WO2008058990A1 - Dérivés de pyrano-[2,3-c]-imidazo-[1,2-a]-pyridine 7,7-disubstitués et leur utilisation en tant qu'inhibiteurs de la sécrétion d'acide gastrique - Google Patents

Dérivés de pyrano-[2,3-c]-imidazo-[1,2-a]-pyridine 7,7-disubstitués et leur utilisation en tant qu'inhibiteurs de la sécrétion d'acide gastrique Download PDF

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Publication number
WO2008058990A1
WO2008058990A1 PCT/EP2007/062327 EP2007062327W WO2008058990A1 WO 2008058990 A1 WO2008058990 A1 WO 2008058990A1 EP 2007062327 W EP2007062327 W EP 2007062327W WO 2008058990 A1 WO2008058990 A1 WO 2008058990A1
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WIPO (PCT)
Prior art keywords
imidazo
dihydro
phenyl
pyrano
pyridin
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PCT/EP2007/062327
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English (en)
Inventor
Wilm Buhr
Peter Jan Zimmermann
Christof Brehm
Andreas Palmer
Wolfgang-Alexander Simon
Stefan Postius
Wolfgang Kromer
Georg Rast
Udo DÖLLING
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Nycomed Gmbh
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Publication of WO2008058990A1 publication Critical patent/WO2008058990A1/fr

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    • 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
    • C07D491/12—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 three hetero rings
    • C07D491/14—Ortho-condensed systems

Definitions

  • the invention relates to novel compounds which are used in the pharmaceutical industry as active compounds for the production of medicaments.
  • U.S. Patent 4,468,400 describes tricyclic imidazo[1 ,2-a] pyridines having different ring systems fused to the imidazopyridine skeleton, which compounds are said to be suitable for treating peptide ulcer disorders.
  • the International Patent Applications WO 95/27714, WO 98/42707, WO 98/54188, WO 00/17200, WO 00/26217, WO 00/50037, WO 00/63211 , WO 01/72756, WO 01/72754, WO 01/72755, WO 01/7 '27 '57 ' , WO 02/34749, WO 03/014120, WO 03/016310, WO 03/014123, WO 03/068774, WO 03/091253, WO 05/058325, WO 05/090358, WO 05/077949, WO 06/040338 and WO 06/13411 1 disclose tricyclic imidazopyridine derivatives having
  • WO 01/72754 describes inter alia different tricyclic imidazopyridine derivatives having a quarternary carbon atom in the tricyclic ring structure.
  • PPI ' s proton pump inhibitors
  • rPPI ' s reversible proton pump inhibitors
  • APA ' s acid pump antagonists
  • P-CAB ' s potassium competitive acid blockers
  • the invention relates to compounds of the formula 1
  • R1 is methyl
  • R2 is hydrogen, methyl or chloro
  • R3 is methyl, ethyl, cyclopropyl or ethenyl
  • R4 is methyl, ethyl, methoxyethyl or 2,2,2-trifluoroethyl, and their salts.
  • Possible salts of compounds of the formula 1 - depending on substitution - are especially all acid addition salts. Particular mention may be made of the pharmacologically tolerable salts of the inorganic and organic acids customarily used in pharmacy. Those suitable are water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, malonic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid, trifluoracetic acid, ascorbic acid, lactic acid, D-glucuronic acid, lactobionic acid (4-O-bet
  • Salts of the compounds of formula I according to the invention can be obtained by dissolving, the free compound in a suitable solvent (for example a ketone such as acetone, methylethylketone or methyli- sobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol) which contains the desired acid or to which the desired acid is then added, if necessary upon heating.
  • a suitable solvent for example a ketone such as acetone, methylethylketone or methyli- sobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight alipha
  • the acid can be employed in salt preparation, depending on whether a mono- or polybasic acid is concerned and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom.
  • the salts are obtained for example by evaporating the solvent or by precipitating upon cooling, by re-precipitating, or by precipitating with a non-solvent for the salt and separation, for example by filtration, of the salt after precipitation.
  • Pharmacologically intolerable salts which can initially be obtained, for example, as process products in the production of the compounds according to the invention on the industrial scale, are converted into the pharmacologically tolerable salts by processes known to the person skilled in the art.
  • the invention therefore also comprises all solvates and in particular all hydrates of the compounds of the formula 1 , and also all solvates and in particular all hydrates of the salts of the compounds of the formula 1.
  • the compounds of the formula 1 have a three centers of chirality in the basic skeleton.
  • the invention thus relates to all feasible stereoisomers in any desired mixing ratio to another, including the pure stereoisomers, which are a preferred subject of the invention.
  • the invention therefore particularly relates to all of the following stereoisomers of the following formulae 1-a, 1-b, 1-c and 1-d:
  • the pure stereoisomers of the compounds of the formula 1 and salts according to the present invention can be obtained e.g. by asymmetric synthesis, by using chiral starting compounds in synthesis or by splitting up stereoisomeric mixtures obtained in synthesis.
  • Stereoisomeric mixtures of compounds of the formula 1 can be split up into the pure stereoisomers by methods known to a person skilled in the art.
  • the mixtures are separated by chromatogra- phy or (fractional) crystallization.
  • the split up is preferably done by forming diastereomeric salts by adding chiral additives like chiral acids, subsequent resolution of the salts and release of the desired compound from the salt.
  • derivatization with chiral auxiliary reagents can be made, followed by diastereomer separation and removal of the chiral auxiliary group.
  • enantiomeric mixtures can be separated using chiral separating columns in chromatography. Another suitable method for the separation of enantiomeric mixtures is the enzymatic separation.
  • Exemplary preferred compounds according to the invention are those compounds of the formulae 1 , 1-a, 1-b, 1-c and 1-d, in which R1 , R2, R3 and R4 have the meanings as given in the following Table A, and the salts of these compounds. These compounds are either described by way of example as final products or can be prepared in an analogous manner using for example the process steps described below.
  • the invention therefore relates to compounds of the formula 1 , in which R1 , R2, R3 and R4 have the meanings as given in the following Table A, and the salts of these compounds.
  • the invention furthermore relates to compounds of the formula 1-a, in which R1 , R2, R3 and R4 have the meanings as given in the following Table A, and the salts of these compounds.
  • the invention furthermore relates to compounds of the formula 1-b, in which R1 , R2, R3 and R4 have the meanings as given in the following Table A, and the salts of these compounds.
  • the invention furthermore relates to compounds of the formula 1-c, in which R1 , R2, R3 and R4 have the meanings as given in the following Table A, and the salts of these compounds.
  • the invention furthermore relates to compounds of the formula 1-d, in which R1 , R2, R3 and R4 have the meanings as given in the following Table A, and the salts of these compounds.
  • Table A :
  • R1 , R2, R3 and R4 have the meanings as given in Table A, and the salts of these compounds.
  • Exemplary particularly preferred compounds according to the invention are those described by way of example and the salts of these compounds.
  • the compounds according to the invention can be synthesized from corresponding starting compounds, for example according to the reaction schemes given below.
  • the synthesis is carried out in a manner known to the expert, for example as described in more detail in the following examples.
  • route I and route II There are two synthesis routes (route I and route II) for the synthesis of compounds of the general formula 1.
  • Starting materials for route I and route Il are compounds of the formula 2.
  • the synthesis of the compounds of the formula 2 are described inter alia in the International patent applications WO 98/54188, WO 01/72755 and WO 02/34749.
  • compounds of formula 2 are alkylated by Grignard reaction with R3MgX wherein X is a halogen radical, like for example Br or Cl, as described for example in the International patent application WO 98/54188 (e.g. using R3MgBr or R3MgCI) to give compounds of formula 3.
  • R3 ethyl
  • the Grignard reaction took place with vinyl magnesium bromide, followed by hydrogenation with Palladium on carbon by using standard conditions.
  • the alkylation of compounds of the formula 2 can be performed by using lithium organic compounds (e.g. using R3U), which are familiar to the person skilled in the art.
  • the compounds of formula 3 are etherified in a subsequent step under acidic conditions with alcohols of the formula R4- OH to give the final compounds of formula 1.
  • the compounds of formula 5 can be obtained by alkylation with lithium organic compounds (e.g. using R3U), which are familiar to the person skilled in the art. Afterwards these compounds of the formula 5 are etherified by using organic triflate compounds of the formula TfO-R4, which are familiar to the person skilled in the art, to compounds of formula 6.
  • Scheme 2 :
  • the syntheses as shown in Schemes 1 , 2 or 3 can provide individual stereoisomers or mixtures of selected, individual stereoisomers of compounds of the formula 1 , for example by starting from one individual stereoisomer of the compounds of the formula 2.
  • each stereoisomer of the final compounds of the formula 1 can be synthesized.
  • the emphasized optically pure compounds of the formula 1-a can be obtained by following the reaction sequences described in the schemes above (preferably route II) by starting from compounds of the formula 2-a as shown in abbreviated form in scheme 4.
  • reaction steps outlined above are carried out in a manner known per se, e.g. as described in more detail in the examples.
  • the excellent gastric protective action and the gastric acid secretion-inhibiting action of the compounds according to the invention can be demonstrated in investigations on animal experimental models, like for example the rat and dog models described below.
  • the compounds of the formula 1 according to the invention investigated in the model mentioned below have been provided with numbers, which correspond to the numbers of these compounds in the examples. 1 ) Testing of the secretion-inhibiting action on the perfused rat stomach
  • the substances to be tested were administered intraduodenally in a 2.5 ml/kg liquid volume 60 min after the start of the continuous pentagastrin infusion.
  • the body temperature of the animals was kept at a constant 37.8-38 0 C by infrared irradiation and heat pads (automatic, stepless control by means of a rectal temperature sensor).
  • the animals held in groups of 2-4 animals/group, were housed at 20-23 0 C, 55-65% relative humidity of the air and under natural daylight / dark-rhythm. Usually, depending on the weather, the animals had daily outside runout in groups. Once per week, body weight and general condition were registered and the fistula region was examined. The animals were used for experiments at intervals not shorter than 7 days.
  • the dogs received standard dog diet "Hundeextrudat” Nr 3358 (Provimi Kliba, Kaiseraugst, Switzerland), once daily at 10 a.m. with tap water ad libitum. 20-22 hours prior to and during the day of the experiment, the animals were fasted.
  • the animals had been chronically instrumented at an age of 1-2 years.
  • a metallic (V4a) fistula was placed at the lowest part of the gastric corpus near the greater curvature. The animals recovered quickly and were trained for the study conditions not earlier than 4-6 weeks after the operation.
  • pentagastrin (6 ⁇ g/kg/h in an infusion volume of 0.33 ⁇ l/kg/min) was infused by pump subcutaneously, using an Abbocath-catheter placed subcutaneously and savely secured by tape on the distal part of the dog's back.
  • pH readings (86400 readings within 24 hours, each covering 1 second) were transferred to a PC by special software (Polygram98, Medtronics, 40547 D ⁇ sseldorf, Germany), yielding individual 24 hour pH-profiles.
  • Polygram98 Medtronics, 40547 D ⁇ sseldorf, Germany
  • pH-profiles Applying a second program (StatpHac2000, the novel, Win- dows2000- and Polygram98- compatible version programmed by Leif Fransson, Karlskrona, Sweden), the individual pH-profiles of one treatment group were processed to establish pH-medians for intervals of 10 minutes each, covering a total of 24 hours (144 x 10 min).
  • the crude product was purified by column chromatography (ethyl acetate / cyclohexane: 3 / 1 ) and crystallized from n- pentane to give 20 mg (0.05 mmol / 20 %) of the title product.
  • the compounds of the formulae 1 , 1-a, 1-b, 1-c and 1-d and their pharmaceutically acceptable salts have valuable pharmacological properties which make them commercially utilizable. In particular, they exhibit marked inhibition of gastric acid secretion and an excellent gastric and intestinal protective or curative action in warm-blooded animals, and consequently in particular humans.
  • the active compounds according to the invention are distinguished by a high selectivity of action, a fast onset of action, an advantageous duration of action, efficient control of the duration of action by the dosage, a particularly good antisecretory efficacy, the absence of significant side effects and a large therapeutic range.
  • the active compounds according to the present invention are particularly distinguished by an excellent efficacy with regard to inhibition of gastric acid secretion, especially with regard to the efficacy in different warm-blooded animal models.
  • the compounds according to the present invention show an excellent efficacy with regard to inhibition of gastric acid secretion in more than one warm-blooded animal model, especially where the warm-blooded animals used in these different models are selected from different species. This in turn leads to a more reliable prediction for the efficacy with regard to inhibition of gastric acid secretion in further warm-blooded animals, and consequently also in humans.
  • Gastric and intestinal protection or cure in this connection is understood to include, according to general knowledge, the prevention, the treatment and the maintenance treatment of gastrointestinal diseases, in particular of gastrointestinal inflammatory diseases and lesions (such as, for example, reflux esophagitis, gastritis, hyperacidic or drug-related functional dyspepsia, and peptic ulcer disease [including peptic ulcer bleeding, gastric ulcer, duodenal ulcer]), which can be caused, for example, by microorganisms (e.g. Helicobacter pylori), bacterial toxins, drugs (e.g. certain antiinflammatories and antirheumatics, such as NSAIDs and COX-inhibitors), chemicals (e.g. ethanol), gastric acid or stress situations.
  • gastrointestinal inflammatory diseases and lesions such as, for example, reflux esophagitis, gastritis, hyperacidic or drug-related functional dyspepsia, and peptic ulcer disease [including peptic ulcer bleeding, gastric ulcer, duo
  • gastrointestinal diseases is understood to include, according to general knowledge,
  • GSD gastroesophageal reflux disease
  • GERD extra-esophageal manifestations of GERD that include, but are not limited to, acid-related asthma, bronchitis, laryngitis and sleep disorders.
  • C) other diseases that can be connected to undiagnosed reflux and/or aspiration include, but are not limited to, airway disorders such as asthma, bronchitis, COPD (chronic obstructive pulmonary disease).
  • gastrointestinal diseases comprise other gastrointestinal conditions that might be related to acid secretion, such as Zollinger-Ellison syndrome, acute upper gastrointestinal bleeding, nausea, vomiting due to chemotherapy or post-operative conditions, stress ulceration, IBD (inflammatory bowel disease) and particularly IBS (irritable bowel syndrome).
  • the active compounds according to the invention surprisingly prove to be clearly superior to the compounds known from the prior art in various models in which the antiulcero- genic and the antisecretory properties are determined.
  • the active compounds according to the invention are outstandingly suitable for use in human and veterinary medicine, where they are used, in particular, for the treatment and/or prophylaxis of disorders of the stomach and/or intestine and/or upper digestive tract, particularly of the abovementioned diseases.
  • a further subject of the invention are therefore the active compounds according to the invention for use in the treatment and/or prophylaxis of the abovementioned diseases.
  • the invention likewise includes the use of the active compounds according to the invention for the production of medicaments which are employed for the treatment and/or prophylaxis of the above- mentioned diseases.
  • the invention furthermore includes the use of the active compounds according to the invention for the treatment and/or prophylaxis of the abovementioned diseases.
  • a further subject of the invention are medicaments which comprise one or more active compounds according to the invention.
  • the invention further relates to a compound according to the invention or a pharmaceutically acceptable salt thereof, for the treatment and/or prophylaxis of gastrointestinal disorders.
  • the invention further relates to a pharmaceutical composition, comprising a compound according to the invention or a pharmaceutically acceptable salt thereof, for the treatment and/or prophylaxis of gastrointestinal disorders.
  • the active compounds according to the invention are either employed as such, or preferably in combination with suitable pharmaceutical excipients in the form of tablets, coated tablets (e.g. film-coated tablets), multi unit particulate system tablets, capsules, suppositories, granules, powders (e.g. lyophilized compounds), pellets, patches (e.g. as TTS [transdermal therapeutic system]), emulsions, suspensions or solutions.
  • suitable pharmaceutical excipients in the form of tablets, coated tablets (e.g. film-coated tablets), multi unit particulate system tablets, capsules, suppositories, granules, powders (e.g. lyophilized compounds), pellets, patches (e.g. as TTS [transdermal therapeutic system]), emulsions, suspensions or solutions.
  • the content of the active compound is advantageously being between 0.1 and 95wt% (weight percent in the final dosage form), preferably between 1 and 60wt%.
  • ad- ministration form adapted to the active compound and/or to the desired onset and/or duration of action (e.g. a sustained release form or a delayed release form).
  • the active compounds according to the invention can be administered orally, parenterally (e.g. intravenously), rectally or percutaneously. Oral or intravenous administration is preferred.
  • excipients or combinations of excipients which are suitable for the desired pharmaceutical formulations are known to the person skilled in the art on the basis of his/her expert knowledge and are composed of one or more accessory ingredients.
  • solvents antioxidants, stabilizers, surfactants, complexing agents (e.g. cyclodextrins)
  • excipients may be mentioned as examples:
  • gelling agents antifoams, plasticizer, adsorbent agents, wetting agents, colorants, flavorings, sweeteners and/or tabletting excipients (e.g.
  • carriers for intravenous administration, dispersants, emulsifiers, preservatives, solubilizers, buffer substances and/or isotonic adjusting substances.
  • dispersants for intravenous administration, the person skilled in the art may choose as excipients, for example: solvents, gelling agents, polymers, permeation promoters, adhesives, matrix substances and/or wetting agents.
  • a daily dose (given continuously or on-demand) of approximately 0.01 to approximately 20, preferably 0.02 to 5, in particular 0.02 to 1.5, mg/kg of body weight, if appropriate in the form of several, preferably 1 to 2, individual doses to achieve the desired result.
  • a parenteral treatment similar or (in particular in the case of the intravenous administration of the active compounds), as a rule, lower doses can be used.
  • the frequency of administration can be adapted to intermittent, weekly, monthly, even more infrequent (e.g. implant) dosing.
  • the establishment of the optimal dose and manner of administration of the active compounds necessary in each case can easily be carried out by any person skilled in the art on the basis of his/her expert knowledge.
  • the medicaments may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmaceutical science. All methods include the step of bringing the active compounds according to the invention into association with the excipients or a combination of excipients. In general the formulations are prepared by uniformly and intimately bringing into association the active compounds according to the invention with liquid excipients or finely divided solid excipients or both and then, if necessary, formulating the product into the desired medicament.
  • the active compounds according to the invention or their pharmaceutical preparations can also be used in combination with one or more pharmacologically active constituents from other groups of drugs [combination partner(s)].
  • “Combination” is understood to be the supply of both the active compound ⁇ ) according to the invention and the combination partner(s) for separate, sequential, simultaneous or chronologically staggered use.
  • a combination is usually designed with the aim of increasing the principal action in an additive or super-additive sense and/or of eliminating or decreasing the side effects of the combination partner(s), or with the aim to obtain a more rapid onset of action and a fast symptom relief.
  • the drug release profile of the components can be exactly adapted to the desired effect, e.g. the release of one compound and its onset of action is chronologically previous to the release of the other compound.
  • a combination can be, for example, a composition containing all active compounds (for example a fixed combination) or a kit-of-parts comprising separate preparations of all active compounds.
  • a “fixed combination” is defined as a combination wherein a first active ingredient and a second active ingredient are present together in one unit dosage or in a single entity.
  • a “fixed combination” is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture of simultaneous administration, such as in a formulation.
  • Another example of a "fixed combination” is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture.
  • kits-of-parts is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit.
  • a “kit-of-parts” is a combination wherein the said first active ingredient and the said second active ingredient are present separately.
  • the components of the kit-of-parts may be administered separately, sequentially, simultaneously or chronologically staggered.
  • “Other groups of drugs” are understood to include, for example: tranquillizers (for example from the group of the benzodiazepines, like diazepam), spasmolytics (for example butylscopolaminium bromide [Buscopan®]), anticholinergics (for example atropine sulfate, pirenzepine, tolterodine), pain perception reducing or normalizing agents (for example, paracetamol, tetracaine or procaine or especially oxeta- cain), and, if appropriate, also enzymes, vitamins, trace elements or amino acids.
  • tranquillizers for example from the group of the benzodiazepines, like diazepam
  • spasmolytics for example butylscopolaminium bromide [Buscopan®]
  • anticholinergics for example atropine sulfate, pirenzepine, tolterodine
  • pain perception reducing or normalizing agents for example, paraceta
  • histamine-H2 blockers e.g. cimetidine, ranitidine
  • peripheral anticholinergics e.g. pirenzepine
  • gastrin antagonists such as CCK2 antagonists (cholestocystokinin 2 receptor antagonists).
  • CCK2 antagonists cholestocystokinin 2 receptor antagonists.
  • cephalosporins such as, for example, cifuroximaxetil
  • (B) penicillines such as, for example, amoxicillin, ampicillin
  • (E) macrolide antibiotics such as, for example, erythromycin, clarithromycin, azithromycin
  • glycoside antibiotics such as, for example, gentamicin, streptomycin
  • gyrase inhibitors such as, for example, ciprofloxaxin, gatifloxacin, moxifloxacin
  • I oxazolidines, such as, for example, linezolid
  • nitrofuranes or nitroimidazoles such as, for example, metronidazole, tinidazole, nitrofurantoin
  • K bismuth salts, such as, for example, bismuth subcitrat (L) other antibacterially active substances and combinations of substances selected from (A) to (L), for example clarithromycin + metronidazole.
  • Preferred is the use of two combination partners. Preferred is the use of two combination partners selected from amoxicillin, clarithromycin and metronidazole. A preferred example is the use of amoxicillin and clarithromycin.
  • the active compounds according to the invention are especially suited for a free or fixed combination with drugs, which are known to cause "drug-induced dyspepsia" or are known to have a certain ulcerogenic potency, such as, for example, acetylsalicylic acid, certain antiinflammatories and antirheumatics, such as NSAIDs (non-steroidal antiinflammatory drugs, e.g. etofenamate, diclofenac, indometacin, ibupro- fen, piroxicam, naproxen, meloxicam), oral steroids, bisphosponates (e.g. alendronate), or even NO- releasing NSAIDs, COX-2 inhibitors (e.g. celecoxib, lumiracoxib).
  • drugs which are known to cause "drug-induced dyspepsia” or are known to have a certain ulcerogenic potency, such as, for example, acetylsalicylic acid, certain antiinflammatories and anti
  • the active compounds according to the invention are suited for a free or fixed combination with motility-modifying or -regulating drugs (e.g. gastroprokinetics like mosapride, tegaserod, itopride, metoclopramid), and especially with pharmaceuticals which reduce or normalize the incidence of transient lower esophageal sphincter relaxation (TLESR), such as, for example, GABA-B agonists (e.g. baclofen, (2R)-3-amino-2-fluoropropylphosphinic acid) or allosteric GABA-B agonists (e.g.
  • motility-modifying or -regulating drugs e.g. gastroprokinetics like mosapride, tegaserod, itopride, metoclopramid
  • pharmaceuticals which reduce or normalize the incidence of transient lower esophageal sphincter relaxation (TLESR) such as, for example, GABA-B agonists (e.g. baclofen
  • GABA re-uptake inhibitors e.g. tiagabine
  • metabotropic glutamate receptor type 5 (mGluR5) antagonists e.g. 2-methyl-6- (phenylethynyl)pyridine hydrochloride
  • CB1 (cannabinoid receptor) agonists e.g. [(3R)-2,3-dihydro-5- methyl-3-(4-morpholinyl-methyl)pyrrolo[1 ,2,3,de]-1 ,4-benzoxazin-6-yl]-1-naphthalenyl-methanone mesylate).
  • compositions used for the treatment of IBS or IBD are also suitable combination partners), such as, for example: 5-HT4 receptor agonists like mosapride, tegaserod; 5-HT3 receptor antagonists like alosetron, cilansetron; NK2 antagonists like saredutant, nepadutant; ⁇ -opiate agonists like fedotozine.
  • 5-HT4 receptor agonists like mosapride, tegaserod
  • 5-HT3 receptor antagonists like alosetron, cilansetron
  • NK2 antagonists like saredutant, nepadutant
  • ⁇ -opiate agonists like fedotozine.
  • Suitable combination partner(s) also comprise airway therapeutica, for example for the treatment of acid-related asthma and bronchitis.
  • a hypnotic aid such as, for example, Zolpidem [Bikalm®]
  • combination partner(s) may be rational, for example for the treatment of GERD-induced sleep disorders.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés représentés par la formule (1), dans laquelle les substituants et les symboles sont tels que définis dans la description. Les composés inhibent la sécrétion de l'acide gastrique.
PCT/EP2007/062327 2006-11-16 2007-11-14 Dérivés de pyrano-[2,3-c]-imidazo-[1,2-a]-pyridine 7,7-disubstitués et leur utilisation en tant qu'inhibiteurs de la sécrétion d'acide gastrique WO2008058990A1 (fr)

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WO2008114123A1 (fr) * 2007-03-21 2008-09-25 Raqualia Pharma Inc. Dérivés de spiro benzimidazole comme inhibiteurs de pompe à acide
WO2011004882A1 (fr) 2009-07-09 2011-01-13 ラクオリア創薬株式会社 Antagoniste de la pompe à acide destiné au traitement de maladies associées à un transit gastro-intestinal anormal

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WO2002034749A1 (fr) * 2000-10-25 2002-05-02 Altana Pharma Ag Imidazopyridines polysubstituees utilisees comme inhibiteurs des secretions gastriques

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WO2001072754A1 (fr) * 2000-03-29 2001-10-04 Altana Pharma Ag Derives imidazopyridine alkyles
WO2002034749A1 (fr) * 2000-10-25 2002-05-02 Altana Pharma Ag Imidazopyridines polysubstituees utilisees comme inhibiteurs des secretions gastriques

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* Cited by examiner, † Cited by third party
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WO2008114123A1 (fr) * 2007-03-21 2008-09-25 Raqualia Pharma Inc. Dérivés de spiro benzimidazole comme inhibiteurs de pompe à acide
WO2011004882A1 (fr) 2009-07-09 2011-01-13 ラクオリア創薬株式会社 Antagoniste de la pompe à acide destiné au traitement de maladies associées à un transit gastro-intestinal anormal

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