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WO1993018027A1 - Composes azotes heterocycliques utiles comme medicaments - Google Patents

Composes azotes heterocycliques utiles comme medicaments Download PDF

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Publication number
WO1993018027A1
WO1993018027A1 PCT/GB1993/000395 GB9300395W WO9318027A1 WO 1993018027 A1 WO1993018027 A1 WO 1993018027A1 GB 9300395 W GB9300395 W GB 9300395W WO 9318027 A1 WO9318027 A1 WO 9318027A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
compound according
hydrogen
formula
compound
Prior art date
Application number
PCT/GB1993/000395
Other languages
English (en)
Inventor
Francis David King
Laramie Mary Gaster
Paul Adrian Wyman
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 EP93904259A priority Critical patent/EP0629198A1/fr
Priority to JP5515422A priority patent/JPH07504428A/ja
Priority to AU35718/93A priority patent/AU666357B2/en
Publication of WO1993018027A1 publication Critical patent/WO1993018027A1/fr
Priority to KR1019940703105A priority patent/KR950700285A/ko

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/02—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing not further condensed quinolizine ring systems

Definitions

  • 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-HT 4 receptor antagonists in the treatment of atrial arrhythmias and stroke.
  • EP-A-501322 (Giaxo Group Limited) describes indole derivatives having 5-HT4 antagonist activity.
  • EP-A-309423 (Istituto de Angeli S.p.A) and EP-A-247266 (Beecham Group p.l.c.) describe 5-HT3 receptor antagonists derived from a benzimidazolone or indoline nucleus.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof:
  • X 1 -X 2 is NR 2 -CO or CR 1 R 2 -CR 3 R 4 where
  • R z and R 1 to R 4 are independently hydrogen or C 1-6 alkyl; and/or R 1 /R 2 and R 3 /R 4 together are a bond and/or R 1 /R 2 /R 3 /R 4 are joined to form
  • R a is hydrogen, halo, C 1 -6 alkyl, amino, nitro or C 1-6 alkyl;
  • R5 is hydrogen, halo, C 1 -6 alkyl or C 1-6 alkoxy
  • Y is O or NH
  • Z is of sub-formula (a), (b) or (c):
  • R 5 is hydrogen, C 1-12 alkyl, aralkyi or R 5 is (CH 2 ) z -R 10 wherein z 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 11 R 12 , NR 11 COR 12 , SO 2 NR 11 R 12 or NR 1 1 SO 2 R 12 wherein R 11 and R 12 are hydrogen or C 1-6 alkyl; and
  • R 6 , R 7 and R 8 are independently hydrogen or C 1 -6 alkyl
  • R 9 is hydrogen or C 1 -10 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 12 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 (d):
  • 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.
  • X 1 -X 2 is preferably NR z -CO, however, such as NH-CO or NEt-CO.
  • R a is preferably hydrogen.
  • R b is preferably hydrogen or halo, such as iodo.
  • Y is preferably O or NH.
  • n 1 is preferably 2, 3 or 4 when the azacycle is attached at the nitrogen atom and n 1 is preferably 1 when the azacycle is attached at a carbon atom, such as the 4-position when q is 2.
  • n 2 is preferably such that the number of carbon atoms between the ester or amide linkage is from 2 to 4 carbon atoms.
  • n 3 is preferably 2, 3 or 4.
  • R 8 and R 9 are preferably both alkyl, especially one of R 8 and R 9 is C 4 or larger alkyl.
  • the invention also provides novel compounds within formula (I) with side chains (i), (ii), (iii), (iv), (v), (vi) or (vii).
  • the piperidine ring in (i), (ii) or (iii) may be replaced by pyrrolidinyl or azetidinyl, and/or the N-substituent in (i) or (ii) may be replaced by C 3 or larger alkyl or optionally substituted benzyl.
  • N-substituent in formula (i) or (ii) may be replaced by (CH 2 ) n R 4 as defined in EP-A-501322 in respect of formula (I) and the specific examples therein.
  • 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
  • Suitable methods are as described in GB 2125398A (Sandoz Limited), GB 1593146A and EP-A-36269 (Beecham Group p.l.c), EP-A-429984 (Nisshin Flour Milling Co.) and EP-A-328200 (Merck Sharp & Dohme Limited). Reference is also made to EP-A-501322 (Glaxo Group Limited).
  • Aza(bi)cyclic side chain intermediates are known compounds or may be prepared according to the methods described in PCT/GB92/01519 and /01612 (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 gastrointestinal disorders, cardiovascular disorders and CNS disorders. They are of potential interest in the treatment of irritable bowel syndrome (IBS), in particular the diarrhoea aspects of IBS, i.e., 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.
  • 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.
  • they are of potential use in the treatment of the nausea and gastric symptoms of gastro-oesophageal reflux disease and dyspepsia.
  • Antiemetic activity is determined in known animal models of cytotoxic-agent/radiation induced emesis.
  • Cerebral embolism is the most common cause of ischaemic stroke and the heart the most common source of embolic material. Of particular concern is the frequency of embolism associated with atrial fibrillation.
  • Anxiolytic activity is likely to be effected via the hippocampus (Dumuis et al 1988, Mol Pharmacol., 34, 880-887). Activity may 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-HT4 receptors, and hence that administration of a 5-HT4 antagonist is of potential benefit in relieving a migraine attack.
  • 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. Sublingual or transdermal administration is also envisaged. Orally administrable compositions are preferred, since they are more convenient for general use. 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, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol;
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia
  • non-aqueous vehicles which may include edible oils
  • almond oil fractionated coconut oil
  • oily esters such as esters of g
  • 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
  • suspensions, solutions, emulsions, syrups, or elixirs are 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, 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
  • 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 of irritable bowel syndrome, gastro-oesophagal reflux disease, 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.
  • the method comprises treatment of IBS or atrial arrhythmias and stroke.
  • An amount effective to treat the disorders hereinbefore described depends on the relative efficacies of the compounds of the invention, the nature and severity of the disorder being treated and the weight of the mammal.
  • a unit dose for a 70 kg adult will normally contain 0.05 to 1000 mg for example 0.5 to 500 mg, 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 50 mg/kg/day, more usually 0.0002 to 25 mg/kg/day. No adverse toxicological effects are indicated within the aforementioned dosage ranges.
  • 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 as a 5-HT4 receptor antagonist in the treatment of the disorders hereinbefore described.
  • the invention also provides the use of a compound of formula (I) in the manufacture of a medicament for use as a 5-HT 4 receptor antagonist in the treatment of the disorders hereinbefore described.
  • the following Examples illustrate the preparation of compounds of formula (I); the following Descriptions illustrate the preparation of intermediates. It will be appreciated that any compound example wherein X is O may be prepared as the corresponding compound wherein Y is NH and vice versa.
  • HCI Salt - 1 H NMR 250MHz (CD 3 OD) ⁇ : 7.94 (dd, 1 H), 7.20-7.40 (m, 3H), 4.45 (d, 2H), 4.01 (q, 2H), 3.65-3.77 (m, 2H), 3.00-3.23 (m, 4H), 2.13-2.30 (m, 2H), 1.70-1.90 (m, 4H), 1.40-1.60 (m, 3H), 1.37 (t, 3H), 1.08 (t, 3H).
  • Free base - 1 H NMR (250MHz) (CDCI 3 ) ⁇ : 8.22(d,1H), 7.52-7.68(m,2H), 7.20-7.41 (m, 2H), 6.62(d,1H), 4.54(t,2H), 2.80(t,2H), 2.50(t,4H), 1.52- 1.68(m,4H), 1.45(m,2H).
  • guinea-pigs Male guinea-pigs, weighing 250-400g are used. Longitudinal musclemyenteric 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, dimethyiphenylpiperazinium (DMPP).
  • DMPP dimethyiphenylpiperazinium
  • increasing concentrations of a putative 5-HT4 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, pIC50 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% 02/5% CO2) Tyrodes solution at 37°C. All experiments are performed in pargyline pretreated 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Preventing Corrosion Or Incrustation Of Metals (AREA)

Abstract

On décrit des composés de formule (I) et les sels pharmaceutiquement acceptables de ceux-ci ainsi que leur utilisation comme médicaments pour traiter les troubles gastro-intestinaux, cardiovasculaires et ceux du système nerveux central.
PCT/GB1993/000395 1992-03-03 1993-02-25 Composes azotes heterocycliques utiles comme medicaments WO1993018027A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP93904259A EP0629198A1 (fr) 1992-03-03 1993-02-25 Composes azotes heterocycliques utiles comme medicaments
JP5515422A JPH07504428A (ja) 1992-03-03 1993-02-25 医薬として有用な窒素含有複素環化合物
AU35718/93A AU666357B2 (en) 1992-03-03 1993-02-25 Indole or benzimidazole derivatives
KR1019940703105A KR950700285A (ko) 1992-03-03 1994-09-02 약제로서 유용한 질소 함유 헤테로시클릭 화합물(Nitrogen containing heterocyclk compounds useful as pharmaceuticals)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9204565.7 1992-03-03
GB929204565A GB9204565D0 (en) 1992-03-03 1992-03-03 Pharmaceuticals

Publications (1)

Publication Number Publication Date
WO1993018027A1 true WO1993018027A1 (fr) 1993-09-16

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ID=10711400

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1993/000395 WO1993018027A1 (fr) 1992-03-03 1993-02-25 Composes azotes heterocycliques utiles comme medicaments

Country Status (11)

Country Link
EP (1) EP0629198A1 (fr)
JP (1) JPH07504428A (fr)
KR (1) KR950700285A (fr)
AU (1) AU666357B2 (fr)
CA (1) CA2131381A1 (fr)
GB (1) GB9204565D0 (fr)
MX (1) MX9301157A (fr)
NZ (1) NZ249217A (fr)
TW (1) TW279857B (fr)
WO (1) WO1993018027A1 (fr)
ZA (1) ZA931430B (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994008965A1 (fr) * 1992-10-16 1994-04-28 Smithkline Beecham Plc Esters/amides n-alkylpiperidinyl-4-methyl carboxyliques des systemes de cycles condenses en tant qu'inhibiteurs de recepteurs 5-ht4
WO1996028424A1 (fr) * 1995-03-14 1996-09-19 Boehringer Ingelheim Italia S.P.A. Esters et amides de 1,4-piperidine disubstituee a activite antagoniste de 5-ht¿4?
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
US6294555B1 (en) 1998-04-28 2001-09-25 Dainippon Pharmaceutical Co., Ltd. 1-[(1-Substituted-4-piperidinyl)methyl]-4-piperidine derivative, process for producing the same, medicinal compositions containing the same and intermediates of these compounds
WO2005021539A1 (fr) * 2003-09-03 2005-03-10 Pfizer Japan, Inc. Composes de benzimidazolone a activite d'agonistes du recepteur 5-ht4
WO2005123718A2 (fr) * 2004-06-15 2005-12-29 Pfizer Japan Inc. Derives de benzimidazolone d'acide carboxylique
WO2006090279A1 (fr) * 2005-02-22 2006-08-31 Pfizer Japan Inc. Derives d'oxyindole utilises comme agonistes du recepteur 5ht4
WO2006097808A1 (fr) * 2005-03-15 2006-09-21 Pfizer Japan Inc. Derives de benzimidazolone en tant que ligands de recepteur cb2
EP0699194B1 (fr) * 1993-05-22 2006-11-29 SmithKline Beecham plc Antagonistes de recepteur de 5-ht4
US7737163B2 (en) 2004-06-15 2010-06-15 Pfizer Inc. Benzimidazolone carboxylic acid derivatives
AP2418A (en) * 2004-06-15 2012-06-04 Pfizer Benzimidazolone carboxylic acid derivatives.
EP2585066A2 (fr) * 2010-06-24 2013-05-01 Alkermes Pharma Ireland Limited Promédicaments de composés nh-acides : dérivés esters, carbonates, carbamates et phosphonates

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008509088A (ja) * 2004-09-02 2008-03-27 ファイザー株式会社 ベンズイミダゾロンカルボン酸誘導体

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0247266A1 (fr) * 1986-01-07 1987-12-02 Beecham Group Plc Dérivés d'indole ayant une chaîne latérale azabicyclique, procédé pour leur préparation, produits intermédiaires et compositions pharmaceutiques
EP0309423A2 (fr) * 1987-09-23 1989-03-29 BOEHRINGER INGELHEIM ITALIA S.p.A. Dérivés de l'acide benzimidazoline-2-oxo-1-carboxylique utiles commes antagonistes des 5-HT récepteurs

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0247266A1 (fr) * 1986-01-07 1987-12-02 Beecham Group Plc Dérivés d'indole ayant une chaîne latérale azabicyclique, procédé pour leur préparation, produits intermédiaires et compositions pharmaceutiques
EP0309423A2 (fr) * 1987-09-23 1989-03-29 BOEHRINGER INGELHEIM ITALIA S.p.A. Dérivés de l'acide benzimidazoline-2-oxo-1-carboxylique utiles commes antagonistes des 5-HT récepteurs

Cited By (33)

* 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
WO1994008965A1 (fr) * 1992-10-16 1994-04-28 Smithkline Beecham Plc Esters/amides n-alkylpiperidinyl-4-methyl carboxyliques des systemes de cycles condenses en tant qu'inhibiteurs de recepteurs 5-ht4
EP0699194B1 (fr) * 1993-05-22 2006-11-29 SmithKline Beecham plc Antagonistes de recepteur de 5-ht4
WO1996028424A1 (fr) * 1995-03-14 1996-09-19 Boehringer Ingelheim Italia S.P.A. Esters et amides de 1,4-piperidine disubstituee a activite antagoniste de 5-ht¿4?
US6294555B1 (en) 1998-04-28 2001-09-25 Dainippon Pharmaceutical Co., Ltd. 1-[(1-Substituted-4-piperidinyl)methyl]-4-piperidine derivative, process for producing the same, medicinal compositions containing the same and intermediates of these compounds
WO2005021539A1 (fr) * 2003-09-03 2005-03-10 Pfizer Japan, Inc. Composes de benzimidazolone a activite d'agonistes du recepteur 5-ht4
US7776885B2 (en) 2003-09-03 2010-08-17 Pfizer, Inc. Benzimidazolone compounds having 5-HT4 receptor agonistic activity
EA009457B1 (ru) * 2003-09-03 2007-12-28 Пфайзер Инк. Бензимидазолоновые соединения, обладающие агонистической активностью в отношении 5-нтрецепторов
KR100738784B1 (ko) 2003-09-03 2007-07-12 화이자 인코포레이티드 5-ｈｔ4 수용체 효능 활성을 갖는 벤즈이미다졸론
AP2418A (en) * 2004-06-15 2012-06-04 Pfizer Benzimidazolone carboxylic acid derivatives.
US7737163B2 (en) 2004-06-15 2010-06-15 Pfizer Inc. Benzimidazolone carboxylic acid derivatives
EA010891B9 (ru) * 2004-06-15 2012-08-30 Пфайзер Инк. Производные бензимидазолонкарбоновой кислоты
EA010891B1 (ru) * 2004-06-15 2008-12-30 Пфайзер Инк. Производные бензимидазолонкарбоновой кислоты
AU2005254800B2 (en) * 2004-06-15 2010-12-09 Pfizer Inc. Benzimidazolone carboxylic acid derivatives
WO2005123718A3 (fr) * 2004-06-15 2006-05-04 Pfizer Japan Inc Derives de benzimidazolone d'acide carboxylique
US7595329B2 (en) 2004-06-15 2009-09-29 Pfizer Inc Benzimidazolone carboxylic acid derivatives
WO2005123718A2 (fr) * 2004-06-15 2005-12-29 Pfizer Japan Inc. Derives de benzimidazolone d'acide carboxylique
US7705020B2 (en) 2004-06-15 2010-04-27 Pfizer Inc. Benzimidazolone carboxylic acid derivatives
US7589109B2 (en) 2005-02-22 2009-09-15 Pfizer Inc Oxyindole derivatives
EA012615B1 (ru) * 2005-02-22 2009-10-30 Пфайзер Инк. Производные оксииндола в качестве агонистов 5-htрецептора
KR100908547B1 (ko) 2005-02-22 2009-07-20 화이자 인코포레이티드 ５ｈｔ４ 수용체 작용제로서의 옥시인돌 유도체
AU2006217534B2 (en) * 2005-02-22 2011-08-11 Pfizer Inc. Oxyindole derivatives as 5HT4 receptor agonists
AU2006217534B8 (en) * 2005-02-22 2011-12-08 Pfizer Inc. Oxyindole derivatives as 5HT4 receptor agonists
AU2006217534A8 (en) * 2005-02-22 2011-12-08 Pfizer Inc. Oxyindole derivatives as 5HT4 receptor agonists
WO2006090279A1 (fr) * 2005-02-22 2006-08-31 Pfizer Japan Inc. Derives d'oxyindole utilises comme agonistes du recepteur 5ht4
US8138177B2 (en) 2005-03-15 2012-03-20 Pfizer Inc. Benzimidazolone derivatives as CB2 receptor ligands
WO2006097808A1 (fr) * 2005-03-15 2006-09-21 Pfizer Japan Inc. Derives de benzimidazolone en tant que ligands de recepteur cb2
EP2585066A2 (fr) * 2010-06-24 2013-05-01 Alkermes Pharma Ireland Limited Promédicaments de composés nh-acides : dérivés esters, carbonates, carbamates et phosphonates
JP2013541494A (ja) * 2010-06-24 2013-11-14 アルカーメス ファーマ アイルランド リミテッド Ｎｈ酸性化合物のプロドラッグ：エステル、カルボネート、カルバメートおよびホスホネートの誘導体
EP2585066A4 (fr) * 2010-06-24 2014-06-11 Alkermes Pharma Ireland Ltd Promédicaments de composés nh-acides : dérivés esters, carbonates, carbamates et phosphonates
US9072788B2 (en) 2010-06-24 2015-07-07 Alkermes Pharma Ireland Limited Prodrugs of NH-acidic compounds: ester, carbonate, carbamate and phosphonate derivatives

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MX9301157A (es) 1994-07-29
AU666357B2 (en) 1996-02-08
AU3571893A (en) 1993-10-05
EP0629198A1 (fr) 1994-12-21
ZA931430B (en) 1993-10-22
JPH07504428A (ja) 1995-05-18
NZ249217A (en) 1996-06-25
GB9204565D0 (en) 1992-04-15
CA2131381A1 (fr) 1993-09-16
TW279857B (fr) 1996-07-01
KR950700285A (ko) 1995-01-16

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