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WO1993003725A1 - Antagonistes du recepteur 5-ht4 - Google Patents

Antagonistes du recepteur 5-ht4 Download PDF

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Publication number
WO1993003725A1
WO1993003725A1 PCT/GB1992/001519 GB9201519W WO9303725A1 WO 1993003725 A1 WO1993003725 A1 WO 1993003725A1 GB 9201519 W GB9201519 W GB 9201519W WO 9303725 A1 WO9303725 A1 WO 9303725A1
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WO
WIPO (PCT)
Prior art keywords
butyl
piperidyl
solution
nmr
carboxylate
Prior art date
Application number
PCT/GB1992/001519
Other languages
English (en)
Inventor
Francis David King
Laramie Mary Gaster
Graham Francis Joiner
Shirley Katherine Rahman
Gareth John Sanger
Kay Alison Wardle
Gordon Smith Baxter
Guy Anthony Kennett
Rodney Christopher Young
Mythily Vimal
Alberto Julio Kaumann
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 GB919117943A external-priority patent/GB9117943D0/en
Priority claimed from GB919119692A external-priority patent/GB9119692D0/en
Priority claimed from GB929201414A external-priority patent/GB9201414D0/en
Priority claimed from GB929203977A external-priority patent/GB9203977D0/en
Priority claimed from GB929208321A external-priority patent/GB9208321D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to EP92917490A priority Critical patent/EP0600955A1/fr
Priority to JP5504191A priority patent/JPH06510283A/ja
Publication of WO1993003725A1 publication Critical patent/WO1993003725A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • This invention relates to the use of compounds as 5-HT 4 receptor antagonists in the treatment of gastrointestinal disorders, CNS disorders and/or cardiovascular disorders, and to certain novel compounds having 5-HT 4 receptor antagonist activity.
  • PCT/GB91/00650 (SmithKline and French Laboratories Limited) describes the use of cardiac 5-HT 4 receptor antagonists in the treatment of atrial arrhythmias and stroke.
  • 5- ⁇ T 3 receptor antagonists have been disclosed as of potential use in the treatment of certain aspects of irritable bowel syndrome [see
  • 5- ⁇ T 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- ⁇ T 3 receptor antagonists to cause constipation in volunteers.
  • 5- ⁇ T 3 receptor antagonists have been disclosed as of potential use in the treatment of gastrointestinal disorders associated with upper gut motility [see EP-A-226266 (Glaxo Group Ltd.) and EP-A- 189002 (Sandoz limited)].
  • 5- ⁇ T 3 receptor antagonists are also well known antiemetics, such as ondansetron, granisetron and tropisetron (see Drugs of the Future 1989, 14 (9) p.875 - F.D. King and G.J. Sanger).
  • EP-A-189002 (Sandoz Limited) and EP-A-429984 disclose compounds which are described as 5- ⁇ T 3 receptor antagonists useful in the treatment of gastrointestinal disorders. We have now discovered that certain of these compounds and related compounds act as antagonists at 5-HT 4 receptors and are 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.
  • 'treatment' includes prophylaxis as appropriate.
  • the invention therefore provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • X is a group of formula (a), (b) or (c):
  • L is N or CR s wherein R s is hydrogen, C 1-6 alkoxy, halogen, C 1-4 alkyl or cyano;
  • Q is NR 1 , CH 2 , O or S
  • W is CH or N
  • R a is hydrogen, halo, C 1-6 alkyl, amino, nitro or C 1-6 alkoxy
  • R b is hydrogen, halo, C 1-6 alkyl or C 1-6 alkoxy
  • R 1 is hydrogen, C 1-10 alkyl, C 2-3 alkenyl, aralkyl, C 2-6 alkanoyl or C 2-6 alkanoyl C 1-3 alkyl;
  • R 2 is C 1-6 alkoxy
  • R 3 is hydrogen, chloro or fluoro
  • R 4 is hydrogen, C 1-6 alkyl, amino optionally substituted by a C 1-6 alkyl group, halo, hydroxy or C 1-6 alkoxy;
  • R 5 is hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, nitro, amino or C 1-6
  • R 6 is hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy or amino
  • R c is hydrogen, C 1-6 alkoxy, halo or C 1-6 alkyl
  • Y is O or NH
  • Z is of sub-formula (d) or (e):
  • q 0, 1, 2 or 3;
  • R d is hydrogen, C 1-12 alkyl or aralkyl
  • R 7 and R 8 are 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 11 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.
  • Alkenyl includes all suitable values including E and Z forms.
  • Aryl includes phenyl and naphthyl optionally substituted by one or more substituents selected from halo, C- ⁇ .g alkyl and C 1-6 alkoxy.
  • Halo includes fluoro, chloro, bromo and iodo.
  • n 1 is preferably 2, 3 or 4 when the azacycle is attached at the nitrogen atom and n* 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 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) or (iv).
  • the invention also provides novel compounds within formula (I) wherein X is of formula (a) wherein L is C-OCH 3 , C-CH 3 or C- Cl, in particular those wherein the side chain Z is of sub-formula (i), (ii), (iii) or (iv).
  • X is of formula (a) wherein L is C-OCH 3 , C-CH 3 or C- Cl, in particular those wherein the side chain Z is of sub-formula (i), (ii), (iii) or (iv).
  • Other values of Z of interest are described with reference to the Examples, such as those in Examples 19 onwards.
  • side chain of formula (i) or (ii) is replaced by a corresponding side chain with an alkyl or optionally substituted benzyl N-substituent and/or wherein the 4- piperidinyl group is replaced by 3-azetidinyl or 3-pyrrolidinyl.
  • L in formula (a) is favourably C-H, C-CH 3 , C-Cl or C-OCH 3 .
  • Q in formula (a) is favourably NR 1 , usually NH or N-methyl.
  • R 1 is preferably hydrogen or a methyl or ethyl group.
  • R 2 is preferably methoxy.
  • R 4 is preferably amino.
  • R 5 is preferably halo.
  • R 6 is preferably hydrogen.
  • a substituent when halo is selected from fluoro, chloro, bromo and iodo, preferably chloro.
  • R b when halo is preferably iodo.
  • Y is preferably O.
  • Particularly suitable examples of compounds of formula (I) include those described in the Examples hereinafter and in Example 2 of EP-A-429984.
  • 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, suc ⁇ nic, 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, suc ⁇ nic, 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 cydoalkyl, and T is a radical corr ⁇ esponding to an anion of an add.
  • R x include methyl, ethyl and n- and iso-propyl; and benzyl and phenethyl.
  • Suitable examples of T indude halide such as chloride, bromide and iodide.
  • Examples of pharmaceutically acceptable salts also indude internal salts such as N-oxides.
  • 5-HT 4 receptor antagonist activity may be identified according to
  • the compound of formula (I) is a more potent antagonist at 5-HT 4 receptors than at 5- ⁇ T 3 receptors.
  • the 5-HT 4 receptor antagonist of formula (I) is in substantially pure pharmaceutically acceptable form.
  • the compounds of formula (I) may be prepared as described in the aforementioned patent references, or by analogous methods thereto.
  • 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 assodated 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 assodated with IBS.
  • They may also be of potential use in other gastrointestinal disorders, such as those assodated 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
  • 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 sodal 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 5-HT 4 antagonist pharmaceutical
  • composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pha ⁇ naceutically acceptable carrier.
  • compositions are prepared by admixture and are usually adapted for enteral such as oral, nasal or rectal, or parenteral a ⁇ jmmstration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, nasal sprays, suppositri.es, injectable and infusable solutions or suspensions.
  • 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 exdpients 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 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 ledthin, sorbitan monooleate, or acada; 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; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic add, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats
  • emulsifying agents for example ledthin, sorbitan monooleate, or acada
  • 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 vehide.
  • 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 induded 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, 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.
  • an amount effective to treat the disorders hereinbefore described depends on the relative efficades of the compounds to be administered, 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.
  • 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.
  • 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-oesophagal reflux disease, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine.
  • R 4 NH 2
  • R 4 NH 2
  • R 4 NH 2
  • E20 (as E1) O CH 2 -(1-butyl-3-pyrrolidinyl)
  • E21 (as E2) O (CH 2 ) 2 -(1-pentyl-3-pyrrolidinyl)
  • E22 (as E1) O (CH 2 ) 2 -(1-pentyl-3-pyrrolidinyl)
  • E25 (as E2) O (CH 2 ) 2 -(1-butyl-3-piperidyl)
  • E26 (as El) O (CH 2 ) 2 -(1-butyl-3-piperidyl)
  • E30 (as E2) O 1-butyl-4-piperidyl
  • E31 (as E2) O CH 2 -(1-butyl-1,2,5,6- tetrahydropyridyl)
  • the aqueous phase was basified with 50% aqueous sodium hydroxide and extracted with diethyl ether.
  • the organic phase was washed with water, dried (Na 2 SO 4 ) and concentrated in vacuo to afford an oil. Distillation under reduced pressure gave pure 3-chloromethyl-1- pentylpyrrolidine (5.79g).
  • a stirred solution of 3-chloromethyl-1-pentyl pyrrolidine (5.415g), tricaprylmethyl ammonium chloride (375 mg), and sodium cyanide (7.25g) in water (12.5 ml) was heated at 100°C for 24h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate.
  • acetonitrile (1.51) was added, dropwise chlorotrimethylsilane (203ml) at - 5°C under nitrogen. Stirring was continued at room temperature for 1 1 ⁇ 2 h.
  • 1-benzyl-4-chloro-3-hydroxybutylamine (310g) was added to the reaction and the resulting mixture heated to reflux for 72h, with vigorous stirring. The mixture was cooled to room temperature, toluene (21) was added and the mixture left to stand overnight. The predpitate was removed by filtration, slu ⁇ ied in petrol (bp 60-80°C) (21) and washed with water (200ml). The filtrate was concentrated in vacuo and the residue partitioned between water and petrol (bp 60-80°C) (11).
  • Example 1 (1-Ethyl-4-piperidyl)methyl-1H-indole-3-carboxylate (E1) A suspension of indole-3-carboxylic add (500 mg, 0.003 mole) in
  • dichloromethane 50 ml was treated with oxalyl chloride (0.635, 0.005 mole) and two drops of dimethylformamide. The mixture was stirred at room temperature for one and a half hours then the solvent was removed in vacuo. The residue was redissolved in dichloromethane (50 ml) and a solution of triethylamine (612 mg, 0.006 mole) and 1-ethyl-4- hydroxymethylpiperidine (430 mg, 0.003 mole) in dichloromethane (20 ml) was added dropwise. The reaction mixture was stirred at room
  • the imidazolide was dissolved in dry THF (20 ml) and the resulting solution added dropwise to the solution of the lithium alkoxide at 0°C.
  • the reaction mixture was allowed to warm to room temperature and was stirred for 3 hours.
  • the solvent was removed in vacuo and the residue partitioned between chloroform and water.
  • the chloroform was separated, washed several times with water, dried and concentrated to give a white solid (recrystallised from ether/petroleum ether) yield 2.6g, mp 135-6°C.
  • the title compound was prepared from 4-amino-5-chloro-2- methoxybenzoic add and 1-butyl-4-piperidinemethanol by the method described for Example 2. It was isolated as a white solid, mp 52-53°C.
  • the title compound was prepared in a similar manner to the compound of Example 6, from the 1-methylindazole add (EP-A-323105) m.p. 190°C. (hydrochloride salt).
  • the title compound was prepared in a similar manner to the compound of example 2, from 5-chloro-2-methoxy-4-methylbenzoic add (J. Chem. Soc, 1963, p.730), and isolated as the hydrochloride salt, m.p. 185-186°C.
  • dichloromethane 50 ml was treated with oxalyl chloride (0.635g, 0.005 mole) and two drops of dimethylformamide. The mixture was stirred at lOom temperature for 11 ⁇ 2 hours then the solvent was removed in vacuo to leave the add chloride.
  • the title compound was prepared from 4-amino-3,5-dichloro-2- methoxybenzoic add and 1-butyl-4-piperidylmethanol by the method described in Example 2, except that MeLi was used in place of n BuLi.
  • the product was isolated as the hydrochloride salt. mp 190-191°C 1 ⁇ NMR (200MHz) CDCl 3 (free base) ⁇ : 7.72(s,1H), 4.9(bs,2H), 4.12(d,2H), 3.85(s,3H), 2.85-3.0(bd,2H), 2.2-2.34(m,2H), 1.2-2.00(m, 1 1H), 0.90(t,3H).
  • 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-HT2 and 5- ⁇ T 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,
  • ⁇ jmethylphenylpiperazinium DMPP
  • 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.
  • pIC 50 values are determined, being defined as the -log concentration of antagonist which reduces the contraction by 50%.
  • a compound which reduces the response to 5-HT but not to DMPP is believed to act as a 5-HT 4 receptor antagonist.
  • Rat oesophageal tunica muscularis mucosae is set up according to Baxter et. al. Naunyn-Schmiedeberg's Arch. Pharmacol., 343, 439-446 (1991).
  • the inner smooth muscle tube of the muscularis mucosae is isolated and mounted for isometric tension recording in oxygenated (95% O 2 /5% CO 2 ) 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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  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Cardiology (AREA)
  • Neurosurgery (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention se rapporte à des composés de la formule X-CO-Y-Z, dans laquelle se trouvent les groupes variables tels que définis dans la spécification, utilisés dans le traitement de troubles gastrointestinaux, de troubles cardiovasculaires et de troubles du système nerveux central.
PCT/GB1992/001519 1991-08-20 1992-08-18 Antagonistes du recepteur 5-ht4 WO1993003725A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP92917490A EP0600955A1 (fr) 1991-08-20 1992-08-18 Antagonistes du recepteur 5-ht4
JP5504191A JPH06510283A (ja) 1991-08-20 1992-08-18 ５−ｈｔ４レセプター拮抗薬

Applications Claiming Priority (10)

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GB9117943.2 1991-08-20
GB919117943A GB9117943D0 (en) 1991-08-20 1991-08-20 Medicaments
GB919119692A GB9119692D0 (en) 1991-09-14 1991-09-14 Pharmaceuticals
GB9119692.3 1991-09-14
GB9201414.1 1992-01-23
GB929201414A GB9201414D0 (en) 1992-01-23 1992-01-23 Medicaments
GB929203977A GB9203977D0 (en) 1992-02-25 1992-02-25 Pharmaceuticals
GB9203977.5 1992-02-25
GB9208321.1 1992-04-15
GB929208321A GB9208321D0 (en) 1992-04-15 1992-04-15 Pharmaceuticals

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WO1993003725A1 true WO1993003725A1 (fr) 1993-03-04

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PCT/GB1992/001519 WO1993003725A1 (fr) 1991-08-20 1992-08-18 Antagonistes du recepteur 5-ht4

Country Status (8)

Country Link
EP (1) EP0600955A1 (fr)
JP (1) JPH06510283A (fr)
AU (2) AU2435092A (fr)
CA (1) CA2116024A1 (fr)
MX (1) MX9204786A (fr)
NZ (1) NZ243993A (fr)
PT (1) PT100785A (fr)
WO (1) WO1993003725A1 (fr)

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WO1993024117A2 (fr) * 1992-05-23 1993-12-09 Smithkline Beecham Plc Medicaments pour le traitement de l'anxiete
WO1994000113A2 (fr) * 1992-06-27 1994-01-06 Smithkline Beecham Plc Medicaments renfermant des antagonistes du recepteur de 5-ht¿4?
WO1994010174A1 (fr) * 1992-11-05 1994-05-11 Smithkline Beecham Plc Derives de piperidine utiles comme antagonistes de recepteur de 5-ht4
ES2056728A1 (es) * 1992-10-28 1994-10-01 Smithkline Beecham Plc Nuevos derivados de piperidilo y aminoalquilo con actividad antagonista del receptor 5-ht4
WO1994029298A1 (fr) * 1993-06-16 1994-12-22 Smithkline Beecham Plc 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
FR2717174A1 (fr) * 1994-03-14 1995-09-15 Sanofi Sa Utilisation de pipéridinoéthyl esters de l'acide 4-amino-5-chloro-2-méthoxybenzoïque comme 5-HT4 agonistes.
WO1995025100A1 (fr) * 1994-03-14 1995-09-21 Sanofi Utilisation d'esters de l'acide 4-amino-5-chloro-2-methoxybenzoique comme 5-ht4 agonistes
EP0683161A1 (fr) * 1994-05-17 1995-11-22 MIDY S.p.A. Nouvel ester de l'acide 4-amino-5-chloro-2-méthoxybenzoique, procédé pour sa préparation et compositions pharmaceutiques le contenant
WO1996005166A1 (fr) * 1994-08-11 1996-02-22 Yamanouchi Pharmaceutical Co., Ltd. Derive d'amine substitue et composition medicamenteuse le contenant
WO1996010026A1 (fr) * 1994-09-27 1996-04-04 Janssen Pharmaceutica N.V. Derives benzoates bicycliques de phenyl-oxo-alkyl-(4-piperidinyle)
WO1996010027A1 (fr) * 1994-09-27 1996-04-04 Janssen Pharmaceutica N.V. Derives benzoates bicycliques de piperidinyle n-substitue
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?
FR2741069A1 (fr) * 1995-11-09 1997-05-16 Synthelabo Derives de 5-phenyl-3-(piperidin-4-yl)-1,3,4-oxadiazol-2(3h) -one, leur preparation et leur application en therapeutique
US5654320A (en) * 1995-03-16 1997-08-05 Eli Lilly And Company Indazolecarboxamides
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
US5798367A (en) * 1995-03-16 1998-08-25 Eli Lilly And Company Indazolecarboxamides
WO1998046589A2 (fr) * 1997-04-15 1998-10-22 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Composes d'amide d'indazole utilises comme agents serotoninergiques
US5852014A (en) * 1992-03-12 1998-12-22 Smithkline Beecham P.L.C. Condensed indole derivatives as 5HT4 -receptor antagonists
FR2766484A1 (fr) * 1997-07-25 1999-01-29 Logeais Labor Jacques Nouveaux derives benzamides stimulants de la motricite gastrointestinale haute et basse
WO1999017772A1 (fr) * 1997-10-07 1999-04-15 Eli Lilly And Company Agonistes et antagonistes de 5-ht¿4?
US5945434A (en) * 1995-05-31 1999-08-31 Nisshin Flour Milling Co., Ltd. Indazole derivatives having monocyclic amine
US5998409A (en) * 1992-03-12 1999-12-07 Smithkline Beecham Plc Condensed indole derivatives as 5HT4 -receptor antagonists
US6127379A (en) * 1993-02-01 2000-10-03 Smithkline Beecham P.L.C. Benzopyran, benzothiopyran and benzofuran derivatives as 5-HT4 antagonists
US6166015A (en) * 1998-11-20 2000-12-26 Syntex (U.S.A.) Inc. Pyrrolidine derivatives-CCR-3 receptor antagonists
US6172062B1 (en) * 1998-09-10 2001-01-09 Syntex (Usa) Llc Dihydrobenzodioxine carboxamide and ketone derivatives
FR2821356A1 (fr) * 2001-02-23 2002-08-30 Cerep Nouveaux derives d'arylcarbamates et d'arylurees, preparations et utilisations
US6635643B2 (en) 1997-07-11 2003-10-21 Janssen Pharmaceutica, N.V. Bicyclic benzamides of 3- or 4-substituted 4-(aminomethyl)-piperidine derivatives
US6750195B2 (en) 1991-12-21 2004-06-15 Smithkline Beecham Corporation P.L.C. Use of 5-HT4 modulators for the manufacture of a medicament for the treatment of the bladder diseases
WO2005013989A1 (fr) * 2003-07-18 2005-02-17 Aziende Chimiche Riunite Angelini Francesco A.C.R..A.F. S.P.A. Derives d'indazol utilises pour traiter les douleurs neuropathiques
EP0699194B1 (fr) * 1993-05-22 2006-11-29 SmithKline Beecham plc Antagonistes de recepteur de 5-ht4
US7205410B2 (en) 1998-12-22 2007-04-17 Janssen Pharmaceutica, N.V. 4-(aminomethyl)-piperidine benzamides for treating gastrointestinal disorders
US7351704B2 (en) 2004-02-18 2008-04-01 Theravance, Inc. Indazole-carboxamide compounds as 5-HT4 receptor agonists
US7375114B2 (en) 2004-04-07 2008-05-20 Theravance, Inc. Quinolinone-carboxamide compounds as 5-HT4 receptor agonists
US7396933B2 (en) 2004-11-05 2008-07-08 Theravance, Inc. Quinolinone-carboxamide compounds
US7399862B2 (en) 2004-11-05 2008-07-15 Theravance, Inc. 5-HT4 receptor agonist compounds
US7419989B2 (en) 2004-12-22 2008-09-02 Theravance, Inc. Indazole-carboxamide compounds
US7446114B2 (en) 2005-03-02 2008-11-04 Theravance, Inc. Quinolinone compounds as 5-HT4 receptor agonists
US7728006B2 (en) 2004-04-07 2010-06-01 Theravance, Inc. Quinolinone-carboxamide compounds as 5-HT4 receptor agonists
US8309575B2 (en) 2004-04-07 2012-11-13 Theravance, Inc. Quinolinone-carboxamide compounds as 5-HT4 receptor agonists
US8829028B2 (en) 2002-05-16 2014-09-09 Serodus As 5-HT4 receptor antagonists for the treatment of heart failure
FR3006686A1 (fr) * 2013-06-05 2014-12-12 Univ Caen Composes inhibiteurs de l'acetylcholinesterase et agonistes des recepteurs serotoninergiques 5ht4, a effet promnesiant, leurs procedes de preparation et compositions pharmaceutiques les contenant
US10759804B2 (en) 2015-06-29 2020-09-01 Imperial College Innovations Limited Compounds and their use as inhibitors of N-myristoyl transferase

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Cited By (87)

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Publication number Priority date Publication date Assignee Title
US6750195B2 (en) 1991-12-21 2004-06-15 Smithkline Beecham Corporation P.L.C. Use of 5-HT4 modulators for the manufacture of a medicament for the treatment of the bladder diseases
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
WO1993024117A2 (fr) * 1992-05-23 1993-12-09 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
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?
WO1994000113A2 (fr) * 1992-06-27 1994-01-06 Smithkline Beecham Plc Medicaments renfermant des antagonistes du recepteur de 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
ES2056728A1 (es) * 1992-10-28 1994-10-01 Smithkline Beecham Plc Nuevos derivados de piperidilo y aminoalquilo con actividad antagonista del receptor 5-ht4
WO1994010174A1 (fr) * 1992-11-05 1994-05-11 Smithkline Beecham Plc Derives de piperidine utiles comme antagonistes de recepteur de 5-ht4
US5705498A (en) * 1992-11-05 1998-01-06 Smithkline Beecham Plc. Piperidine derivatives as 5-HT4 receptor antagonists
US6127379A (en) * 1993-02-01 2000-10-03 Smithkline Beecham P.L.C. Benzopyran, benzothiopyran and benzofuran derivatives as 5-HT4 antagonists
EP0699194B1 (fr) * 1993-05-22 2006-11-29 SmithKline Beecham plc Antagonistes de recepteur de 5-ht4
WO1994029298A1 (fr) * 1993-06-16 1994-12-22 Smithkline Beecham Plc 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
WO1995025100A1 (fr) * 1994-03-14 1995-09-21 Sanofi Utilisation d'esters de l'acide 4-amino-5-chloro-2-methoxybenzoique comme 5-ht4 agonistes
FR2717174A1 (fr) * 1994-03-14 1995-09-15 Sanofi Sa Utilisation de pipéridinoéthyl esters de l'acide 4-amino-5-chloro-2-méthoxybenzoïque comme 5-HT4 agonistes.
EP0683161A1 (fr) * 1994-05-17 1995-11-22 MIDY S.p.A. Nouvel ester de l'acide 4-amino-5-chloro-2-méthoxybenzoique, procédé pour sa préparation et compositions pharmaceutiques le contenant
WO1995031449A1 (fr) * 1994-05-17 1995-11-23 Sanofi Nouveaux esters de 3,5-dimethylpiperidin-1-ylalkyle
WO1996005166A1 (fr) * 1994-08-11 1996-02-22 Yamanouchi Pharmaceutical Co., Ltd. Derive d'amine substitue et composition medicamenteuse le contenant
WO1996010027A1 (fr) * 1994-09-27 1996-04-04 Janssen Pharmaceutica N.V. Derives benzoates bicycliques de piperidinyle n-substitue
US5872131A (en) * 1994-09-27 1999-02-16 Janssen Pharmaceutica, N.V. Phenyl-oxo-alkyl-(4-piperidinyl)benzoate derivatives
WO1996010026A1 (fr) * 1994-09-27 1996-04-04 Janssen Pharmaceutica N.V. Derives benzoates bicycliques de phenyl-oxo-alkyl-(4-piperidinyle)
US5817676A (en) * 1995-03-16 1998-10-06 Eli Lilly And Company Indazolecarboxamides
US5654320A (en) * 1995-03-16 1997-08-05 Eli Lilly And Company Indazolecarboxamides
AU700842B2 (en) * 1995-03-16 1999-01-14 Eli Lilly And Company Indazolecarboxamides
US5798367A (en) * 1995-03-16 1998-08-25 Eli Lilly And Company Indazolecarboxamides
CN1112923C (zh) * 1995-03-16 2003-07-02 伊莱利利公司 吲唑甲酰胺
US5945434A (en) * 1995-05-31 1999-08-31 Nisshin Flour Milling Co., Ltd. Indazole derivatives having monocyclic amine
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?
FR2741069A1 (fr) * 1995-11-09 1997-05-16 Synthelabo Derives de 5-phenyl-3-(piperidin-4-yl)-1,3,4-oxadiazol-2(3h) -one, leur preparation et leur application en therapeutique
US6509339B2 (en) 1996-02-29 2003-01-21 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
WO1997031897A1 (fr) * 1996-02-29 1997-09-04 Janssen Pharmaceutica N.V. Nouvelles 4-((4'-aminobenzoyl)-oxymethyl)-piperidines n-substituees ayant des proprietes gastrocinetiques
US6291481B1 (en) 1996-02-29 2001-09-18 Janssen Pharmaceutica, N.V. N-substituted 4-(4′-aminobenzoyl)-oxymethyl)-piperidines having gastric prokinetic properties
WO1998046589A3 (fr) * 1997-04-15 1999-01-28 Angelini Ricerche Spa Composes d'amide d'indazole utilises comme agents serotoninergiques
KR100563867B1 (ko) * 1997-04-15 2006-03-24 아지엔드 키미쉐 리유나이트 안젤리니 프란체스코 에이.씨.알.에이.에프. 에스.피.에이 혈관 수축제로써의 인다졸 아마이드 화합물
CN1318416C (zh) * 1997-04-15 2007-05-30 方济各安吉利克化学联合股份有限公司 5－羟色胺能试剂吲唑酰胺化合物
US6197769B1 (en) * 1997-04-15 2001-03-06 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Indazole amide compounds as serotoninergic agents
WO1998046589A2 (fr) * 1997-04-15 1998-10-22 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Composes d'amide d'indazole utilises comme agents serotoninergiques
EA002352B1 (ru) * 1997-04-15 2002-04-25 Ацьенде Кимике Рьюните Анджелини Франческо А.К.Р.А.Ф. С.П.А. Производные индазоламида в качестве серотонинергических агентов
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
US6635643B2 (en) 1997-07-11 2003-10-21 Janssen Pharmaceutica, N.V. Bicyclic benzamides of 3- or 4-substituted 4-(aminomethyl)-piperidine derivatives
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US7790750B2 (en) 1997-07-11 2010-09-07 Janssen Pharmaceutica N.V. Bicyclic benzamides of 3- or 4-substituted 4-(aminomethyl)-piperidine derivatives
WO1999005106A1 (fr) * 1997-07-25 1999-02-04 Laboratoires Jacques Logeais Nouveaux derives benzamides stimulants de la motricite gastrointestinale haute et basse
FR2766484A1 (fr) * 1997-07-25 1999-01-29 Logeais Labor Jacques Nouveaux derives benzamides stimulants de la motricite gastrointestinale haute et basse
WO1999017772A1 (fr) * 1997-10-07 1999-04-15 Eli Lilly And Company Agonistes et antagonistes de 5-ht¿4?
US6069152A (en) * 1997-10-07 2000-05-30 Eli Lilly And Company 5-HT4 agonists and antagonists
US6117882A (en) * 1997-10-07 2000-09-12 Eli Lilly And Company 5-HT4 agonists and antagonists
US6172062B1 (en) * 1998-09-10 2001-01-09 Syntex (Usa) Llc Dihydrobenzodioxine carboxamide and ketone derivatives
US6166015A (en) * 1998-11-20 2000-12-26 Syntex (U.S.A.) Inc. Pyrrolidine derivatives-CCR-3 receptor antagonists
US7205410B2 (en) 1998-12-22 2007-04-17 Janssen Pharmaceutica, N.V. 4-(aminomethyl)-piperidine benzamides for treating gastrointestinal disorders
FR2821356A1 (fr) * 2001-02-23 2002-08-30 Cerep Nouveaux derives d'arylcarbamates et d'arylurees, preparations et utilisations
WO2002068399A1 (fr) * 2001-02-23 2002-09-06 Cerep Derives d'arylcarbamates, preparation et utilisations
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US7238693B2 (en) 2001-02-23 2007-07-03 Cerep Aryl carbamate derivatives, preparation and use thereof
US8829028B2 (en) 2002-05-16 2014-09-09 Serodus As 5-HT4 receptor antagonists for the treatment of heart failure
US7638534B2 (en) 2003-07-18 2009-12-29 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Use of indazole derivatives for the treatment of neuropathic pain
WO2005013989A1 (fr) * 2003-07-18 2005-02-17 Aziende Chimiche Riunite Angelini Francesco A.C.R..A.F. S.P.A. Derives d'indazol utilises pour traiter les douleurs neuropathiques
KR101073993B1 (ko) * 2003-07-18 2011-10-17 아지엔드 키미쉐 리유나이트 안젤리니 프란체스코 에이.씨.알.에이.에프. 에스.피.에이 신경병증성 통증의 치료를 위한 인다졸 유도체의 용도
EA008144B1 (ru) * 2003-07-18 2007-04-27 Ацьенде Кимике Рьюните Анджелини Франческо A.K.P.A.Ф. С.П.А. Применение производных индазола для лечения невропатической боли
AU2004262878B2 (en) * 2003-07-18 2009-12-17 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Use of indazole derivatives for the treatment of neuropathic pain
US7351704B2 (en) 2004-02-18 2008-04-01 Theravance, Inc. Indazole-carboxamide compounds as 5-HT4 receptor agonists
US8044045B2 (en) 2004-02-18 2011-10-25 Theravance, Inc. Indazole-carboxamide compounds as 5-HT4 receptor agonists
US9873692B2 (en) 2004-04-07 2018-01-23 Theravance Biopharma R&D Ip, Llc Quinolinone-carboxamide compounds as 5-HT4 receptor agonists
US8309575B2 (en) 2004-04-07 2012-11-13 Theravance, Inc. Quinolinone-carboxamide compounds as 5-HT4 receptor agonists
US7763637B2 (en) 2004-04-07 2010-07-27 Theravance, Inc. Quinolinone-carboxamide compounds as 5-HT4, receptor agonists
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US7375114B2 (en) 2004-04-07 2008-05-20 Theravance, Inc. Quinolinone-carboxamide compounds as 5-HT4 receptor agonists
US7728006B2 (en) 2004-04-07 2010-06-01 Theravance, Inc. Quinolinone-carboxamide compounds as 5-HT4 receptor agonists
US9353106B2 (en) 2004-04-07 2016-05-31 Theravance Biopharma R&D Ip, Llc Quinolinone-carboxamide compounds as 5-HT4 receptor agonists
US7399862B2 (en) 2004-11-05 2008-07-15 Theravance, Inc. 5-HT4 receptor agonist compounds
US7396933B2 (en) 2004-11-05 2008-07-08 Theravance, Inc. Quinolinone-carboxamide compounds
US7498442B2 (en) 2004-11-05 2009-03-03 Theravance, Inc. Quinolinone-carboxamide compounds
US7534889B2 (en) 2004-11-05 2009-05-19 Theravance, Inc. 5-HT4 receptor agonist compounds
US7419989B2 (en) 2004-12-22 2008-09-02 Theravance, Inc. Indazole-carboxamide compounds
US8003664B2 (en) 2004-12-22 2011-08-23 Theravance, Inc. Indazole-carboxamide compounds
US7786136B2 (en) 2004-12-22 2010-08-31 Theravance, Inc. Indazole-carboxamide compounds
US7875629B2 (en) 2005-03-02 2011-01-25 Theravance, Inc. Quinolinone compounds as 5-HT4 receptor agonists
US7446114B2 (en) 2005-03-02 2008-11-04 Theravance, Inc. Quinolinone compounds as 5-HT4 receptor agonists
FR3006686A1 (fr) * 2013-06-05 2014-12-12 Univ Caen Composes inhibiteurs de l'acetylcholinesterase et agonistes des recepteurs serotoninergiques 5ht4, a effet promnesiant, leurs procedes de preparation et compositions pharmaceutiques les contenant
EP3004058B1 (fr) * 2013-06-05 2020-06-10 Université de Caen Composes inhibiteurs de l'acetylcholinesterase et agonistes des recepteurs serotoninergiques 5ht4, a effet promnesiant, leurs procedes de preparation et compositions pharmaceutiques les contenant
US10759804B2 (en) 2015-06-29 2020-09-01 Imperial College Innovations Limited Compounds and their use as inhibitors of N-myristoyl transferase
US11466011B2 (en) 2015-06-29 2022-10-11 Imperial College Innovations Limited Compounds and their use as inhibitors of N-myristoyl transferase

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EP0600955A1 (fr) 1994-06-15
MX9204786A (es) 1993-04-01
AU5194496A (en) 1996-07-18
PT100785A (pt) 1994-04-29
AU2435092A (en) 1993-03-16
JPH06510283A (ja) 1994-11-17
NZ243993A (en) 1994-10-26
CA2116024A1 (fr) 1993-03-04

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