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WO1994008998A1 - Derives d'imidazopyridine utilises comme antagonistes de recepteur de 5-ht¿4? - Google Patents

Derives d'imidazopyridine utilises comme antagonistes de recepteur de 5-ht¿4? Download PDF

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Publication number
WO1994008998A1
WO1994008998A1 PCT/EP1993/002808 EP9302808W WO9408998A1 WO 1994008998 A1 WO1994008998 A1 WO 1994008998A1 EP 9302808 W EP9302808 W EP 9302808W WO 9408998 A1 WO9408998 A1 WO 9408998A1
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WO
WIPO (PCT)
Prior art keywords
formula
hydrogen
compound
compound according
replaced
Prior art date
Application number
PCT/EP1993/002808
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English (en)
Inventor
Francis David King
Laramie Mary Gaster
Original Assignee
Smithkline Beecham Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to AU51770/93A priority Critical patent/AU5177093A/en
Priority to EP93922942A priority patent/EP0664808A1/fr
Priority to JP6509615A priority patent/JPH08502274A/ja
Publication of WO1994008998A1 publication Critical patent/WO1994008998A1/fr

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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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • Imidazopyridi ne derivatives as 5-HT4 receptor antagoni sts
  • This invention relates to novel compounds having pharmacological activity, to a process for their preparation and to their use as pharmaceuticals.
  • WO 91/16045 (SmithKline and French Laboratories Limited) describes the use of cardiac 5-HT4 receptor antagonists in the treatment of atrial arrhythmias and stroke.
  • EP-A-501322 (Glaxo Group Limited) describes indole derivatives having 5-HT4 antagonist activity.
  • PCT/GB93/00506 (SmithKline Beecham pic) describe compounds having 5-HT 4 receptor antagonist activity.
  • EP-A-504679 (G.D. Searle & Co.) describes 5-HT3 receptor antagonists with inter alia, an imidazopyridine nucleus.
  • 'treatment' includes prophylaxis as appropriate.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof:
  • R 1 is hydrogen or C 1-6 alkyl
  • R 2 is hydrogen or halo
  • Z is of sub-formula (i), (ii), (iii), (iv) or (v):
  • R 3 is hydrogen or C 1- 12 alkyl, aralkyl or R 3 is (CH 2 ) r -R 10 wherein r is 2 or 3 and
  • R 10 is selected from cyano, hydroxyl, C 1 -6 alkoxy, phenoxy, C(O)C 1-6 alkyl, COC 6 H 5 , -CONR 1 1 R 12 , NR 1 1 COR 12 , SO 2 NR 1 1 R 12 or NR 1 1 SO 2 R 12 wherein R 1 1 and R 12 hydrogen or C 1-6 alkyl;
  • alkyl or alkyl containing groups include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 ,
  • C 7 , C 8 , C 9 , C 10 C 1 1 or C 1 2 branched, straight chained or cyclic alkyl, as appropriate.
  • C 1-4 alkyl groups include methyl, ethyl n- and iso-propyl, n-, iso-, sec- and tert-butyl.
  • Cyclic alkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Aryl includes phenyl and naphthyl optionally substituted by one or more substituents selected from halo, C 1-6 alkyl and C 1-6 alkoxy.
  • Halo includes fluoro, chloro, bromo and iodo.
  • a suitable bioisostere for the amide or ester linkage containing Y in formula (I), is of formula: wherein
  • H, J and I independently represent oxygen, sulphur, nitrogen or carbon, provided that at least one of H, J and I is other than carbon; U represents nitrogen or carbon.
  • Suitable examples of (d) are as described for X, Y and Z in EP-A-328200 (Merck Sharp & Dohme Ltd.), such as an oxadiazole moiety.
  • Rj is preferably hydrogen.
  • R2 is preferably hydrogen.
  • Y is preferably O or NH.
  • N-substituent in formula (i) or (ii) may be replaced by optionally substituted benzyl or by (CH 2 ) n R 4 , as defined in formula (I) and in relation to the specific examples of EP-A-501322.
  • the pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts with conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric acids and pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, ⁇ -keto glutaric, ⁇ -glycerophosphoric, and glucose-1-phosphoric acids.
  • conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric acids
  • pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, ⁇ -keto glutaric, ⁇ -glycerophosphoric, and glucose-1-phosphoric acids.
  • Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula (I) such as the compounds quaternised by compounds R x -T wherein R x is C 1-6 alkyl, phenyl-C 1-6 alkyl or C 5-7 cycloalkyl, and T is a radical corresponding to an anion of an acid.
  • R x include methyl, ethyl and n- and iso-propyl; and benzyl and phenethyl.
  • Suitable examples of T include halide such as chloride, bromide and iodide.
  • Examples of pharmaceutically acceptable salts also include internal salts such as N-oxides.
  • the compounds of the formula (I), their pharmaceutically acceptable salts, (including quaternary derivatives and N-oxides) may also form pharmaceutically acceptable solvates, such as hydrates, which are included wherever a compound of formula (I) or a salt thereof is herein referred to.
  • Azabicyclic values of Z may exist in ⁇ and ⁇ forms.
  • the compounds of formula (I) may be prepared by conventional coupling of the moiety with Z. Suitable methods are as described in GB 2125398 A (Sandoz Limited), GB 1593146A and EP-A-36269 (Beecham Group p.l.c). When CO-Y is replaced by a heterocyclic bioisostere, suitable methods are described in
  • EP-A-328200 (Merck Sharp & Dohme Limited). Reference is also made to
  • EP-A-501322 (Glaxo Group Limited).
  • Imidazopyridine intermediates may be prepared as described in EP-A-504679.
  • Aza(bi)cyclic side chain intermediates are known compounds or may be prepared according to the methods described in the aformentioned patent publications (SmithKline Beecham p.l.c).
  • the compounds of the present invention are 5-HT 4 receptor antagonists and it is thus believed may generally be used in the treatment or prophylaxis of
  • IBS irritable bowel syndrome
  • these compounds block the ability of 5-HT to stimulate gut motility via activation of enteric neurones. In animal models of IBS, this can be conveniently measured as a reduction of the rate of defaecation. They are also of potential use in the treatment of urinary incontinence which is often associated with IBS.
  • They may also be of potential use in other gastrointestinal disorders, such as those associated with upper gut motility, and as antiemetics. In particular, they are of potential use in the treatment of the nausea and gastric symptoms of
  • Antiemetic activity is determined in known animal models of cytotoxic-agent/radiation induced emesis.
  • Anxiolytic activity is likely to be effected via the hippocampus (Dumuis et al 1988, Mol Pharmacol., 34, 880-887). Activity can be demonstrated in standard animal models, the social interaction test and the X-maze test. Migraine sufferers often undergo situations of anxiety and emotional stress that precede the appearance of headache (Sachs, 1985, Migraine, Pan Books, London). It has also been observed that during and within 48 hours of a migraine attack, cyclic AMP levels are considerably increased in the cerebrospinal fluid (Welch et al., 1976, Headache 16, 160-167). It is believed that a migraine, including the prodomal phase and the associated increased levels of cyclic AMP are related to stimulation of 5-HT 4 receptors, and hence that administration of a 5-HT 4 antagonist is of potential benefit in relieving a migraine attack.
  • CNS disorders of interest include schizophrenia, Parkinson's disease and Huntingdon's chorea.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • compositions are prepared by admixture and are usually adapted for enteral such as oral, nasal or rectal, or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, nasal sprays, suppositories, injectable and infusable solutions or suspensions.
  • enteral such as oral, nasal or rectal, or parenteral administration
  • enteral such as oral, nasal or rectal, or parenteral administration
  • enteral such as oral, nasal or rectal, or parenteral administration
  • enteral such as oral, nasal or rectal, or parenteral administration
  • enteral such as oral, nasal or rectal, or parenteral administration
  • enteral such as oral, nasal or rectal, or parenteral administration
  • enteral such as oral, nasal or rectal, or parenteral administration
  • oral liquid preparations powders, granules, lozenges, reconstitutable powders, nasal sprays, s
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents.
  • the tablets may be coated according to well known methods in the art, for example with an enteric coating.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch derivatives such as sodium starch glycollate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose,
  • non-aqueous vehicles which may include edible oils
  • preservatives for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • Oral liquid preparations are usually in the form of aqueous or oily
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and flavouring or colouring agents.
  • the oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
  • fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle.
  • the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure of ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
  • the invention further provides a method of treatment or prophylaxis of irritable bowel syndrome, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine in mammals, such as humans, which comprises the administration of an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
  • a unit dose for a 70kg adult will normally contain 0.05 to 1000mg for example 0.5 to 500mg, of the compound of the invention.
  • Unit doses may be administered once or more than once a day, for example, 2, 3 or 4 times a day, more usually 1 to 3 times a day, that is in the range of approximately 0.0001 to 50mg/kg/day, more usually 0.0002 to 25 mg/kg/day.
  • the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance, in particular for use in the treatment of irritable bowel syndrome, gastio-oesophageal reilux disease, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine.
  • guinea-pigs Male guinea-pigs, weighing 250-400g are used. Longitudinal muscle-myenteric plexus preparations, approximately 3cm long, are obtained from the distal colon region. These are suspended under a 0.5g load in isolated tissue baths containing Krebs solution bubbled with 5% CO 2 in O 2 and maintained at 37°C. In all experiments, the Krebs solution also contains methiothepin 10 -7 M and granisetron 10 -6 M to block effects at 5-HT 1 , 5-HT 2 and 5-HT 3 receptors.
  • a concentration of 5-HT is selected so as to obtain a contraction of the muscle approximately 40-70% maximum(10 -9 M approx).
  • the tissue is then alternately dosed every 15min with this concentration of 5-HT and then with an approximately equi-effective concentration of the nicotine receptor stimulant, dimethylphenylpiperazinium (DMPP).
  • DMPP dimethylphenylpiperazinium
  • increasing concentrations of a putative 5-HT 4 receptor antagonist are then added to the bathing solution.
  • the effects of this compound are then determined as a percentage reduction of the contractions evoked by 5-HT or by DMPP. From this data, pIC 50 values are determined, being defined as the -log concentration of antagonist which reduces the contraction by 50%.
  • a compound which reduces the response to 5-HT but not to DMPP is believed to act as a 5-HT 4 receptor antagonist.
  • Rat oesophageal tunica muscularis mucosae is set up according to Baxter et. al. Naunyn-Schmiedeberg's Arch. Pharmacol., 343, 439-446 (1991).
  • the inner smooth muscle tube of the muscularis mucosae is isolated and mounted for isometric tension recording in oxygenated (95% 0 ⁇ 5% CO 2 ) Tyrodes solution at 37°C. All experiments are performed in pargyline pre-treated preparations (100 ⁇ M for 15 min followed by washout) and in the presence of cocaine (30 ⁇ M). Relaxant responses to 5-HT are obtained after pre-contracting the oesophagus tissue with carbachol (3 ⁇ M).

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

L'invention se rapporte à des composés de la formule (I), à leurs sels pharmaceutiquement acceptables, ainsi qu'à l'utilisation d'un composé de la formule (I) ou d'un sel pharmaceutiquement acceptable de ce dernier, formule dans laquelle R1 représente hydrogène ou alkyle C1-6; R2 représente hydrogène ou halo; Y représente O ou NH; Z répond à la sous-formule (i), (ii), (iii), (iv) ou (v), où le noyau pipéridine en (i) ou (ii) est remplacé par pyrrolidinyle, et/ou le substituant N en (i) ou (ii) est remplacé par R3, R3 représentant hydrogène ou alkyle C1-12, aralkyle ou (CH2)r-R10, r valant 2 ou 3 et R10 étant chosi entre cyano, hydroxyle, alcoxy C1-6, phénoxy, C(O)C1-6alkyle, COC6H5,-CONR11R12,NR11COR11COR12,SO2NR11R12 or NR11SO2R12, R11 et R12 représentant hydrogène ou alkyle C1-6. L'invention se rapporte également à un composé de la formule (I) dans lequel la liaison CO-Y est remplacée par un bioisostère hétérocyclique. Ces composés présentent une activité d'antagonistes de récepteur de 5-HT4.
PCT/EP1993/002808 1992-10-13 1993-10-12 Derives d'imidazopyridine utilises comme antagonistes de recepteur de 5-ht¿4? WO1994008998A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU51770/93A AU5177093A (en) 1992-10-13 1993-10-12 Imidazopyridine derivatives as 5-ht4 receptor antagonists
EP93922942A EP0664808A1 (fr) 1992-10-13 1993-10-12 Derives d'imidazopyridine utilises comme antagonistes de recepteur de 5-ht 4?
JP6509615A JPH08502274A (ja) 1992-10-13 1993-10-12 ５−ｈｔ▲下４▼レセプターアンタゴニスト用イミダゾピリジン誘導体

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9221468.3 1992-10-13
GB929221468A GB9221468D0 (en) 1992-10-13 1992-10-13 Pharmaceuticals

Publications (1)

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WO1994008998A1 true WO1994008998A1 (fr) 1994-04-28

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EP (1) EP0664808A1 (fr)
JP (1) JPH08502274A (fr)
CN (1) CN1092775A (fr)
AU (1) AU5177093A (fr)
CA (1) CA2146928A1 (fr)
GB (1) GB9221468D0 (fr)
MX (1) MX9306310A (fr)
WO (1) WO1994008998A1 (fr)
ZA (1) ZA937505B (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997029739A2 (fr) * 1996-02-15 1997-08-21 Janssen Pharmaceutica N.V. Utilisation d'antagonistes du recepteur de 5ht4 pour lutter contre les effets gastro-intestinaux d'inhibiteurs de reabsorption de la serotonine
US5726187A (en) * 1992-10-16 1998-03-10 Smithkline Beecham Plc N-alkylpiperidinyl-4-methyl carboxylic esters/amides of condensed ring systems as 5-HT4 receptor antagonists
US5852014A (en) * 1992-03-12 1998-12-22 Smithkline Beecham P.L.C. Condensed indole derivatives as 5HT4 -receptor antagonists
US5998409A (en) * 1992-03-12 1999-12-07 Smithkline Beecham Plc Condensed indole derivatives as 5HT4 -receptor antagonists
FR2797630A1 (fr) * 1999-08-20 2001-02-23 Univ Caen Basse Normandie DERIVES ETHERS DE PYRROLO[1,2-a] QUINOXALINES, LEUR PROCEDE DE PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE
WO2003035649A1 (fr) * 2001-10-22 2003-05-01 Pfizer Japan Inc. Composes d'imidazopyridine en tant que modulateurs du recepteur 5-ht¿4?
US6624162B2 (en) 2001-10-22 2003-09-23 Pfizer Inc. Imidazopyridine compounds as 5-HT4 receptor modulators
WO2004026868A1 (fr) * 2002-09-20 2004-04-01 Pfizer Japan Inc. Composes de piperidinyl-imidazopyridine n-substitues utilises comme modulateurs du recepteur 5-ht4
WO2004026869A1 (fr) * 2002-09-20 2004-04-01 Pfizer Japan Inc. Composes d'imidazopyridine comme agonistes du recepteur 5-ht4
WO2004094418A1 (fr) * 2003-04-21 2004-11-04 Pfizer Inc. Composes imidazopyridiques ayant une activite agoniste anti-recepteur 5-ht4 et une activite antagoniste anti-recepteur 5-ht3
US6979690B2 (en) 2002-01-07 2005-12-27 Pfizer Inc. Oxo or oxy-pyridine compounds as 5-HT4 receptor modulators
US7595329B2 (en) 2004-06-15 2009-09-29 Pfizer Inc Benzimidazolone carboxylic acid derivatives
US7737163B2 (en) 2004-06-15 2010-06-15 Pfizer Inc. Benzimidazolone carboxylic acid derivatives
US8829028B2 (en) 2002-05-16 2014-09-09 Serodus As 5-HT4 receptor antagonists for the treatment of heart failure
CN104725376A (zh) * 2015-03-31 2015-06-24 山东友帮生化科技有限公司 6-氯-8-羧基咪唑并[1,2-a]吡啶的合成方法
CN104761551A (zh) * 2015-03-31 2015-07-08 山东友帮生化科技有限公司 6-碘-8-羧基咪唑并(1,2-a)吡啶的合成方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0501322A1 (fr) * 1991-02-25 1992-09-02 Glaxo Group Limited Esters pipéridimylmethyl substitués d'acide indole-3-carbonyligne
WO1992015593A1 (fr) * 1991-03-07 1992-09-17 G.D. Searle & Co. Nouvelles imidazopyridines utilisees comme antagonistes serotonergiques de 5-ht¿3?

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0501322A1 (fr) * 1991-02-25 1992-09-02 Glaxo Group Limited Esters pipéridimylmethyl substitués d'acide indole-3-carbonyligne
WO1992015593A1 (fr) * 1991-03-07 1992-09-17 G.D. Searle & Co. Nouvelles imidazopyridines utilisees comme antagonistes serotonergiques de 5-ht¿3?

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5852014A (en) * 1992-03-12 1998-12-22 Smithkline Beecham P.L.C. Condensed indole derivatives as 5HT4 -receptor antagonists
US5998409A (en) * 1992-03-12 1999-12-07 Smithkline Beecham Plc Condensed indole derivatives as 5HT4 -receptor antagonists
US5726187A (en) * 1992-10-16 1998-03-10 Smithkline Beecham Plc N-alkylpiperidinyl-4-methyl carboxylic esters/amides of condensed ring systems as 5-HT4 receptor antagonists
WO1997029739A3 (fr) * 1996-02-15 1999-10-28 Janssen Pharmaceutica Nv Utilisation d'antagonistes du recepteur de 5ht4 pour lutter contre les effets gastro-intestinaux d'inhibiteurs de reabsorption de la serotonine
US5990159A (en) * 1996-02-15 1999-11-23 Janssen Pharmaceutica, N.V. Use of 5HT4 receptor antagonists for overcoming gastrointestinal effects of serotonin reuptake inhibitors
WO1997029739A2 (fr) * 1996-02-15 1997-08-21 Janssen Pharmaceutica N.V. Utilisation d'antagonistes du recepteur de 5ht4 pour lutter contre les effets gastro-intestinaux d'inhibiteurs de reabsorption de la serotonine
FR2797630A1 (fr) * 1999-08-20 2001-02-23 Univ Caen Basse Normandie DERIVES ETHERS DE PYRROLO[1,2-a] QUINOXALINES, LEUR PROCEDE DE PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE
WO2001014381A1 (fr) * 1999-08-20 2001-03-01 Universite De Caen Basse-Normandie Derives ethers de pyrrolo[1,2-a]quinoxalines, leur procede de preparation et leur application en therapeutique
WO2003035649A1 (fr) * 2001-10-22 2003-05-01 Pfizer Japan Inc. Composes d'imidazopyridine en tant que modulateurs du recepteur 5-ht¿4?
US6624162B2 (en) 2001-10-22 2003-09-23 Pfizer Inc. Imidazopyridine compounds as 5-HT4 receptor modulators
US6979690B2 (en) 2002-01-07 2005-12-27 Pfizer Inc. Oxo or oxy-pyridine compounds as 5-HT4 receptor modulators
US8829028B2 (en) 2002-05-16 2014-09-09 Serodus As 5-HT4 receptor antagonists for the treatment of heart failure
WO2004026868A1 (fr) * 2002-09-20 2004-04-01 Pfizer Japan Inc. Composes de piperidinyl-imidazopyridine n-substitues utilises comme modulateurs du recepteur 5-ht4
US6951867B2 (en) 2002-09-20 2005-10-04 Pfizer Inc. N-substituted piperidinyl-imidazopyridine compounds as 5-HT4 receptor modulators
US7012080B2 (en) 2002-09-20 2006-03-14 Pfizer Inc. Imidazopyridine compounds as 5-HT4 receptor agonists
WO2004026869A1 (fr) * 2002-09-20 2004-04-01 Pfizer Japan Inc. Composes d'imidazopyridine comme agonistes du recepteur 5-ht4
WO2004094418A1 (fr) * 2003-04-21 2004-11-04 Pfizer Inc. Composes imidazopyridiques ayant une activite agoniste anti-recepteur 5-ht4 et une activite antagoniste anti-recepteur 5-ht3
US7595329B2 (en) 2004-06-15 2009-09-29 Pfizer Inc Benzimidazolone carboxylic acid derivatives
US7705020B2 (en) 2004-06-15 2010-04-27 Pfizer Inc. Benzimidazolone carboxylic acid derivatives
US7737163B2 (en) 2004-06-15 2010-06-15 Pfizer Inc. Benzimidazolone carboxylic acid derivatives
CN104725376A (zh) * 2015-03-31 2015-06-24 山东友帮生化科技有限公司 6-氯-8-羧基咪唑并[1,2-a]吡啶的合成方法
CN104761551A (zh) * 2015-03-31 2015-07-08 山东友帮生化科技有限公司 6-碘-8-羧基咪唑并(1,2-a)吡啶的合成方法

Also Published As

Publication number Publication date
GB9221468D0 (en) 1992-11-25
ZA937505B (en) 1994-07-22
CN1092775A (zh) 1994-09-28
EP0664808A1 (fr) 1995-08-02
CA2146928A1 (fr) 1994-04-28
AU5177093A (en) 1994-05-09
MX9306310A (es) 1994-04-29
JPH08502274A (ja) 1996-03-12

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