt und gewünschtenfalls anschließend in die Salze überführt, oder f) - falls Verbindungen der Formel I, worin R4 eine unter physiologischen Be¬ dingungen leicht abspaltbare Gruppe darstellt, die herzustellenden Verfahrens produkte sind - daß man Verbindungen der Formel I, worin R4 Wasserstoff bedeu tet, mit Verbindungen der Formel R4'-Y' (XIII), worin R4' die gewünschte, unt physiologischen Bedingungen leicht abspaltbare Gruppe oder gemeinsam mit Y' i Vorläufer ist, umsetzt und gewünschtenfalls anschließend in die Salze über¬ führt, oderimplemented and, if desired, subsequently converted into the salts, or f) - if compounds of the formula I in which R4 is a group which can easily be split off under physiological conditions are the process products to be prepared - that compounds of the formula I in which R4 is hydrogen are reacted with compounds of the formula R4'-Y ' (XIII), in which R4 'is the desired group which can easily be split off under physiological conditions or is a precursor together with Y' i and, if desired, is subsequently converted into the salts, or
g) - falls Verbindungen der Formel I, worin R4 Wasserstoff bedeutet, die herzu stellenden Verfahrensprodukte sind - daß man Verbindungen der Formel I, worin R4 eine unter physiologischen Bedingungen leicht abspaltbare Gruppe darstellt, solvolysiert, und die erhaltenen Produkte gewünschtenfalls in die Salze über¬ führt, oderg) - if compounds of the formula I, in which R4 is hydrogen, are the process products to be prepared - that compounds of the formula I, in which R4 is a group which can be split off easily under physiological conditions, are solvolysed and the products obtained, if desired, are transferred into the salts leads, or
h) - falls Verbindungen der Formel I, worin R5 1-6C-A1kyl bedeutet, die herzu¬ stellenden Verfahrensprodukte sind - daß man Verbindungen der Formel I, worin R5 Wasserstoff bedeutet, mit Verbindungen der Formel R5-Y'1 (XIV), worin R5 1-6C-A1kyl bedeutet, alkyliert und gewünschtenfalls anschließend in die Salze überführt,h) - if compounds of the formula I in which R5 is 1-6C-alkyl are the process products to be prepared - that compounds of the formula I in which R5 is hydrogen are reacted with compounds of the formula R5-Y ' 1 (XIV), wherein R5 is 1-6C-A1kyl, alkylated and, if desired, subsequently converted into the salts,
wobei Y, Y1', Z, V und Z'1 geeignete Abgangsgruppen darstellen, Y' eine Ab¬ gangs- bzw. Reaktivgruppe darstellt, M für ein Alkalimetallatom (Li, Na oder K steht, M' für das Äquivalent eines Metallatoms steht und Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO und n (sofern nicht anders definiert) die in Anspruch 1 an gegebenen Bedeutungen haben.where Y, Y 1 ', Z, V and Z' 1 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) and Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO and n (unless otherwise defined) have the meanings given in claim 1.
9. Arzneimittel enthaltend eine oder mehrere Verbindungen nach einem oder mehreren der Ansprüche 1 bis 7 und/oder ihre pharmakologi ch verträglichen Salze.9. Medicament containing one or more compounds according to one or more of claims 1 to 7 and / or their pharmacologically acceptable salts.
10. Verbindungen nach einem oder mehreren der Ansprüche 1 bis 7 und ihre phar makologisch verträglichen Salze zur Anwendung bei der Behandlung und/oder Pro¬ phylaxe von Krankheiten des Magens und/oder Darms und solcher Krankheiten, die auf einer erhöhten Magensäuresekretion beruhen. 10. Compounds according to one or more of claims 1 to 7 and their pharmacologically acceptable salts for use in the treatment and / or prophylaxis of diseases of the stomach and / or intestine and those diseases which are based on increased gastric acid secretion.
EP89906099A 1988-05-25 1989-05-23 New fluoralkoxy compounds Withdrawn EP0415990A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH1977/88 1988-05-25
CH197788 1988-05-25

Publications (1)

Publication Number Publication Date
EP0415990A1 true EP0415990A1 (en) 1991-03-13

Family

ID=4223038

Family Applications (1)

Application Number Title Priority Date Filing Date
EP89906099A Withdrawn EP0415990A1 (en) 1988-05-25 1989-05-23 New fluoralkoxy compounds

Country Status (4)

Country Link
EP (1) EP0415990A1 (en)
JP (1) JPH03504497A (en)
AU (1) AU3690289A (en)
WO (1) WO1989011479A1 (en)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL166209B1 (en) * 1990-06-20 1995-04-28 Astra Ab Method of obtaining novel derivatives of benzimidazole
SE9002206D0 (en) * 1990-06-20 1990-06-20 Haessle Ab NEW COMPOUNDS
AT394368B (en) * 1990-08-07 1992-03-25 Byk Gulden Lomberg Chem Fab Process for the preparation of 3,4-dialkoxypyridines
DE59109225D1 (en) * 1990-09-14 2002-01-17 Byk Gulden Lomberg Chem Fab USE OF PYRIDYLMETHYLSULFINYL-1H-BENZIMIDAZOLE DERIVATIVES FOR TREATING DISEASES CAUSED BY HELICOBACTER
EP0481764B1 (en) * 1990-10-17 2000-03-29 Takeda Chemical Industries, Ltd. Pyridine derivatives, their production and use
AU6551198A (en) * 1997-05-30 1998-12-30 Dr. Reddy's Research Foundation Novel benzimidazole derivatives as antiulcer agents, process for their preparation and pharmaceutical compositions containing them
DE19745692A1 (en) * 1997-07-24 1999-01-28 Bayer Ag Process for the preparation of 2-chloro-benzimidazole derivatives

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU193408B (en) * 1983-05-03 1987-10-28 Byk Gulden Lomberg Chem Fqb Process for production of new tree-cycle compounds
IL71664A (en) * 1983-05-03 1987-11-30 Byk Gulden Lomberg Chem Fab Fluoroalkoxy compounds,process for their preparation and pharmaceutical compositions containing the same
JPS6150978A (en) * 1984-08-16 1986-03-13 Takeda Chem Ind Ltd Pyridine derivative and preparation thereof
IL76839A (en) * 1984-10-31 1988-08-31 Byk Gulden Lomberg Chem Fab Picoline derivatives,processes for the preparation thereof and pharmaceutical compositions containing the same
CA1327010C (en) * 1986-02-13 1994-02-15 Tadashi Makino Stabilized solid pharmaceutical composition containing antiulcer benzimidazole compound and its production
DE3722810A1 (en) * 1987-07-10 1989-01-19 Hoechst Ag SUBSTITUTED BENZIMIDAZOLES, METHOD FOR THE PRODUCTION THEREOF, THE PHARMACEUTICAL PREPARATIONS CONTAINING THEM AND THE USE THEREOF

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8911479A1 *

Also Published As

Publication number Publication date
AU3690289A (en) 1989-12-12
WO1989011479A1 (en) 1989-11-30
JPH03504497A (en) 1991-10-03

Similar Documents

Publication Publication Date Title
EP0201575B1 (en) New picoline derivatives, preparation process thereof, utilization thereof and drugs containing them
EP0134400B1 (en) Fluoroalkoxysubstituted pyridylmethylthio-(or sulfinyl-)benzimidazoles having a secretolytic activity
EP0080602A1 (en) Substituted benzimidazoles, process for their preparation, their use and medicaments containing them
EP0166287B1 (en) Dialkoxyridines, process for their preparation, their application and medicaments containing them
EP0127763B1 (en) Tricyclic ethers, process for their preparation, their use and medicaments containing them
DE60002855T2 (en) Haloalkoxy IMIDAZONAPHTHYRIDINE
DE2746244A1 (en) SPIRO-HYDANTOIN COMPOUNDS AND THEIR USE
WO2004014894A1 (en) Novel prodrugs of 1-methyl-2(4-amidinophenylaminomethyl)-benzimidazol-5-yl-carboxylic acid-(n-2-pyridil-n-2-hydroxycarbonylethyl)-amide, production and use thereof as medicaments
DE19513048C2 (en) New 5-pyrrolyl-6-halogen-2-pyridylmethylsulfinylbenzimidazole derivatives
DE2838892A1 (en) 2-SUBSTITUTED-5-HYDROXY-1H-IMIDAZOLE-4-CARBOXAMIDE DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND THE PHARMACEUTICAL PRODUCTS CONTAINING THEM
EP0415990A1 (en) New fluoralkoxy compounds
EP0198208A1 (en) Substituted benzimidazole derivatives, process for their preparation, pharmaceutical compositions containing them and their use as inhibitors of gastric-acid secretion
WO1991017164A1 (en) Novel pyridazines
WO1989005299A1 (en) Novel benzimidazole derivatives
DE3415971A1 (en) Acylated benzimidazoles, processes for their preparation, their use and medicaments containing them
DD262230A5 (en) PROCESS FOR PREPARING NEW DERIVATIVES OF 4,5-DIHYDRO-OXAZOLENE
EP0201094A2 (en) Thieno[2,3-d]imidazole derivatives and process for their preparation
WO1992006979A1 (en) New diazines
EP0232399A1 (en) New amines, process for their manufacture, their use and medicines containing them
EP0138034B1 (en) Substituted pyrido[1,2-c]imidazo[1,2-a]benzimidazoles, process for their preparation, their use and pharmaceutical preparations containing them
EP0882048B1 (en) 3-alkylimidazopyridines
EP0271733A2 (en) Substituted thienoimidazotoluidine derivatives, process for their preparation, pharmaceutical compositions containing them and their use as gastric-acid secretion inhibitors
EP0200777A1 (en) New amino compounds, preparation process thereof, utilization thereof and drugs containing them
EP0773944A1 (en) Benzyl-imidazopyridines
DE3827276A1 (en) SUBSTITUTED THIENOIMIDAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME AND THEIR USE AS AN INGESTIC ACID INHIBITOR

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19901119

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

17Q First examination report despatched

Effective date: 19930114

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19930525