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WO1993016072A1 - Derives de benzopyrane, de benzothiopyrane et de coumarone utilises comme antagonistes du recepteur 5-ht4 - Google Patents

Derives de benzopyrane, de benzothiopyrane et de coumarone utilises comme antagonistes du recepteur 5-ht4 Download PDF

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Publication number
WO1993016072A1
WO1993016072A1 PCT/GB1993/000214 GB9300214W WO9316072A1 WO 1993016072 A1 WO1993016072 A1 WO 1993016072A1 GB 9300214 W GB9300214 W GB 9300214W WO 9316072 A1 WO9316072 A1 WO 9316072A1
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Prior art keywords
alkyl
hydrogen
compound according
formula
halo
Prior art date
Application number
PCT/GB1993/000214
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English (en)
Inventor
Francis David King
Laramie Mary Gaster
Graham Francis Joiner
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
Priority claimed from GB929202510A external-priority patent/GB9202510D0/en
Priority claimed from GB929215499A external-priority patent/GB9215499D0/en
Priority claimed from GB929221446A external-priority patent/GB9221446D0/en
Priority claimed from GB929225788A external-priority patent/GB9225788D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to NZ246915A priority Critical patent/NZ246915A/en
Priority to AU34572/93A priority patent/AU667874B2/en
Priority to US08/284,448 priority patent/US6127379A/en
Priority to EP93917412A priority patent/EP0625149A1/fr
Priority to JP5513865A priority patent/JPH07503480A/ja
Publication of WO1993016072A1 publication Critical patent/WO1993016072A1/fr
Priority to KR1019940702728A priority patent/KR950700288A/ko

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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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to the use of compounds as 5-HT 4 receptor antagonists in the treatment of gastrointestinal disorders, CNS disorders including migraine and/or cardiovascular disorders, and to certain novel compounds having 5-HT 4 receptor antagonist activity.
  • EP-A-501322 (Glaxo Group Limited) describes indole derivatives having 5-HT 4 antagonist activity.
  • 5-HT 3 receptor antagonists have been disclosed as of potential use in the treatment of certain aspects of irritable bowel syndrome [EP-A-189002 (Sandoz Limited) and EP-A-201165 (Beecham Group p.l.c)].
  • 5-HT 3 receptor interactions which are of potential use in the treatment of IBS are those associated either with the visceral pain and abnormal perception of sensation aspects of this disease, or they are related to the ability of some 5- HT 3 receptor antagonists to cause constipation in volunteers.
  • 5-HT 3 receptor antagonists have been disclosed as of potential use in the treatment of gastrointestinal disorders associated with upper gut motility [EP-A-226266 (Glaxo Group Ltd.) and EP-A-189002 (Sandoz Limited)].
  • 5-HT 3 receptor antagonists are also well known antiemetics, such as ondansetron, granisetron and tropisetron [Drugs of the Future 1989, 14 (9) p.875 - F.D. King and G.J. Sanger].
  • EP-A-234872 (Adria), US 4859683 (Rorer) and EP-A-307172 (Lilly) describe 5-HT 3 receptor antagonists derived from a benzoic acid nucleus, 2,3-disubstituted by alkyleneoxy. It has now been discovered that certain of the compounds embraced by the general formulae disclosed therein, and related compounds, have 5-HT 4 receptor antagonist properties, and are therefore of potential use in the treatment of IBS or atrial arrhythmias and stroke.
  • the compounds of the present invention also have a potential use in the treatment of CNS disorders such as anxiety and/or migraine, in the treatment of upper gut motility disorders and as antiemetics.
  • the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • one of X-) and X2 is O, S or CH 2 and the other is CH 2 ;
  • x is 1 , 2 or 3;
  • R 1 is hydrogen, amino, halo, C 1-6 alkyl, hydroxy or C 1-6 alkoxy;
  • R 2 is hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, nitro, amino or C 1-6 alkylthio;
  • R 3 is hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy or amino
  • R 4 and R 5 are independently hydrogen or C 1-6 alkyl
  • Y is O or NH
  • Z is of sub-formula (a), (b) or (c):
  • R a is hydrogen or a lipophilic group, such as C 1-12 alkyl or aralkyl; or
  • R a is (CH 2 ) r -R 10 wherein r is 2 or 3 and R 10 is selected from cyano,
  • R 1 1 and R 12 are hydrogen or C 1-6 alkyl
  • 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 examples include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9t 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 -(CH 2 ) 2 -X 2 is O-(CH 2 ) 2 -CH 2 .
  • R 1 is preferably hydrogen or amino.
  • R 2 is preferably hydrogen or halo.
  • R 3 is preferably hydrogen or halo.
  • R 4 and R 5 are often hydrogen. When R 4 /R 5 is C 1-6 alkyl, it is often methyl. In particular R 4 and R 5 are methyl such that the disubstituent containing X 1 and X 2 is X 1 -C(CH 3 ) 2 -X 2 .
  • 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.
  • the N-substituent in formula (i) or (ii) may be replaced by (CH 2 ) n R 4 , as defined in formula(l) and in relation to the specific examples of EP-A-501322.
  • the invention also provides novel compounds within formula (I) having
  • 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 (CH 2 ) n 2 moiety in compounds of formula (I) wherein Z is (b), may adopt an ⁇ or ⁇ or configuration with respect to the fused azabicyclic moiety.
  • the compounds of formula (I) wherein CO-Y is an ester or amide linkage are prepared by conventional coupling of the Z moiety with the appropriate acid. Suitable methods are as described in GB 2125398A (Sandoz Limited), GB 1593146A, EP-A-36269 and EP-A-289170 (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).
  • 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.
  • 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.
  • Anxiolytic activity is likely to be effected via the hippocampus (Dumais 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.
  • 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.
  • Such compositions are prepared by admixture and are usually adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges,
  • reconstitutable powders injectable and infusable solutions or suspensions or suppositories.
  • 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 ortabletting. 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 anodide
  • 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.
  • 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 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, gastrooesophageal reflux disease, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine.
  • 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, gastrooesophageal 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 residual acid chloride was dissolved in dry THF (20 ml) and added dropwise to a solution of the lithium anion of 1-butyl-4-piperidinemethanol in dry THF, prepared by treating a solution of 1-butyl-4-piperidinemethanol (0.29g) in dry THF (20ml) with butyllithium (1.1 ml of a 1.6 molar solution in hexane), at 0°C under nitrogen for 15 minutes. After stirring at ambient temperature overnight, the reaction mixture was diluted with water, the volatile solvent was evaporated under reduced pressure, and the product was extracted into dichloromethane. The organic phase was dried (Na 2 SO 4 ) and the solvent was evaporated under reduced pressure.
  • Methyllithium (1.5M in diethyl ether, 0.97 ml) was added dropwise to a cooled (0°C) solution of 1-butyl-4-piperidinemethanol (250 mg) in dry THF (10 ml) under a nitrogen atmosphere. Stirring was continued at room temperature for 10 min. A solution of the imidazolide in dry THF (10ml) was added and stirring continued overnight. Water was added and the solvent concentrated in vacuo. The residue was partitioned between chloroform and water. The organic phase was dried (Na 2 SO 4 ), filtered and concentrated. The residue was chromatographed on silica using chloroform and ethanol as eluant to afford pure ester (471 mg) as an oil.
  • Methylthiochroman-4-one-8-carboxylate (0.500g, 2.25mmol) was dissolved with stirring in ethanol (20 ml). After 1 h, the reaction mixture was evaporated under reduced pressure and the residue partitioned between ethyl acetate and water.
  • Methyl thiochroman-4-ol-8-carboxylate (0.337g, 1.50 mmol) was dissolved in toluene (25ml) and was treated with p-toluenesulphonic acid (0.028g, 0.15 mmol). The mixture was then heated to reflux with stirring. After 2h, the reaction mixture was allowed to cool and was washed with sodium hydrogen carbonate solution.
  • Methyl-2H-thiochromene-8-carboxylate (1.83g, 8.88 mmol) was dissolved in ethanol (100ml) and treated with 10% PdC (1.5g). The mixture was then hydrogenated at atmospheric pressure at room temperature. After 19h the reaction mixture was filtered through celite and evaporated under reduced pressure to give a colourless oil which was dried in vacuo to give the title compound (1.25g, 68%) 1 H NMR (200 MHz, CDCI 3 ), ⁇ 7.80 (d, 1 H), 7.62 (d, 1 H), 6.97 (t, 1 H), 3.89 (s, 3H), 2.97 (t, 2H), 2.87 (t, 2H), 2.12 (m, 2H).
  • 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 4 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, plC 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% 02/5% 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).
  • the compound E3 showed inhibition at a dose of 10 ⁇ g kg - 1 .

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Abstract

L'invention se rapporte à des composés de la formule (I) et à des sels pharmaceutiquement acceptables de ceux-ci, dans laquelle X1-(CH2)x-X2 et les atomes de carbone aromatiques auxquels ils sont fixés forment un noyau de 5 à 7 éléments dans lequel un élément parmi X1 et X2 représente O, S ou CH2 et l'autre représente CH2; x est 1, 2, ou 3; R1 représente hydrogène, amino, halo, alkyle C1-6, hydroxy ou alcoxy C1-6; R2 représente hydrogène, halo et alkyle C1-6, alcoxy C1-6, nitro, amino ou alkylthio C1-6; R3 représente hydrogène, halo, alkyle C1-6, alcoxy C1-6 ou amino; R4 et R5 représentent indépendamment hydrogène ou alkyle C1-6; Y représente O ou NH; Z représente la sous-formule (a), (b) ou (c), dans laquelle n1 est 1, 2, 3 ou 4; n2 est 1 ou 2; n3 est 2, 3, 4 ou 5; q est 0, 1, 2 ou 3; p est 0, 1 ou 2; m est 0, 1 ou 2; R¿a? représente hydrogène ou un groupe lipophilee tel qu'alkyle C1-12 ou aralkyle; ou Ra représente (CH2)ΗR10 où r est 2 ou 3 et R10 est sélectionné parmi cyano, hydroxyle, alcoxy C1-6, phénoxy, alkyle C(O)C1-6, COC6H5, -CR11R12, NR11COR12, SO2NR11R12 ou NR11SO2R12 où R11 et R12 représentent hydrogène ou alkyle C1-6; et R6, R7 et R8 représentent indépendamment hydrogène ou alkyle C1-6; et R9 représente hydrogène ou alkyle C1-10; ou un composé de la formule (I) dans laquelle la liaison CO-Y est remplacée par un bioisostère hétérocyclique; l'invention se rapporte également à l'utilisation de ces composés comme produits pharmaceutiques dans le traitement de troubles gastro-intestinaux, de troubles cardiovasculaires et de troubles du système nerveux central (SNC).
PCT/GB1993/000214 1992-02-06 1993-02-01 Derives de benzopyrane, de benzothiopyrane et de coumarone utilises comme antagonistes du recepteur 5-ht4 WO1993016072A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
NZ246915A NZ246915A (en) 1992-02-06 1993-02-01 Benzopyran, benzothiopyran and benzofuran derivatives, preparation and pharmaceutical compositions thereof
AU34572/93A AU667874B2 (en) 1992-02-06 1993-02-01 Benzopyran, benzothiopyran and benzofuran derivatives as 5-HT4 antagonists
US08/284,448 US6127379A (en) 1993-02-01 1993-02-01 Benzopyran, benzothiopyran and benzofuran derivatives as 5-HT4 antagonists
EP93917412A EP0625149A1 (fr) 1992-02-06 1993-02-01 Derives de benzopyrane, de benzothiopyrane et de coumarone utilises comme antagonistes du recepteur 5-ht4
JP5513865A JPH07503480A (ja) 1992-02-06 1993-02-01 ５−ｈｔ４拮抗薬としてのベンゾピラン，ベンゾチオピランおよびベンゾフラン誘導体
KR1019940702728A KR950700288A (ko) 1992-02-06 1994-08-05 5-에이취티4 길항제로서의 벤조피란, 벤조티오피란 및 벤조푸란 유도체(Benzopyran, benzothiopyran and benzofuran derivatives as 5-HT4 antagonists)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
GB9202510.5 1992-02-06
GB929202510A GB9202510D0 (en) 1992-02-06 1992-02-06 Pharmaceuticals
GB929215499A GB9215499D0 (en) 1992-07-21 1992-07-21 Pharmaceuticals
GB9215499.6 1992-07-21
GB9221446.9 1992-10-13
GB929221446A GB9221446D0 (en) 1992-10-13 1992-10-13 Pharmaceuticals
GB929225788A GB9225788D0 (en) 1992-12-10 1992-12-10 Pharmaceuticals
GB9225788.0 1992-12-10

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EP (1) EP0625149A1 (fr)
JP (1) JPH07503480A (fr)
KR (1) KR950700288A (fr)
AU (1) AU667874B2 (fr)
CA (1) CA2129112A1 (fr)
MX (1) MX9300616A (fr)
NZ (1) NZ246915A (fr)
WO (1) WO1993016072A1 (fr)

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WO1993024117A3 (fr) * 1992-05-23 1994-04-14 Smithkline Beecham Plc Medicaments pour le traitement de l'anxiete
WO1994000113A3 (fr) * 1992-06-27 1994-04-14 Smithkline Beecham Plc Medicaments renfermant des antagonistes du recepteur de 5-ht¿4?
WO1994008994A1 (fr) * 1992-10-13 1994-04-28 Smithkline Beecham Plc Esters ou amides heterocycliques utilises comme antagonistes de recepteur de 5-ht¿4?
WO1994008995A1 (fr) * 1992-10-13 1994-04-28 Smithkline Beecham Plc Derives heterocycliques condenses d'acide benzoique utilises comme antagonistes des recepteurs 5-ht¿4?
WO1994019344A1 (fr) * 1993-02-19 1994-09-01 Smithkline Beecham Plc Composes d'amide a activite pharmacologique
WO1996033186A1 (fr) * 1995-04-18 1996-10-24 Pharmacia & Upjohn S.P.A. Derives de dihydrobenzofurane substitues utilises en tant qu'agonistes de 5-ht¿4?
WO1997017345A1 (fr) * 1995-11-09 1997-05-15 Synthelabo Derives de 5-phenyl-3-(piperidin-4-yl)-1,3,4-oxadiazol-2(3h)-one, utiles comme ligands des recepteurs 5-ht4 ou h¿3?
WO1997031897A1 (fr) * 1996-02-29 1997-09-04 Janssen Pharmaceutica N.V. Nouvelles 4-((4'-aminobenzoyl)-oxymethyl)-piperidines n-substituees ayant des proprietes gastrocinetiques
FR2745574A1 (fr) * 1996-03-04 1997-09-05 Synthelabo Derives de 5-phenyl-3-(piperidin-4-yl)-1, 3, 4-oxadiazol-2 (3h)-one, leur preparation et leur application en therapeutique
AU682317B2 (en) * 1992-09-10 1997-10-02 Smithkline Beecham Plc Heteroaryl compounds used as pharmaceuticals
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
FR2762316A1 (fr) * 1997-04-18 1998-10-23 Sanofi Synthelabo Derives de 5-aryl-3-(8-azabicyclo[3.2.1] octan-3-yl)-1,3,4- oxadiazol-2(3h)-one, leur preparation et leur application en therapeutique
WO1998050381A1 (fr) * 1997-05-06 1998-11-12 Sanofi-Synthelabo Derives de 3-(pyrrolidin-3-yl)-1,3,4-oxadiazol-2(3h)-one et leur utilisation comme ligands 5-ht4
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
WO2000015636A1 (fr) * 1998-09-10 2000-03-23 F. Hoffmann-La Roche Ag Dihydrobenzodioxine carboxamide et derives de cetone utilises comme antagonistes du recepteur 5-ht4
WO2000037461A1 (fr) * 1998-12-22 2000-06-29 Janssen Pharmaceutica N.V. 4-(aminomethyl)-piperidine benzamides permettant de traiter les troubles gastro-intestinaux
US6635643B2 (en) 1997-07-11 2003-10-21 Janssen Pharmaceutica, N.V. Bicyclic benzamides of 3- or 4-substituted 4-(aminomethyl)-piperidine derivatives
WO2005003122A1 (fr) * 2003-06-19 2005-01-13 Janssen Pharmaceutica N.V. 4-(aminomethyl)-piperidine benzamides antagonistes des recepteurs 5ht4

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US5708174A (en) * 1992-03-12 1998-01-13 Smithkline Beecham P.L.C. Heterocyclic-esters or -amides used as 5-HT4 receptor antagonists
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
WO1993024117A3 (fr) * 1992-05-23 1994-04-14 Smithkline Beecham Plc Medicaments pour le traitement de l'anxiete
US5763459A (en) * 1992-05-23 1998-06-09 Smithkline Beecham P.L.C. Medicaments for the treatment of anxiety
WO1994000113A3 (fr) * 1992-06-27 1994-04-14 Smithkline Beecham Plc Medicaments renfermant des antagonistes du recepteur de 5-ht¿4?
AU682317B2 (en) * 1992-09-10 1997-10-02 Smithkline Beecham Plc Heteroaryl compounds used as pharmaceuticals
US5696129A (en) * 1992-09-29 1997-12-09 Smithkline Beecham P.L.C. 5-HT4 antagonists
WO1994007859A1 (fr) * 1992-09-29 1994-04-14 Smithkline Beecham Plc Antagonistes du 5-ht4
WO1994008994A1 (fr) * 1992-10-13 1994-04-28 Smithkline Beecham Plc Esters ou amides heterocycliques utilises comme antagonistes de recepteur de 5-ht¿4?
WO1994008995A1 (fr) * 1992-10-13 1994-04-28 Smithkline Beecham Plc Derives heterocycliques condenses d'acide benzoique utilises comme antagonistes des recepteurs 5-ht¿4?
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
WO1994019344A1 (fr) * 1993-02-19 1994-09-01 Smithkline Beecham Plc Composes d'amide a activite pharmacologique
WO1996033186A1 (fr) * 1995-04-18 1996-10-24 Pharmacia & Upjohn S.P.A. Derives de dihydrobenzofurane substitues utilises en tant qu'agonistes de 5-ht¿4?
CN1077891C (zh) * 1995-11-09 2002-01-16 圣诺菲-合成实验室公司 作为5-ht4或h3受体配位体有效的5-苯基-3-(哌啶-4-基)-1,3,4-噁二唑-2(3h)-酮衍生物
WO1997017345A1 (fr) * 1995-11-09 1997-05-15 Synthelabo Derives de 5-phenyl-3-(piperidin-4-yl)-1,3,4-oxadiazol-2(3h)-one, utiles comme ligands des recepteurs 5-ht4 ou h¿3?
US6291481B1 (en) 1996-02-29 2001-09-18 Janssen Pharmaceutica, N.V. N-substituted 4-(4′-aminobenzoyl)-oxymethyl)-piperidines having gastric prokinetic properties
US6800628B2 (en) 1996-02-29 2004-10-05 Janssen Pharmaceutica N.V. N-substituted 4-((-4′-aminobenzoyl)-oxymethyl)-piperidines having gastric prokinetic properties
US6509339B2 (en) 1996-02-29 2003-01-21 Janssen Pharmaceutica N.V. N-substituted 4-((4′-aminobenzoyl)-oxymethyl)-piperidines having gastric prokinetic properties
WO1997031897A1 (fr) * 1996-02-29 1997-09-04 Janssen Pharmaceutica N.V. Nouvelles 4-((4'-aminobenzoyl)-oxymethyl)-piperidines n-substituees ayant des proprietes gastrocinetiques
FR2745574A1 (fr) * 1996-03-04 1997-09-05 Synthelabo Derives de 5-phenyl-3-(piperidin-4-yl)-1, 3, 4-oxadiazol-2 (3h)-one, leur preparation et leur application en therapeutique
FR2762316A1 (fr) * 1997-04-18 1998-10-23 Sanofi Synthelabo Derives de 5-aryl-3-(8-azabicyclo[3.2.1] octan-3-yl)-1,3,4- oxadiazol-2(3h)-one, leur preparation et leur application en therapeutique
WO1998047898A1 (fr) * 1997-04-18 1998-10-29 Sanofi-Synthelabo Derives de 5-aryl-3-(8-azabicyclo(3.2.2)oct-3-yl)-1,3,4-oxadiazol-2(3h)-one en tant que ligands des recepteurs 5-ht4
RU2186066C2 (ru) * 1997-04-18 2002-07-27 Санофи-Синтелябо Производные 5-арил-3-(8-азабицикло[3.2.1]окт-3-ил)-1,3,4-оксадиазол-2(3h)-она, способ их получения, лекарственное средство и фармацевтическая композиция
WO1998050381A1 (fr) * 1997-05-06 1998-11-12 Sanofi-Synthelabo Derives de 3-(pyrrolidin-3-yl)-1,3,4-oxadiazol-2(3h)-one et leur utilisation comme ligands 5-ht4
US6248757B1 (en) 1997-05-06 2001-06-19 Sanofi-Synthelabo 3-(Pyrrolidin-3-yl)-1,3,4-oxadiazol-2(3H)-one derivatives and their use as 5-HT4 ligands
FR2763068A1 (fr) * 1997-05-06 1998-11-13 Synthelabo Derives de 3-(pyrrolidin-3-yl)-1,3,4-oxadiazol-2(3h)-one, leur preparation et leur application en therapeutique
US8063070B2 (en) 1997-07-11 2011-11-22 Janssen Pharmaceutica, N.V. Bicyclic benzamides of 3-or 4-substituted 4-(aminomethyl)-piperidine derivatives
US8318742B2 (en) 1997-07-11 2012-11-27 Janssen Pharmaceutica, N.V. Bicyclic benzamides of 3- or 4-substituted 4-(aminomethyl)-piperidine derivatives
US7790750B2 (en) 1997-07-11 2010-09-07 Janssen Pharmaceutica N.V. Bicyclic benzamides of 3- or 4-substituted 4-(aminomethyl)-piperidine derivatives
US6635643B2 (en) 1997-07-11 2003-10-21 Janssen Pharmaceutica, N.V. Bicyclic benzamides of 3- or 4-substituted 4-(aminomethyl)-piperidine derivatives
USRE40793E1 (en) 1997-07-11 2009-06-23 Janssen Pharmaceutica, N.V. Bicyclic benzamides of 3-or 4-substituted 4-(aminomethyl)-piperidine derivatives
US6172062B1 (en) * 1998-09-10 2001-01-09 Syntex (Usa) Llc Dihydrobenzodioxine carboxamide and ketone derivatives
WO2000015636A1 (fr) * 1998-09-10 2000-03-23 F. Hoffmann-La Roche Ag Dihydrobenzodioxine carboxamide et derives de cetone utilises comme antagonistes du recepteur 5-ht4
US7205410B2 (en) 1998-12-22 2007-04-17 Janssen Pharmaceutica, N.V. 4-(aminomethyl)-piperidine benzamides for treating gastrointestinal disorders
AU770397B2 (en) * 1998-12-22 2004-02-19 Janssen Pharmaceutica N.V. 4-(aminomethyl)-piperidine benzamides for treating gastrointestinal disorders
CZ300851B6 (cs) * 1998-12-22 2009-08-26 Janssen Pharmaceutica N. V. 4-(Aminomethyl)piperidinbenzamid, zpusob a meziprodukt pro jeho prípravu a farmaceutická kompozice s jeho obsahem pro lécení gastrointestinálních poruch
US6544997B1 (en) 1998-12-22 2003-04-08 Janssen Pharmaceutica, N.V. 4-(aminomethyl)-piperidine benzamides for treating gastrointestinal disorders
WO2000037461A1 (fr) * 1998-12-22 2000-06-29 Janssen Pharmaceutica N.V. 4-(aminomethyl)-piperidine benzamides permettant de traiter les troubles gastro-intestinaux
WO2005003122A1 (fr) * 2003-06-19 2005-01-13 Janssen Pharmaceutica N.V. 4-(aminomethyl)-piperidine benzamides antagonistes des recepteurs 5ht4
EA010630B1 (ru) * 2003-06-19 2008-10-30 Янссен Фармацевтика Н.В. 4-(аминометил) пиперидинбензамиды, обладающие 5нт-антагонистической активностью
US7635706B2 (en) 2003-06-19 2009-12-22 Janssen Pharmaceutica Nv 5HT4-antagonistic 4-(aminomethyl)-piperidine benzamides

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AU3457293A (en) 1993-09-03
KR950700288A (ko) 1995-01-16
CA2129112A1 (fr) 1993-08-19
AU667874B2 (en) 1996-04-18
NZ246915A (en) 1996-05-28
MX9300616A (es) 1993-09-01
EP0625149A1 (fr) 1994-11-23
JPH07503480A (ja) 1995-04-13

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