WO2004113338A1 - Nouveau compose imidazopyridine i presentant un effet therapeutique - Google Patents

Nouveau compose imidazopyridine i presentant un effet therapeutique Download PDF

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Publication number
WO2004113338A1
WO2004113338A1 PCT/SE2004/001012 SE2004001012W WO2004113338A1 WO 2004113338 A1 WO2004113338 A1 WO 2004113338A1 SE 2004001012 W SE2004001012 W SE 2004001012W WO 2004113338 A1 WO2004113338 A1 WO 2004113338A1
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Prior art keywords
compound
acid
formula
compound according
diseases
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PCT/SE2004/001012
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English (en)
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Peter Nordberg
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Astrazeneca Ab
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Publication of WO2004113338A1 publication Critical patent/WO2004113338A1/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 -NKf ⁇
  • 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 III
  • the acid and base can be selected from HC1, H2SO4 and NaOH.
  • compound of the Formula IJJ 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 tetramethyluronium tetrafluoroborate
  • the reaction can be carried out in an inert solvent, such as dimethyl formamide (DMF), methylenchloride and acetonitrile, or mixture thereof, under standard conditions.
  • the reaction according to step a) above can be carried out by hydrolyzing a compound of Formula II 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.
  • aqueous alcohol such as aqueous methanol or ethanol at reflux for 1 to 3 hours.
  • a further process for producing the compound of the invention comprises the following steps
  • R represents a Cj-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.
  • 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 to 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 the 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-EUison syndrome, and peptic ulced 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 invention in 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 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
  • aminoglycosides such as gentamycin, kanamycin or amikacin
  • 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
  • H2-blockers e.g. cimetidine, ranitidine
  • H K -ATPase inhibitors
  • gastroprokinetics e.g. cisapride or mosapride
  • the compound according to the invention can also be used together or in combination for simultaneous, separate or sequential use with other active ingredients, e.g. for the treatment or prophylaxis of conditions involving medicament induced gastric ulcer.
  • active ingredients may be a NSAID, 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 a CCK2 antagonist.
  • a further aspect of the invention is a new intermediate compound which is useful in the synthesis of the compound according to the invention.
  • the invention includes compound of Formula III
  • the reaction mixture was stirred for 18 h before the solvent was removed under reduced pressure.
  • the residue was purified by flash chromatography on silica gel, using a gradient of 2-10% ethanol in dicloromethane (DCM) as eluent.
  • DCM dicloromethane
  • the product was crystallized from acetonitrile (6 ml), which gave 0.854 g (73 %) of the desired product as a white solid.
  • the inhibitory value for the compound of the invention was determined, as IC50, to 0.27 ⁇ mol/1.
  • the IC5 0 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 KCl 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 0.38 ⁇ mol/I.
  • the IC50 was determined to 0.75 ⁇ mol/1 for 8-[(2,6-dimethylbenzyl)amino]-N-(2- hydroxyethyl)-2,3-dimethylimidazo[l,2-a]pyridine-6-carboxamide.
  • 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.
  • Rats of the Sprague-Dawley strain are used. One to three days prior to the experiments all rats are prepared by cannulation of the left carotid artery under anaesthesia. The rats used for intravenous experiments are also cannulated in the jugular vein (Popovic (1960) J. Appl. Physiol. 15, 727-728). The cannulas are exteriorized at the nape of the neck.
  • 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. Before secretory tests the animals are fasted for about 18 h but water is freely allowed. Gastric acid secretion is stimulated for up to 6.5 h infusion of histamine dihydrochloride (12 ml h) at a dose producing about 80 % of the individual maximal secretory response, and gastric juice collected in consecutive 30-min fractions. Test substance or vehicle is given orally, i.d.
  • 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.
  • Fasted State Simulated Intestinal fluid The method describes a procedure to measure solubility of solid material in FaSSIF (Fasted State Simulated Intestinal fluid).
  • the FaSSIF 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 3 mmol 1 and 0.75 mmol/1 respectively.
  • the solubility of the compound of the invention measured after 24 hours, was 7 ⁇ mol/1 and the solubility of the compound of the compound of the invention as mesylate salt, measured after 24 hours, was 16 ⁇ mol/1.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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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/SE2004/001012 2003-06-26 2004-06-23 Nouveau compose imidazopyridine i presentant un effet therapeutique WO2004113338A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0301905-6 2003-06-26
SE0301905A SE0301905D0 (sv) 2003-06-26 2003-06-26 Novel imidazopyridine compound I with therapeutic effect

Publications (1)

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WO2004113338A1 true WO2004113338A1 (fr) 2004-12-29

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AR (1) AR044853A1 (fr)
SE (1) SE0301905D0 (fr)
TW (1) TW200508234A (fr)
UY (1) UY28385A1 (fr)
WO (1) WO2004113338A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007039464A1 (fr) * 2005-09-22 2007-04-12 Nycomed Gmbh Dérivés de l'imidazopyridine porteurs de substitutions par des isotopes pour le traitement de troubles gastro-intestinaux
WO2010063876A1 (fr) 2008-12-03 2010-06-10 Dahlstroem Mikael Dérivés d'imidazopyridine inhibant la sécrétion d'acide gastrique
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

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 (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007039464A1 (fr) * 2005-09-22 2007-04-12 Nycomed Gmbh Dérivés de l'imidazopyridine porteurs de substitutions par des isotopes pour le traitement de troubles gastro-intestinaux
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
KR101742328B1 (ko) 2008-12-03 2017-06-01 미카엘 달스트롬 위산의 분비를 억제하는 이미다조피리딘 유도체
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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UY28385A1 (es) 2005-01-31
SE0301905D0 (sv) 2003-06-26
AR044853A1 (es) 2005-10-05
TW200508234A (en) 2005-03-01

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