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WO2004113340A1 - Nouveau compose imidazopyridine iii presentant un effet therapeutique - Google Patents

Nouveau compose imidazopyridine iii presentant un effet therapeutique Download PDF

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Publication number
WO2004113340A1
WO2004113340A1 PCT/SE2004/001014 SE2004001014W WO2004113340A1 WO 2004113340 A1 WO2004113340 A1 WO 2004113340A1 SE 2004001014 W SE2004001014 W SE 2004001014W WO 2004113340 A1 WO2004113340 A1 WO 2004113340A1
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WIPO (PCT)
Prior art keywords
compound
formula
acid
compound according
diseases
Prior art date
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PCT/SE2004/001014
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English (en)
Inventor
Peter Nordberg
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AstraZeneca AB
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AstraZeneca AB
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Publication of WO2004113340A1 publication Critical patent/WO2004113340A1/fr
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    • 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
    • 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

Definitions

  • the present invention relates to a novel compound, and therapeutically acceptable salts thereof, which inhibit exogenously or endogenously stimulated gastric acid secretion and thus can be used in the prevention and treatment of gastrointestinal inflammatory diseases.
  • the invention relates to the compound of the invention for use in therapy; to processes for preparation of such new compound; to pharmaceutical compositions containing the compound of the invention, or a therapeutically acceptable salt thereof, as active ingredient; and to the use of the compound of the invention in the manufacture of medicaments for the medical use indicated above.
  • Substituted imidazo[l,2-a]pyridines useful in the treatment of peptic ulcer diseases, are known in the art, e.g. from EP-B-0033094 and US 4,450,164 (Schering Corporation); from EP-B-0204285 and US 4,725,601 (Fujisawa Pharmaceutical Co.); from WO99/55706 and WO99/55705 (AstraZeneca); from WO 03/018582 (AstraZeneca); and from publications by J. J. Kaminski et al. in the Journal of Medical Chemistry (vol. 28, 876-892, 1985; vol. 30, 2031-2046, 1987; vol. 30, 2047-2051, 1987; vol. 32, 1686-1700, 1989; and vol. 34, 533-541, 1991).
  • compound of the Formula I is particularly effective as inhibitor of the gastrointestinal H + , K + -ATPase and thereby as inhibitor of gastric acid secretion.
  • the present invention thus relates to a compound of Formula I
  • the end product of the Formula I is obtained either in neutral or salt form. Both the free base and the salts of the end product are within the scope of the invention.
  • such acids are used which form therapeutically acceptable salts.
  • hydrohalogen acids such as hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxyl or sulphonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, p-hydroxybensoic acid, embonic acid, methanesulphonic acid, ethanesulphonic acid, hydroxyethanesulphonic acid, halogenbensenesulphonic acid, toluenesulphonic acid or naphthalenesulphonic acid.
  • hydrohalogen acids such as hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxyl or
  • the present invention also provides the following process for the manufacture of the compound with Formula I.
  • a process for manufacture of compound with Formula I comprises the following steps:
  • R represents a Ci-Cg-alkoxy group or -NH 2
  • R can be hydrolyzed under standard conditions in the presence of an aqueous acid or a base, to the corresponding carboxylic acid compound of Formula HI
  • the acid and base can be selected from HC1, H2SO4 and NaOH.
  • compound of the Formula LTJ can be reacted with amino compound of Formula IV
  • a coupling reagent such as o-benzotriazol-l-yl-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU)
  • TBTU o-benzotriazol-l-yl-N,N,N',N'- tetramethyluronium tetrafluoroborate
  • the reaction can be carried out in an inert solvent, such as dimethylformamide (DMF), methylenchloride and acetonitrate, or a mixture thereof, under standard conditions.
  • DMF dimethylformamide
  • acetonitrate or a mixture thereof
  • the reaction according to step a) above can be carried out by hydrolyzing a compound of Formula TJ to the corresponding acid in the presence of NaOH in an aqueous alcohol, such as aqueous methanol or ethanol, at reflux for 1 to 3 hours.
  • an aqueous alcohol such as aqueous methanol or ethanol
  • a further process for producing the compound of the invention comprises the following compound of Formula V
  • R represents a Ci-C ⁇ -alkoxy group
  • the reaction can be carried out by heating the reactants in the neat amino compound or dissolved in an inert solvent under standard conditions, e.g. in an alcohol such as methanol, at elevated temperature, such as between 40 to 60 °C or at reflux.
  • the reaction can be performed in the presence of a base or a cyanide salt.
  • the reaction is performed in the presence of a base selected from l,8-diacabicyclo(5.4.0)undec-7-ene (DBU) or 1,5- diazabicyclo(4.3.0)non-5-ene (DBN).
  • a base selected from l,8-diacabicyclo(5.4.0)undec-7-ene (DBU) or 1,5- diazabicyclo(4.3.0)non-5-ene (DBN).
  • the reaction is performed in the presence of an alkoxide, such as sodium methoxide, potassium methoxide, or potassium ethoxide.
  • an alkoxide such as sodium methoxide, potassium methoxide, or potassium ethoxide.
  • the compound of Formula V is mixed with the compound of Formula IV in a solvent, such as an alcohol, for example methanol or ethanol.
  • the base is added to the heated reaction mixture and the reaction is completed at an elevated temperature, for example between 40 and 60 °C, or at reflux.
  • the base can be selected from, among others, potassium methoxide, or sodium methoxide.
  • the invention relates to the compound of Formula I for use in therapy.
  • the invention provides the use of a compound of Formula I in the manufacture of a medicament for the inhibition of gastric acid secretion, or for the treatment of gastrointestinal inflammatory diseases.
  • the compound according to the invention may thus be used for prevention and treatment of gastrointestinal inflammatory diseases, and gastric acid-related diseases in mammals including man, such as gastritis, reflux esophagitis, Zollinger-Ellison syndrome, and peptic ulcer disease including gastric ulcer and duodenal ulcer.
  • the compound may be used for treatment of other gastrointestinal disorders where gastric antisecretory effect is desirable, e.g. in patients with gastrinomas, and in patients with acute upper gastrointestinal bleeding.
  • the compound may also be used for effective control and treatment of heartburn and other Gastroesophageal Reflux Disease (GERD) symptoms (acute and maintenance symptomatic GERD, erosive esophagitis healing and maintenance), regurgitation, short and long-term management of acid reflux disease and nausea. They may also be used in patients in intensive care situations, and pre-and postoperatively to prevent acid aspiration and stress ulceration.
  • GFD Gastroesophageal Reflux Disease
  • the typical daily dose of the active substance varies within a wide range and will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease.
  • oral and parenteral dosages will be in the range of 5 to 1000 mg per day of active substance, preferably in the range of 20 to 60 mg, for example 50 mg.
  • the compound of the invention may be administered to the patient in a continuous treatment as well as on-demand treatment, depending on the individual requirements and the disease. By the compound of the invention possibilities to improve the quality of life for the individuals suffering from gastric acid related diseases and/or gastrointestinal inflammatory diseases are given.
  • the invention relates to pharmaceutical compositions containing the compound of the invention, or a therapeutically acceptable salt thereof, as active ingredient.
  • the compound of the invention is formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration.
  • the pharmaceutical formulation contains a compound of the invention in combination with one or more pharmaceutically acceptable ingredients.
  • the carrier may be in the form of a solid, semi-solid or liquid diluent, or a capsule.
  • These pharmaceutical preparations are a further object of the invention.
  • the amount of the compound of the invention is between 0.1-95% by weight of the preparation, preferably between 0.1-20% by weight in preparations for parenteral use and preferably between 0.1-50% by weight in preparations for oral administration.
  • the compound selected may be mixed with solid, powdered ingredients, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • Soft gelatin capsules may be prepared with capsules containing the compound of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules.
  • Hard gelatin capsules may contain granules of the compound of the invention.
  • Hard gelatin capsules may also contain the compound of the inventionin combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.
  • Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the compound of the invention mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule which contains the compound of the invention in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatin rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
  • Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing from 0.1% to 20% by weight of the compound of the invention and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, saccharine and carboxymethyl cellulose or other thickening agent. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
  • Solutions for parenteral administration may be prepared as a solution of the compound of the invention in a pharmaceutically acceptable solvent, preferably in a concentration from 0.1% to 10% by weight. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.
  • the compound according to the invention can also be used in formulations together with other active ingredients, e.g. for the treatment or prophylaxis of conditions involving infection by Helicobacter pylori of human gastric mucosa.
  • active ingredients may be antimicrobial agents, in particular: • ⁇ -lactam antibiotics such as amoxicillin, ampicillin, cephalothin, cefaclor or cefixime;
  • tetracyclines such as tetracycline or doxycycline
  • aminoglycosides such as gentamycin, kanamycin or amikacin
  • quinolones such as norfloxacin, ciprofloxacin or enoxacin; • others such as metronidazole, nitrofurantoin or chloramphenicol; or
  • bismuth salts such as bismuth subcitrate, bismuth subsalicylate, bismuth subcarbonate, bismuth subnitrate or bismuth subgallate.
  • the compound according to the invention can also be used together or in combination for simultaneous, separate or sequential use with antacids such as aluminium hydroxide, magnesium carbonate and magnesium hydroxide or alginic acid, or together or in combination for simultaneous, separate or sequential use with pharmaceuticals which inhibit acid secretion, such as, H2-blockers (e.g. cimetidine, ranitidine), H , K -ATPase inhibitors (e.g. omeprazole, pantoprazole, lansoprazole, rabeprazole or tenatoprazole), or together or in combination for simultaneous, separate or sequential use with gastroprokinetics (e.g. cisapride or mosapride).
  • H2-blockers e.g. cimetidine, ranitidine
  • K -ATPase inhibitors e.g. omeprazole, pantoprazole, lansoprazole, rabeprazole or tenatoprazole
  • the compound according to the invention can also be used together or in combination for simultaneous, separate or sequential use th other active ingredients, e.g. for the treatment or prophylaxis of conditions involving medicament induced gastric ulcer.
  • active ingredients may be a NSATO, a NO-releasing NS AID, a COX-2 inhibitor or a bisphosphonate.
  • the compound according to the invention can also be used together or in combination for simultaneous, separate or sequential use with a gastrin antagonist such as CCK2 antagonist.
  • a further aspect of the invention is a new intermediate compound which are useful in the synthesis of the compound according to the invention.
  • the invention includes compound of Formula III
  • reaction mixture was stirred for 15 h before the solvent was removed under reduced pressure.
  • the residue was dispersed in a solution of acetonitrile and water (5:1, 6 ml) and the mixture was stirred for 2h.
  • the resulting white solid was filtered off, washed with a mixture of acetonitrile and water (5:1, 4 ml) and dried in a vacuum oven (0.163 g, 46 %).
  • the inhibitory effect value for the compound of the invention was determined, as IC50, to 0.28 ⁇ mol/1.
  • the IC50 for 8-[(2,6-dimethylbenzyl)amino]-N-(2-hydroxyethyl)-2,3- dimethylimidazo[l,2-a]pyridine-6-carboxamide was measured to 0.28 ⁇ mol/1.
  • Membrane vesicles (2.5 to 5 ⁇ g) were incubated for 15 min at +37°C in 18 mM Pipes/Tris buffer pH 7.4 containing 2 mM MgCl 2 , 10 mM KC1 and 2 mM ATP.
  • the ATPase activity was estimated as release of inorganic phosphate from ATP, as described by LeBel et al. (1978) Anal. Biochem. 85, 86-89.
  • the inhibitory value, IC50, for the compound of the invention measured was 0.46 ⁇ mol/1. 2.
  • mice of the Sprague-Dawly strain are used. They are equipped with cannulated fistulae in the stomach (lumen) and the upper part of the duodenum, for collection of gastric secretions and administration of test substances, respectively. A recovery period of 14 days after surgery is allowed before testing commenced.
  • Blood samples (0.1 - 0.4 g) are drawn repeatedly from the carotid artery at intervals up to 5.5 hours after given dose. The samples are frozen until analysis of the test compound.
  • Bioavailability is assessed by calculating the quotient between the area under blood/plasma concentration (AUC) curve following (i) intraduodenal (i.d.) or oral (p.o.) administration and (ii) intravenous (i.v.) administration from the rat or the dog, respectively.
  • AUC area under blood/plasma concentration
  • the area under the blood concentration vs. time curve, AUC is determined by the log/linear trapezoidal rule and extrapolated to infinity by dividing the last determined blood concentration by the elimination rate constant in the terminal phase.
  • Labrador retriever or Harrier dogs of either sex are used. They are equipped with a duodenal fistula for the administration of test compounds or vehicle and a cannulated gastric fistula or a Heidenhaim-pouch for the collection of gastric secretion.
  • test substance or vehicle is given orally, i.d. or i.v., 1 or 1.5 h after starting the histamine infusion, in a volume of 0.5 ml/kg body weight.
  • test compound is administered to the acid secreting main stomach of the Heidenham-pouch dog.
  • the acidity of the gastric juice samples are determined by titration to pH 7.0, and the acid output calculated.
  • the acid output in the collection periods after administration of test substance or vehicle are expressed as fractional responses, setting the acid output in the fraction preceding administration to 1.0. Percentage inhibition is calculated from fractional responses elicited by test compound and vehicle.
  • Plasma samples for the analysis of test compound concentration in plasma are taken at intervals up to 4 h after dosing. Plasma is separated and frozen within 30 min after collection and later analyzed. The systemic bioavailability (F%) after oral or i.d. administration is calculated as described above in the rat model.
  • the method describes a procedure to measure solubility of solid material in FaSSIF (Fasted State Simulated Intestinal fluid).
  • the FaSSLF solution is an isotonic phosphate buffer where pH is adjusted to 6.5 to reflect pH in the jejunum.
  • Taurocholic acid and lecithin is added to a concentration of 3mmol/l and 0.75 mmol/1 respectively.
  • 1 mg of solid material, i.e. of the compound of the invention, is added to 1 ml FaSSIF solution and equilibrated at 37 °C.
  • Samples are withdrawn after 1 and 24 hours. The samples are transferred to eppendorf tubes and spun at 10000 G and 37 °C for 10 minutes. A suitable volume of the supernatant is removed and diluted to a suitable concentration.
  • the concentrations of the compound in the samples are analysed with LC/UV/MS.

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  • 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)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des dérivés imidazopyridine de formule (I) permettant d'inhiber une sécrétion d'acide gastrique exogènement ou endogènement stimulée, et pouvant ainsi être utilisés pour la prévention et pour le traitement de maladies associées à l'acide gastrique et de maladies inflammatoires gastro-intestinales.
PCT/SE2004/001014 2003-06-26 2004-06-23 Nouveau compose imidazopyridine iii presentant un effet therapeutique Ceased WO2004113340A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0301903A SE0301903D0 (sv) 2003-06-26 2003-06-26 Novel imidazopyridine compound III with therapeutic effect
SE0301903-1 2003-06-26

Publications (1)

Publication Number Publication Date
WO2004113340A1 true WO2004113340A1 (fr) 2004-12-29

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Application Number Title Priority Date Filing Date
PCT/SE2004/001014 Ceased WO2004113340A1 (fr) 2003-06-26 2004-06-23 Nouveau compose imidazopyridine iii presentant un effet therapeutique

Country Status (4)

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SE (1) SE0301903D0 (fr)
TW (1) TW200505866A (fr)
UY (1) UY28383A1 (fr)
WO (1) WO2004113340A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010063876A1 (fr) 2008-12-03 2010-06-10 Dahlstroem Mikael Dérivés d'imidazopyridine inhibant la sécrétion d'acide gastrique

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999055705A1 (fr) * 1998-04-29 1999-11-04 Astrazeneca Ab Derives d'imidazo pyridine qui inhibent la secretion d'acide gastrique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999055705A1 (fr) * 1998-04-29 1999-11-04 Astrazeneca Ab Derives d'imidazo pyridine qui inhibent la secretion d'acide gastrique

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010063876A1 (fr) 2008-12-03 2010-06-10 Dahlstroem Mikael Dérivés d'imidazopyridine inhibant la sécrétion d'acide gastrique
US8669269B2 (en) 2008-12-03 2014-03-11 Mikael Dahlstrom Imidazopyridine derivatives which inhibit the secretion of gastric acid
RU2509771C2 (ru) * 2008-12-03 2014-03-20 Микаэль ДАХЛСТРЁМ Производные имидазопиридина, ингибирующие секрецию кислоты желудочного сока
US8993589B2 (en) 2008-12-03 2015-03-31 Mikael Dahlström Imidazopyridine derivatives which inhibit the secretion of gastric acid
JP2015063548A (ja) * 2008-12-03 2015-04-09 ダールストロム，ミカエル 胃酸の分泌を抑制するイミダゾピリジン誘導体
CN102239167B (zh) * 2008-12-03 2015-06-17 米卡尔·达尔斯托姆 抑制胃酸分泌的咪唑并吡啶衍生物

Also Published As

Publication number Publication date
SE0301903D0 (sv) 2003-06-26
TW200505866A (en) 2005-02-16
UY28383A1 (es) 2005-01-31

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