Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • 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
• • 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
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• the invention relates to new diazoles, 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 imidazole compounds of the formula I.
• R1 is hydrogen (H) or halogen
• R2 is hydrogen (H), 1-4C-alkyl, hydroxy-1-4C-alkyl, halo-1-4C-alkyl,
• R3 is hydrogen (H), 1-4C-alkyl, formyl, hydroxy-1-4C-alkyl,
• Halo-1-4C-alkyl cyano-1-4C-alkyl, amino-1-4C-alkyl, mono- or di-1-4C-alkylam ⁇ no-1-4C-alkyl, nitroso, nitro, amino, mono- or Di-1-4C-alkylamino or 1-4C-A1 koxycarbonyl,
• R4 is hydrogen (H), 1-4C-alkyl, 1-4C-alkoxy, halogen or trifluoro-. methyl,
• R5 is hydrogen (H), 1-4C-alkyl, 1-4C-alkoxy, halogen or trifluoromethyl,
• R6 is hydrogen or 1-4C-alkyl, n is the number 1 or 2,
• G2 0 oxygen
• NH amino acid
• N-1-4C-alkyl or 1-4C-alkylene
• G3 1-hydroxy-trimethylene (-CH (OH) -CH 2 -CH 2 -), 2-hydroxy-3-methyl-trimethylene (-CH 2 -CH (OH) -CH (CH 3 ) -), 2-Hydroxy-trimethylene (-CH 2 -CH (OH) -CH 2 -), 1-hydroxy-tetramethyl en (-CH (OH) -CH 2 -CH 2 -), 2-hydroxy-tetramethyl en (-CH 2 -CH (OH) -CH 2 -CH 2 -), 1-hydroxy-pentamethylene (-CH (OH) -CH 2 -CH 2 -CH 2 -CH 2 -) or 2-hydroxy- pentamethylene (-CH 2 -CH (OH) -CH 2 -CH 2 -CH 2 -) and
• Halogen in the sense of the present invention is bromine and in particular chlorine and fluorine.
• 1-4C-Alkyl stands for straight-chain or branched alkyl radicals with 1 to 4 carbon atoms. Examples include butyl, isobutyl, sec-butyl, tert. -Butyl, propyl, isopropyl, ethyl and especially the methyl radical.
• 1-4C-ATkoxy residues contain one of the aforementioned 1-4C-alkyl residues in addition to the oxygen atom.
• the methoxy radical is preferred.
• 1-4C-alkoxycarbonyl radicals contain one of the 1-4C-alkyl radicals mentioned above.
• the methoxycarbonyl and the ethoxvcarbonyl radical are preferred.
• Hydroxy-1-4C-alkyl stands for the abovementioned 1-4C-alkyl radicals to which a hydroxyl radical is attached. The hydroxymethyl radical is preferred.
• Halo-1-4C-alkyl stands for the above-mentioned 1-4C-alkyl radicals to which a halogen atom is bonded.
• the chloromethyl residue is preferred.
• Cyano-1-4C-alkyl stands for the above-mentioned 1-4C-alkyl radicals to which a cyano radical is attached.
• the cyanomethyl radical is preferred.
• Amino-1-4C-alkyl stands for the abovementioned 1-4C-alkyl radicals to which an amino group is attached.
• Mono- or di-1-4C-alkylamino stands for amino groups which are substituted by one or two of the 1-4C-alkyl radicals mentioned above.
• the methylamino, ethylamino, diisopropylamino and especially the dimethyl amino group may be mentioned.
• Mono- or di-1-4C-alkylamino-1-4C-alkyl represents the abovementioned 1-4C-alkyl radicals to which one of the abovementioned mono- or di-1-4C-alkylamino groups is bonded.
• the dimethylaminomethyl and dimethylaminoethyl radicals are preferred.
• 1-4C-alkylene stands for straight-chain alkylene radicals with 1 to 4 carbon atoms.
• the preferred alkylene radicals are the ethylene radical (-CH 2 -CH 2 -) and the methylene radical (-CH 2 -).
• Preferred salts for compounds of the formula I are, on the one hand, all acid addition salts. Particular mention should be made of the pharmacologically acceptable salts of the inorganic and organic acids commonly used in galenics.
• Pharmacologically incompatible salts which may initially be obtained as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art.
• Suitable as such are, for example, water-soluble and water-insoluble acid addition salts, such as the hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulfosalicylate, maleate, laurate, malate, fumarate, succinate Oxalate, tartrate, amsonate, embonate, metembonate, stearate, tosylate, 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate or mesylate.
• water-soluble and water-insoluble acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulfo
• quaternary ammonium salts can also be considered as salts, which can be obtained by reacting compounds of the formula I with suitable alkylating agents.
• suitable alkylating agents are 1-4C-alkyl halides, preferably methyl iodide, or benzyl halides, such as benzyl bromide, or allyl halides, such as allyl bromide.
• suitable as salts are all alcoholates which can be obtained by reacting the compounds of the formula I with suitable deprotonating agents (e.g. strong bases).
• suitable deprotonating agents are metal-organic compounds, such as butyllithium, or alkali metal hydrides, such as sodium hydride.
• the invention relates in particular to those compounds of the formula I in which the grouping G2 is linked to a carbon atom of the alkylene group G3 which is in direct proximity to a hydroxyl-substituted carbon atom.
• the compounds according to the invention have at least two asymmetric carbon atoms in group G3.
• the invention encompasses all conceivable configuration combinations, ie when there are two asymmetry centers, the R, R, R, S, S, R and S, S combinations.
• the optically pure compounds of formula I are preferred subject of the invention.
• R1 hydrogen, chlorine or fluorine
• R2 is hydrogen, methyl, ethyl, hydroxymethyl, chloromethyl, cyanomethyl, methoxycarbonyl or ethoxycarbonyl,
• R3 is hydrogen, methyl, formyl, hydroxymethyl, chloromethyl, cyanomethyl, dimethylaminomethyl, amino, dimethylamino, methoxycarbonyl or ethoxycarbonyl,
• R4 is hydrogen, methyl, methoxy, chlorine, fluorine or trifluoromethyl
• R5 is hydrogen, methyl, methoxy, chlorine or fluorine
• R6 is hydrogen or methyl, n is the number 1 or 2,
• G2 0 oxygen
• NH NH
• R1 is hydrogen, chlorine or fluorine
• R2 is hydrogen, methyl, ethyl or hydroxymethyl
• R3 hydrogen, methyl, formyl, hydroxymethyl, cyanomethyl or amino
• R4 hydrogen, methyl, ethyl, methoxy, ethoxy, chlorine, fluorine or trifluoromethyl
• R5 hydrogen, methyl, ethyl, chlorine or fluorine, G1 CH
• G6 denotes -CH 2 -, -CH (CH 3 ) -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -, and their salts.
• R1 is hydrogen or halogen
• R3 is hydrogen, 1-4C-alkyl, formyl, hydroxymethyl, cyanomethyl or amino,
• R4 is hydrogen or halogen
• G2 0 oxygen or NH
• G6 means -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -, and their salts.
• Preferred compounds according to the invention are those of the formula I * in which
• R3 is hydrogen, methyl, hydroxymethyl, cyanomethyl or amino
• R4 is hydrogen or fluorine
• G6 means -CH 2 - or -CH 2 CH 2 - and their salts.
• the invention further relates to a process for the preparation of the compounds according to the invention and their salts.
• the process is characterized in that
• the type of reaction of the imidazopyridines II with the bicycles III depends on the structures of the (reactive) groups G5, X and Z, which in turn are dependent on the desired group G2.
• the following (reactive) groups may be mentioned:
• G2 0 (oxygen)
• X OH
• Z halogen
• G2 N-1-4C-alkyl
• X NH-1-4C-alkyl
• Z halogen
• G2 1-4C-alkylene
• the reaction of II with III is carried out in suitable, inert solvents, the condensation with elimination of H-halogen requiring the presence of a suitable base or prior deprotonation (for example with a hydride such as sodium hydride).
• the reaction with the imidazopyridines II takes place in the presence of aluminum oxide or preferably in polar, proton-containing media in the presence of bases.
• Suitable proton-containing media are water and alcohols, preferably methanol, all or in admixture.
• Alkali or alkaline earth metal hydroxides, preferably alkali carbonates and tertiary organic amines may be mentioned as bases. Depending on the type, they can be used in excess or deficit, preferably in an amount of 0.1-2 moles.
• the reaction in polar media is carried out at temperatures from 0 ° to 100 ° C, preferably at 20 ° to 60 ° C.
• the epoxides can also be prepared from suitable precursors, for example halogen alcohols, in situ and combined with their reaction with compounds II in a one-pot process, using at least one further mole of base.
• suitable precursors for example halogen alcohols
• the substances according to the invention are isolated and purified in a manner known per se, for example by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary cleaning methods, such as, for example, column chromatography on a suitable support material.
• Acid addition salts are obtained by dissolving the free base in a suitable solvent, for example in a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid or to which the desired acid is then added.
• the salts are obtained by filtration, reprecipitation, precipitation with a non-solvent for the addition salt or by evaporation of the solvent.
• Salts obtained can be obtained by alkalization, e.g. with aqueous ammonia solution, are converted into the free bases, which in turn can be converted into acid addition salts. In this way, pharmacologically unacceptable acid addition salts can be converted into pharmacologically unacceptable acid addition salts.
• Quaternary ammonium salts are obtained in an analogous manner by dissolving the free base in a suitable solvent, e.g. in acetone, or in a chlorinated hydrocarbon, such as methylene chloride or chloroform, to which the desired alkylating agent is then added. These salts are also obtained by filtration, falling over, precipitation with a non-solvent for the addition salt or by evaporation of the solvent.
• a suitable solvent e.g. in acetone
• a chlorinated hydrocarbon such as methylene chloride or chloroform
• Alcoholates are obtained, for example, by reacting the compounds according to the invention with alkali metals or alkali metal hydrides.
• Enantiomerically pure compounds I are obtained, for example, by reacting enantiomerically pure bicycles III with the imidazopyridines II.
• the entiomerically pure compounds I with the trans configuration (such as, for example, la '' ', la' '' ', Ib' '' and Ib '"' ) is obtained as trans addition products, preferably by reacting the corresponding enantiomerically pure epoxides with the imidazopyridines II.
• the (enantiomerically pure) compounds I having a cis configuration are, for example, by Epimerization of the trans-configuration isomers accessible, for example, starting from the corresponding mesylate, by reaction with potassium acetate in the presence of a crown ether and subsequent saponification.
• the starting compounds II are known from the literature or can be used in analogy to methods known from the literature, for example in analogy to JJ Kaminski et al. [J.Med.Chem. 28, 876 (1985)] or as in European patent applications 33 094 or 68 378 can be produced.
• the starting compounds II are also known from the literature [see, for example, GH Posner et al., J. Amer. Chem. Soc. 99: 8214 (1977); MN Akhtar et al., J. Chem. Soc. Perk. Trans. I (1979) 2437; DR Boyd et al., J. Chem. Soc. Perk. Trans. I (1982) 2767 and Bull. Soc. Chim. (France) 11, 3092-3095 (1973)] or they can also be prepared analogously to methods known from the literature.
• Preferred embodiments of the method are those in which the substituents and symbols R1, R2, R3, R4, R5, R6, n, G1, G2, G3, G4 and G6 have the meanings given in the subclaims and the dependent claims.
• Example 1 obtained operation.
• the title compound is obtained as a viscous oil by reacting 2,3-dimethyl-8-hydroxyimidazo [1,2-a] pyridine with 1,2,3,4-tetrahydronaphthalene-1,2-oxide according to that given in Example 1 Get work done.
• Example 8 Analogously to Example 8, the title compound of melting point 198-200 ° C. is obtained by reducing 3-formyl-8- (2- (trans) -hydroxy-2,3-dihydro-1-indenylamino) -2-methylimidazo [1,2 -a] pyridine with sodium borohydride.
• the title compound of mp 205 ° C is obtained by reacting 3-formyl-8-hydroxy-2-methylimidazo [1,2-a] pyridine with 5-fluoro-indene-1,2-oxide according to the procedure given in Example 22 and recrystallization from methanol.
• Triethylamine reacted in 425 ml aqueous methanol (350 ml methanol + 75 ml water) at 50 ° C. After 8 h, the mixture is concentrated and the residue is taken up in 150 ml of water. After adding 4 g of sodium carbonate, the mixture is extracted with 4 x 100 ml of ethyl acetate. The organic phases are washed with 2 x 200 ml sodium carbonate solution and 4 x 200 ml water, dried over magnesium sulfate and concentrated.
• 1 g is added to a mixture of 5.1 g of anhydrous potassium acetate, 13.8 g of 1,4,7,10,13,16-hexaoxacyclooctadecane ("18-Crown-6") and 100 ml of anhydrous acetonitrile while stirring and excluding moisture 3-formyl-2-methyl-8- (2- (trans) - methylsulfonyloxy-2,3-dihydro-1-indenyloxy) imidazo [1,2-a] pyridine.
• the brownish suspension is heated to 70 ° C for 18 hours and refluxed for a further 10 hours. After cooling, the mixture is poured onto water and extracted several times with dichloromethane.
• Example A Analogously to Example A, 11.3 g of the title compound, melting at 148-150 ° C., are catalytically reduced by 19.0 g of 2,3-dimethyl-8-nitro-imidazo [1,2-a] pyridine, dissolved in 700 ml of methanol. receive.
• the compounds of the formula I and their salts have valuable pharmacological properties which make them commercially useful. In particular, they have an excellent gastric and intestinal protective effect in warm-blooded animals.
• the compounds according to the invention are distinguished by a high selectivity of action, the absence of essential side effects and a large therapeutic breadth.
• stomach and intestinal protection means the prevention and treatment of gastrointestinal diseases, in particular gastrointestinal inflammatory diseases and lesions (such as, for example, ulcer ventriculi, duodenal ulcer, gastritis, hyperacid or drug-induced irritable stomach), which are caused, for example, by microorganisms, bacterial toxins, Medications (e.g. certain anti-inflammatory drugs and anti-rheumatic drugs), chemicals (e.g. ethanol), stomach acid or stressful situations can be caused.
• gastrointestinal inflammatory diseases and lesions such as, for example, ulcer ventriculi, duodenal ulcer, gastritis, hyperacid or drug-induced irritable stomach
• Medications e.g. certain anti-inflammatory drugs and anti-rheumatic drugs
• chemicals e.g. ethanol
• the compounds according to the invention in their excellent properties, surprisingly prove to be clearly superior to the compounds known from the prior art on various models in which the antiulcerogenic and antisecretory properties are determined.
• the compounds of the formula I and their pharmacologically tolerable salts are outstandingly suitable for use in human and veterinary medicine, with them being used in particular for the treatment and / or prophylaxis of gastric and / or intestinal ulcer diseases.
• the invention therefore furthermore relates to the compounds according to the invention for use in the treatment and / or prophylaxis of the abovementioned diseases.
• the invention also includes the use of the compounds according to the invention for the production of medicaments which are used for the treatment and / or prophylaxis of the abovementioned diseases.
• the invention further comprises the use of the compounds according to the invention for the treatment and / or prophylaxis of the abovementioned diseases.
• the invention further relates to medicaments which contain one or more compounds of the formula I and / or their pharmacologically tolerable salts.
• the pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art.
• auxiliaries or excipients suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
• solvents for example antioxidants, dispersants, emulsifiers, defoamers, taste correctors, preservatives, solubilizers, dyes or in particular permeation promoters and complexing agents (e.g. cyclodextrins) can be used.
• the active ingredients can be administered orally, parenterally or percutaneously.
• the active ingredient (s) when administered orally in a daily dose of about 0.01 to about 20, preferably 0.05 to 5, in particular 0.1 to 1.5 mg / kg of body weight , if necessary in the form of several, preferably 1 to 4 individual doses to achieve the desired result.
• similar or generally lower doses in particular when the active compounds are administered intravenously
• the determination of the respectively required optimal dosage and type of application of the active substances can easily be done by any expert on the basis of his specialist knowledge.
• the pharmaceutical preparations can also contain one or more pharmacologically active constituents of other groups of medicaments, such as antacids, for example aluminum hydroxide, magnesium aluminate; Tranquilizers, such as benzodiazepines, for example diazepam; Spas molytics such as Bietamiverin, Camylofin; Anticholinergics such as oxyphencyclimine, phencarbamide; Local anesthetics, such as tetracaine, procaine; Antibiotics, such as penicillins, tetracyelines, etc. may also contain ferments, vitamins or amino acids.
• antacids for example aluminum hydroxide, magnesium aluminate
• Tranquilizers such as benzodiazepines, for example diazepam
• Spas molytics such as Bietamiverin, Camylofin
• Anticholinergics such as oxyphencyclimine, phencarbamide
• Local anesthetics such
• the combination of the compounds according to the invention with pharmaceuticals which inhibit acid secretion such as, for example, H 2 blockers (for example cimetidine, ranitidine), with so-called peripheral anticholinergics (for example pirenzepine, telenzepine, zolenzepine) with the aim of the main effect, should be emphasized in particular to reinforce in an additive or superadditive sense and / or to eliminate or reduce the side effects, or further with antibacterial substances (such as cephalosporins, tetracyclines, nalidixic acid, penicillins etc.) for combating Campylobacter pyloridis.
• H 2 blockers for example cimetidine, ranitidine
• peripheral anticholinergics for example pirenzepine, telenzepine, zolenzepine
• antibacterial substances such as cephalosporins, tetracyclines, nalidixic acid, penicillins etc.
• the excellent gastric protective effect and the gastric secretion-inhibiting effect of the compounds according to the invention can be demonstrated in studies on animal models.
• the compounds according to the invention investigated in the table below have been given numbers which correspond to the numbers of the examples.
• ED50 dose (interpolated) which 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 takes place in 24 hours fasting rats (female, 180-200 g, 4 animals per cage on a high grating) by pylorus ligation (under diethyl ether anesthesia) and oral application of 100 mg / 10 ml / kg acetylsalicylic acid.
• the substances to be tested are administered intraduodenally (2.5 ml / kg) immediately after the pylorus ligation.
• the wound is closed using Michel clips. 4 hours later, the animals were killed in ether rush by atlas dislocation and resection of the stomach.
• the stomach is opened along the large curvature and stretched out on a cork plate after the amount of gastric juice secreted (volume) and later its HCl content (titration with sodium hydroxide solution) is determined.
• volume the amount of gastric juice secreted
• HCl content titration with sodium hydroxide solution
• 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.

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• 1988
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