WO1994029298A1 - Acide 8-amino-7-chloro-1,4-benzodioxane-5-carboxylique, ester de -1-butyl-4-piperidinyle utilise en tant qu'antagoniste du recepteur de 5-ht4 - Google Patents

Acide 8-amino-7-chloro-1,4-benzodioxane-5-carboxylique, ester de -1-butyl-4-piperidinyle utilise en tant qu'antagoniste du recepteur de 5-ht4 Download PDF

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Publication number
WO1994029298A1
WO1994029298A1 PCT/EP1994/001939 EP9401939W WO9429298A1 WO 1994029298 A1 WO1994029298 A1 WO 1994029298A1 EP 9401939 W EP9401939 W EP 9401939W WO 9429298 A1 WO9429298 A1 WO 9429298A1
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WIPO (PCT)
Prior art keywords
hydrogen
alkyl
halo
alkoxy
amino
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Application number
PCT/EP1994/001939
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English (en)
Inventor
Laramie Mary Gaster
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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 EP94920935A priority Critical patent/EP0703914A1/fr
Priority to JP7501349A priority patent/JPH08511259A/ja
Publication of WO1994029298A1 publication Critical patent/WO1994029298A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero 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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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 (Glaxo Group Limited), WO 93/02677, WO 93/03725, WO 93/05038, WO 93/05040 and WO 93/18036 (SmithKUne Beecham pic) describe compounds having 5-HT 4 receptor antagonist activity.
  • the present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, and the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • X is a group of formula (a), (b), (c) or (d):
  • X 1 -(CH 2 ) x -X 2 forms a 5-7 membered ring wherein Xj is O or S; X 2 is O, S, -CH 2 -, NR or NRCO wherein R is hydrogen or C 1-6 alkyl; and
  • x is 1, 2 or 3;
  • one of X3 and X4 is N and the other is C;
  • X5 is N or CR wherein R is hydrogen, C 1-6 alkoxy, halo, C 1-6 alkyl or cyano;
  • R 1 a is hydrogen, amino, halo, C 1-6 alkyl, hydroxy or C 1-6 alkoxy;
  • R 2 a is hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, nitro, amino or C 1-6 alkylthio;
  • R 3 a is hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy or amino;
  • R 4 a and R 5 a are independently hydrogen or C 1-6 alkyl
  • R 1 b is hydrogen, halogen, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6
  • alkylsulphonyl C 1-6 alkylsulphinyl, C 1-6 acyl, cyano, C 1-6 alkoxycarbonyl, C 1-7 acylamino, hydroxy, nitro or amino, aminocarbonyl, or aminosulphonyl, optionally N-substituted by one or two groups selected from C 1-6 alkyl, C 3-8 cycloalkyl, and C 3-8 cycloalkyl C 1-4 alkyl or disubstituted by C 4 or C 5 polymethylene; phenyl or phenyl C 1-4 alkyl group optionally substituted in the phenyl ring by one or two of halogen, C 1-6 alkoxy or C 1-6 alkyl groups; R 3 b is hydrogen, halo, C 1-6 alkyl, amino, nitro or C 1-6 alkyl;
  • R 4 b is hydrogen, halo, C 1-6 alkyl or C 1-6 alkoxy
  • X 6 -X 7 is NR z -CO or CR 1 c R 2 c -CR 3 c R 4 c
  • R z and R 1 c to R 4 C are independently hydrogen or C 1-6 alkyl; and/or
  • R 1 c /R 2 c and R 3 c /R 4 c together are a bond and/or R 1 c /R 2 c /R 3 c /R 4 c are joined to form C 3-6 polymethylene;
  • R a c is hydrogen, halo, C 1-6 alkyl, amino, nitro or C 1-6 alkyl;
  • R b c is hydrogen, halo, C 1-6 alkyl or C 1-6 alkoxy
  • X d is O, S, SO, SO 2 , CH 2 , CH, N or NR wherein R is hydrogen or C 1-6 alkyl; A is a saturated or unsaturated polymethylene chain of 2 - 4 carbon atoms;
  • R 1 d and R 2 d are hydrogen or C 1-6 alkyl
  • R 3 d is hydrogen, halo, C 1-6 alkyl, amino, nitro or C 1-6 alkoxy;
  • R 4 d is hydrogen, halo, C 1-6 alkyl or C 1-6 alkoxy
  • Y is O or NH
  • q 0, 1, 2 or 3;
  • R a is hydrogen, C 1-12 alkyl, aralkyl or R a is (CH 2 ) z -R 7 wherein z is 2 or 3 and R 7 is selected from cyano, hydroxyl, C 1-6 alkoxy, phenoxy, C(O)C 1-6 alkyl,
  • R 6 is hydrogen or C 1-6 alkyl
  • alkyl or alkyl containing groups examples include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 ,
  • C1.4 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 optionally substituted by one or more alkyl groups of up to 4 carbon atoms.
  • 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, preferably chloro.
  • a suitable bioisostere for the amide or ester linkage containing Y in formula (I) is of formula:
  • the dotted circle represents one or two double bonds in any position in the
  • 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.
  • bioisosteres are as described for X, Y and Z in
  • EP-A-328200 (Merck Sharp & Dohme Ltd.), such as an oxadiazole moiety.
  • Suitable examples of the X 1 -(CH 2 ) x -X 2 moiety include O-(CH 2 ) 2 -O, O-(CH 2 ) 3 -O, O-CH 2 -O, O-(CH 2 ) 2 -NR, O-(CH 2 ) 2 -S or O-CH 2 -CONR, wherein any of the methylene linkages are optionally mono- or di- substituted by C 1-6 alkyl groups, such as methyl.
  • X 1 -(CH 2 ) 2 -X 2 is O-(CH 2 ) 2 -O.
  • X 1 -(CH 2 ) 2 -X 2 is O-(CH 2 ) 2 -CH 2 - R 1 a is preferably hydrogen or amino.
  • R 2 a is preferably hydrogen or halo.
  • R 3 a is preferably hydrogen or halo.
  • R 4 a and R 5 a are often hydrogen.
  • R 4 a /R 5 a is C 1-6 alkyl, it is often methyl.
  • R 4 a and R 5 a are methyl such that the disubstituent containing X 1 and X 2 is O-C(CH 3 ) 2 -O.
  • R 1 b is preferably CF 3 or an ethyl group.
  • X 5 is preferably N, C-H or C-OCH 3 ;
  • R 3 b is preferably hydrogen.
  • R 4 b is preferably hydrogen or halo, such as iodo.
  • X 6 -X 7 is preferably NR z -CO, however, such as NH-CO or NEt-CO.
  • R a c is preferably hydrogen.
  • R b c is preferably hydrogen or halo, such as iodo.
  • Values for A include -CH 2 -(CH 2 ) r -CH 2 - wherein r is 0, 1 or 2;
  • Rjd and R- ⁇ are often hydrogen or R ⁇ - and R2 d are gem-dimethyl.
  • r is often 1.
  • R ⁇ is preferably hydrogen.
  • R4 (i is preferably hydrogen or halo, such as fluoro.
  • Y is preferably O or NH.
  • the azacycle Z is preferably attached at a 4-position carbon atom, when q is 2.
  • Values of Z of interest include 4-piperidinyl and 4-pyrrolidinyl, N-substituted by R a .
  • R a of interest are as described in the aforementioned patent publications.
  • a particularly preferred value is n-butyl.
  • 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.
  • 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 Cj.g 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 w ⁇ -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.
  • solvates such as hydrates, which are included wherever a compound of formula (I) or a salt thereof is herein referred to.
  • Suitable examples of conversions in the Z containing moiety include conventional modifications of the N-substituent by substitution and/or deprotection or, in the case of a 2-, 3- or 4- substituted piperidyl desired end compound, reduction of an appropriate pyridyl derivative.
  • 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.
  • 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.
  • IBS irritable bowel syndrome
  • urinary incontinence which is often associated with IBS.
  • IBS urinary incontinence
  • others 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.
  • Anxiolytic activity is likely to be effected via the hippocampus (Dumuis et al).
  • 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 suspensions, solutions, emulsions, syrups, or elixirs or 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 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, gastro-oesophageal reflux disease, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine.
  • a preferred compound corresponds to any example, but wherein there is an amino substituent in the 4-position and a chloro substituent in the 5-position of the benzoic acid nucleus depicted in formula (I).
  • the gum was purified by flash silica-gel chromatography, with 2% MeOHICHCl 3 as eluant to yield a clear oil (0.22g) which contained 1-butyl-4-piperidinol.
  • 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.
  • the compound of the Example gave a pIC50 value of 8.6.

Abstract

L'invention concerne la préparation de 8-amino-7-chloro-1,4-benzodioxane-5(1-butyl-4-piperidinyl)carboxylate de formule (I) destiné à être utilisé en tant qu'antagoniste du récepteur de 5-HT4 dans le traitement ou la prophylaxie de troubles gastro-intestinaux, vasculaires et du SNC.
PCT/EP1994/001939 1993-06-16 1994-06-14 Acide 8-amino-7-chloro-1,4-benzodioxane-5-carboxylique, ester de -1-butyl-4-piperidinyle utilise en tant qu'antagoniste du recepteur de 5-ht4 WO1994029298A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP94920935A EP0703914A1 (fr) 1993-06-16 1994-06-14 Acide 8-amino-7-chloro-1,4-benzodioxane-5-carboxylique, ester de -1-butyl-4-piperidinyle utilise en tant qu'antagoniste du recepteur de 5-ht4
JP7501349A JPH08511259A (ja) 1993-06-16 1994-06-14 ５−ｈｔ▲下４▼レセプター拮抗物質としての８−アミノ−７−クロロ−１，４−ベンゾジオキサン−５−カルボン酸の１−ブチル−４−ピペリジニルエステル

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9312348.7 1993-06-16
GB939312348A GB9312348D0 (en) 1993-06-16 1993-06-16 Pharmaceuticals

Publications (1)

Publication Number Publication Date
WO1994029298A1 true WO1994029298A1 (fr) 1994-12-22

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EP (1) EP0703914A1 (fr)
JP (1) JPH08511259A (fr)
GB (1) GB9312348D0 (fr)
WO (1) WO1994029298A1 (fr)

Cited By (9)

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WO1997031897A1 (fr) * 1996-02-29 1997-09-04 Janssen Pharmaceutica N.V. Nouvelles 4-((4'-aminobenzoyl)-oxymethyl)-piperidines n-substituees ayant des proprietes gastrocinetiques
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
US6172062B1 (en) * 1998-09-10 2001-01-09 Syntex (Usa) Llc Dihydrobenzodioxine carboxamide and ketone derivatives
US7205410B2 (en) 1998-12-22 2007-04-17 Janssen Pharmaceutica, N.V. 4-(aminomethyl)-piperidine benzamides for treating gastrointestinal disorders
US7589109B2 (en) 2005-02-22 2009-09-15 Pfizer Inc Oxyindole derivatives
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

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GB2176785A (en) * 1985-06-19 1987-01-07 Astra Laekemedel Ab Annellated benzamide derivatives
EP0389037A1 (fr) * 1989-03-22 1990-09-26 Janssen Pharmaceutica N.V. Dérivés du N-(hydroxy-3 pipéridinyl-4)(dihydrobenzofuranne, dihydro-2H-benzopyranne ou dihydrobenzodioxine)carboxamide
EP0407137A2 (fr) * 1989-07-03 1991-01-09 Yoshitomi Pharmaceutical Industries, Ltd. Dérivés de benzazine et leurs applications pharmaceutiques
EP0501322A1 (fr) * 1991-02-25 1992-09-02 Glaxo Group Limited Esters pipéridimylmethyl substitués d'acide indole-3-carbonyligne
WO1993003725A1 (fr) * 1991-08-20 1993-03-04 Smithkline Beecham Plc Antagonistes du recepteur 5-ht4
WO1993005040A1 (fr) * 1991-09-12 1993-03-18 Smithkline Beecham Plc Composes azacycliques utilises comme antagonistes du recepteur 5-ht¿4?
WO1993005038A1 (fr) * 1991-09-12 1993-03-18 Smithkline Beecham Plc Antagonistes de recepteurs 5-hydroxytriptamine 4
WO1993018036A1 (fr) * 1992-03-12 1993-09-16 Smithkline Beecham Plc Derives condenses d'indoles en tant qu'antagonistes du recepteur 5ht¿4?
WO1994005654A1 (fr) * 1992-09-10 1994-03-17 Smithkline Beecham Plc Composes d'heteroaryle utilises en tant que produits pharmaceutiques
WO1994010174A1 (fr) * 1992-11-05 1994-05-11 Smithkline Beecham Plc Derives de piperidine utiles comme antagonistes de recepteur de 5-ht4

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GB2176785A (en) * 1985-06-19 1987-01-07 Astra Laekemedel Ab Annellated benzamide derivatives
EP0389037A1 (fr) * 1989-03-22 1990-09-26 Janssen Pharmaceutica N.V. Dérivés du N-(hydroxy-3 pipéridinyl-4)(dihydrobenzofuranne, dihydro-2H-benzopyranne ou dihydrobenzodioxine)carboxamide
EP0407137A2 (fr) * 1989-07-03 1991-01-09 Yoshitomi Pharmaceutical Industries, Ltd. Dérivés de benzazine et leurs applications pharmaceutiques
EP0501322A1 (fr) * 1991-02-25 1992-09-02 Glaxo Group Limited Esters pipéridimylmethyl substitués d'acide indole-3-carbonyligne
WO1993003725A1 (fr) * 1991-08-20 1993-03-04 Smithkline Beecham Plc Antagonistes du recepteur 5-ht4
WO1993005040A1 (fr) * 1991-09-12 1993-03-18 Smithkline Beecham Plc Composes azacycliques utilises comme antagonistes du recepteur 5-ht¿4?
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WO1994010174A1 (fr) * 1992-11-05 1994-05-11 Smithkline Beecham Plc Derives de piperidine utiles comme antagonistes de recepteur de 5-ht4

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COLLIN, SONIA ET AL: "Molecular structure analysis of benzamide neuroleptics and analogs. XI. exo-2,3-Dihydro-N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-1,3- benzodioxole-5-carboxamide and exo-2,3-dihydro-N-(8-benzyl-8- azabicyclo[3.2.1]oct-3-yl)-1,4-benzodioxin-4-carboxamide", ACTA CRYSTALLOGR., SECT. C: CRYST. STRUCT. COMMUN., vol. C43, no. 3, 1987, pages 572 - 577 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5998409A (en) * 1992-03-12 1999-12-07 Smithkline Beecham Plc Condensed indole derivatives as 5HT4 -receptor antagonists
US5852014A (en) * 1992-03-12 1998-12-22 Smithkline Beecham P.L.C. 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
US6509339B2 (en) 1996-02-29 2003-01-21 Janssen Pharmaceutica N.V. N-substituted 4-((4′-aminobenzoyl)-oxymethyl)-piperidines having gastric prokinetic properties
US6291481B1 (en) 1996-02-29 2001-09-18 Janssen Pharmaceutica, N.V. N-substituted 4-(4′-aminobenzoyl)-oxymethyl)-piperidines having gastric prokinetic properties
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GB9312348D0 (en) 1993-07-28
JPH08511259A (ja) 1996-11-26

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