WO1994027967A1 - Nouveaux composes - Google Patents

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Publication number
WO1994027967A1
WO1994027967A1 PCT/EP1994/001704 EP9401704W WO9427967A1 WO 1994027967 A1 WO1994027967 A1 WO 1994027967A1 EP 9401704 W EP9401704 W EP 9401704W WO 9427967 A1 WO9427967 A1 WO 9427967A1
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WO
WIPO (PCT)
Prior art keywords
dimethoxyphenyl
ethyl
formula
piperidinyl
compound
Prior art date
Application number
PCT/EP1994/001704
Other languages
English (en)
Inventor
Guy Marguerite Marie Gérard NADLER
Marcel Jean-Marie Morvan
Original Assignee
Smithkline Beecham Laboratoires Pharmaceutiques
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 FR9306290A external-priority patent/FR2705674B1/fr
Priority claimed from FR9309326A external-priority patent/FR2708607A1/fr
Application filed by Smithkline Beecham Laboratoires Pharmaceutiques filed Critical Smithkline Beecham Laboratoires Pharmaceutiques
Priority to JP7500224A priority Critical patent/JPH09501404A/ja
Priority to AU69717/94A priority patent/AU6971794A/en
Priority to EP94918376A priority patent/EP0700385A1/fr
Publication of WO1994027967A1 publication Critical patent/WO1994027967A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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

  • the invention relates to certain novel compounds, to pharmaceutical compositions containing such compounds, to a process for the preparation of such compounds and to the use of such compounds as active therapeutic agents.
  • European Patent Application, Publication Number 0416581 discloses certain substituted N-benzylpiperidine amides which are stated to be useful in the treatment of cardiac arrhythmias.
  • Anti-arrhythmic agents are classified according to their electrophysiological effects on the cardiac cell (Vaugham-Williams, 1970, 1989) : class 1 agents block the fast sodium current, class II agents are beta-adrenergic blockers, class III agents block potassium currents, class IV agents block the calcium current, and class V agents are specific sinus node inhibitors.
  • a majority of ventricular and atrial arrhythmias are related to reentrant circuit.
  • the prolongation of myocardial refractoriness within or surrounding such a reentrant circuit is a potential mechanism for the management of cardiac arrhythmias.
  • class III antiarrhythmic agents block cardiac potassium currents, they prolong the repolarisation process and increase refractoriness. Consequently class HI agents represent the most specific class to treat reentrant arrhythmias. However, due to their mechanism of action, i.e. a concentration dependent increase in the cardiac action potential duration, higher doses of class III antiarrhythmic agents may trigger arrhythmias. Such arrhythmias, called Torsade de Pointe represent the main adverse effect for all pure class III compounds currently in development. It has been discovered that certain novel piperidine derivatives induce a self- limiting increase of the cardiac action potential duration, related to a dual blockade of cardiac potassium and calcium channels.
  • Consequendy they are considered to be useful anti-arrhythmic agents having an improved pharmacological profile over pure class in anti-arrhythmic agents, in particular they area considered to show a low proarrhythmic potential and readily restore the contractile function of the ischaemic myocardium. They are considered to be particularly useful for the treatment of atrial or ventricular cardiac arrhythmias.
  • A represents (CH2) n wherein n represents zero or an integer 1 or 2;
  • B represents a C2.4 n-alkylene group wherein each carbon is optionally substituted by a C ⁇ _6 alkyl group;
  • Z represents a bond (CH2) m wherein m is an integer in the range of form 1 to 4 or X-CH2-CH2 wherein X represents O or S;
  • Q represents aryl, aralkyl, aralkenyl or aralkynyl, wherein the aryl moiety may be substituted or unsubstituted with 1 to 5 substituents selected from the list consisting of nitro, halogen, alkylsulfonamide, 1-imidazo, alkyl or haloalkyl, or Q represents substituted furanyl, substituted thienyl or substituted or unsubstituted: pyranyl, thiazolyl, imidazolyl, triazolyl or the benzo fused equivalents of furanyl, pyranyl, thienyl, thiazolyl, imidazolyl or triazolyl, indolyl, oxoindolyl, indenyl, isoindenyl, indazolyl, indolizinyl or pyridinyl or cycloalkyl optionally fused to an aryl group; R ⁇ , R2 and R3
  • B represents an unsubstituted C2.4 n-alkylene group.
  • B represents CH2CH2.
  • Z represents a bond, (CH2) m wherein m is an integer in the range of from 1 to 4, preferably m is 1, or 2.
  • Z represents a bond, CH2 or (CH2)2, preferably a bond.
  • Q represents aryl, aralkyl, aralkenyl or aralkynyl, wherein the aryl moiety may be substituted or unsubstituted with 1 to 5, suitably 1 to 3, substituents selected from the list consisting of nitro, halogen, alkylsulfonamido, 1-imidazo, alkyl or haloalkyl, favourably nitro, halogen or alkylsulphonylamido, preferably nitro.
  • Q represents substituted furanyl, substituted thienyl or substituted or unsubstituted: pyranyl, thiazolyl, imidazolyl, triazolyl or the benzo fused equivalents of furanyl, pyranyl, thienyl, thiazolyl, imidazolyl or triazolyl; indolyl, oxoindolyl, indenyl, isoindenyl, indazolyl, indolizinyl or pyridinyl or cycloalkyl optionally fused to an aryl group.
  • Q represents aryl.
  • Q represents substituted thienyl or substituted or unsubstituted: pyranyl.
  • Q represents the benzo fused equivalents of furanyl or pyranyl; or indolyl.
  • Q represents pyridinyl.
  • An example of a substituent for Q is a nitro group, a halogen, a methylsulphonamide group or a 1-imidazo group.
  • Q is phenyl or substituted phenyl, most preferably nitrophenyl such as 4-nitrophenyl.
  • one or two of Rj , R2 and R3 represents alkoxy, for example methoxy or ethoxy, preferaby methoxy, the remaining member(s) being H.
  • Ar represents a substituted or unsubstituted heteroaryl group, generally unsubstituted.
  • Ar represents substituted or unsubstituted aryl, wherein the optional substituents are the above defined Rj, R2 and R3, especially alkoxy such as methoxy.
  • Ar alkoxy phenyl such as dimethoxyphenyl, in particular 3,4-dimethoxyphenyl.
  • alkyl includes straight or branched chain alkyl groups having from 1 to 12, favourably 1 to 6, carbon atoms and shall include such alkyl groups when forming part of other groups such as alkoxy or arylalkyl groups.
  • alkenyl includes straight or branched chain alkylene groups having from 2 to 12, favourably 2 to 6, carbon atoms and one or more double bonds.
  • alkynyl includes straight or branched chain alkynlene groups having from 2 to 12, favourably 2 to 6, carbon atoms and one or more triple bonds.
  • aryl includes phenyl and naphthyl, preferably phenyl.
  • optional substituents for aryl include up to five, preferably up to three, groups selected from halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxyalkyl, hydroxy, amino, nitro, cyano, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy or alkylcarbonyl groups.
  • Suitable heteroaryl groups include substituted or unsubstituted, single or fused ring heteroaryl groups having 5 or 6 ring atoms which comprise up to 4 hetero atoms in each ring selected from oxygen, sulphur or nitrogen.
  • the heteraryl group comprises 1, 2 or 3 heteroatoms, in each ring especially 1 or 2, selected from oxygen, sulphur or nitrogen.
  • Suitable heteroaryl groups include benzo fused 5 or 6 membered hetero ring, such as indole, benzofuran and benzothiophene groups.
  • Suitable substituents for the heteroaryl group include the substituents as described herein with regard to the aryl group.
  • cycloalkyl includes cyclic alkyl carbon-carbon linkages of four to seven carbon atoms.
  • halogen includes fluorine, chlorine or bromine.
  • alkylsulfonamido includes a radical of the formula
  • R x is an alkyl group
  • cardiac arrhythmia relates to any variation from the normal rhythm of heart beat, including, without limitation, sinus arrhythmia, premature heartbeat, heartblock, fibrillation, flutter, tachycardia, paroxysmal tachycardia and premature ventricular contractions.
  • the compounds of formula (I) may possess a chiral carbon atom (for example when B represents a branched alkylene group) and it may therefore exist in more than one stereoisomeric form.
  • the invention extends to any of the stereoisomeric forms, including enantiomers of the compounds of formula (I) and to mixtures thereof, including racemates.
  • the different stereoisomeric forms may be separated or resolved one from the other by conventional methods or any given isomer may be obtained by conventional stereospecific or asymmetric syntheses.
  • the pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts with pharmaceutically acceptable mineral acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric and pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, ⁇ -keto-glutaric, ⁇ -glycerophosphoric, and glucose- 1- phosphoric acids.
  • pharmaceutically acceptable salts also include quaternary salts.
  • quaternary salts include such compounds quaternised by compounds such as R v -T wherein R v is Cj.g alkyl, phenyl-Cj.6 alkyl or C5.7 cycloalkyl, and T is a radical corresponding to an anion of an acid.
  • R v include methyl, ethyl and n- and iso- propyl; and benzyl and phenethyl.
  • T includes halide such as chloride, bromide and iodide.
  • Pharmaceutically acceptable salts also include pharmaceutically acceptable N- oxides, and the invention extends to these.
  • the compounds of the formula (I) and their salts may also form solvates, especially pharmaceutically acceptable solvates, such as hydrates, and the invention extends to these, and especially to the pharmaceutically acceptable solvates.
  • salts of the compounds of the formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the preparation of pharmaceutically acceptable salts of compounds of formula (I) or the compounds of the formula (I) themselves, and as such form an aspect of the present invention.
  • a compound of formula (I) or a salt thereof, or a solvate thereof, may be prepared by reacting a compound of formula (II):
  • reaction conditions for the reaction between compounds of formulae (II) and (HI) are conventional conditions appropriate to the nature of the reagent used, generally however the reaction may be carried out in an inert solvent, such as methylene chloride, at any suitable temperature providing a convenient rate of formation of the desired product, generally at an ambient to elevated temperature, conveniently at the reflux temperature of the solvent and preferably in the presence of a base such as triethylamine.
  • the compounds of formula (II) may be prepared by reducing a compound of formula (IV)
  • the reduction of the compound of formula (III) may be effected using any appropriate reduction method, for example metal hydride reduction using a lithium hydride such as lithium aluminium hydride in an aprotic solvent such as tetrahydrofuran (THF), at any suitable temperature which provides a convenient rate of reaction, generally at ambient to an elevated temperature, conveniently at ambient temperature.
  • metal hydride reduction using a lithium hydride such as lithium aluminium hydride in an aprotic solvent such as tetrahydrofuran (THF) at any suitable temperature which provides a convenient rate of reaction, generally at ambient to an elevated temperature, conveniently at ambient temperature.
  • a compound of formula (IV) may be prepared by reacting a compound of formula (V):
  • the reaction between the compounds of formulae (V) and (VI) may be carried out in a solvent such as toluene, at any suitable temperature providing a convenient rate of formation of the desired product, generally at an elevated temperature and conveniently at the reflux temperature of the solvent; the water produced in the reaction is removed by any conventional means, for example by means of a Dean and Stark apparatus.
  • a solvent such as toluene
  • a compound of formula (VI) may be prepared by reacting a compound of formula (VII):
  • B and Ar are as defined in relation to the compound of formula (VI) and represents a leaving group, such as halide, especially chloride, or a mesylate.
  • the reaction between the compounds of formulae (VII) and (VIII) may suitably be carried out in an aprotic solvent such as acetonitrile, at any suitable temperature providing a convenient rate of formation of the desired product, generally at an elevated temperature and conveniently at the reflux temperature of the solvent; preferably the reaction is carried out in the presence of a base such as potassium carbonate.
  • the compounds of formulae (VII) are known commercially available compounds and may also be prepared according to known procedures such as those described in .Belstein, Vol 21, 1st Edition, page 262.
  • the compounds of formulae (VIII) are known compounds and may be prepared according to known procedures such as those to described in Chemical
  • a compound of formula (II), wherein Z represents a bond may also be obtained by the methods illustrated in Scheme I.
  • A, Ar, B, R- * , R2 and R3 are as defined in relation to formula (I), Bj represents C2-3 alkylene and L3 represents a halide such as chloride or bromide.
  • a compound of formula (II), wherein Z represents a bond may also be obtained starting from N-benzyl-4-oxo piperidine as illustrated in Scheme II
  • A, Ar, B, Rj, R2 and R3 are as defined in relation to formula (I) and P represents a protecting group such as an acyl group, for example an acetyl group.
  • P represents a protecting group such as an acyl group, for example an acetyl group.
  • the insertion and removal of P may be achieved in the conventional manner depending upon the nature of the protecting group used.
  • the debenzylation can be achieved by conventional means, for example with hydrogen in the presence of a catalyst like palladium on charcoal.
  • the present invention accordingly provides a compound of formula (I), or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of and/or prophylaxis of arrhythmia, especially cardiac arrhythmia such as ventricular arrhythmia, and also ischaemic rhythm disorders.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier. Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of the general formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof is normally administered in unit dosage form.
  • an amount effective to treat the disorder hereinbefore described depends upon such factors as the efficacy of a compound of formula (I) , the particular nature of the pharmaceutically acceptable salt or pharmaceutically acceptable solvate chosen, the nature and severity of the disorders being treated and the weight of the mammal.
  • a unit dose will normally contain 0.1 to 500 mg for example 2 to 50 mg, of the compound of the invention.
  • Unit doses will normally be administered once or more than once a day, for example 2,3,4,5 or 6 times a day, more usually 2 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 0.1 to 2500 mg, more usually 50 to 2000 mg, for example 10 to 75mg, that is in the range of approximately 0.002 to 35 mg kg/day, more usually 1 to 30 mg/kg/day, for example 0.15 to 1 mg/kg/day.
  • the compound may be administered by any suitable route, e.g. by the oral, parenteral or topical routes.
  • the compound will normally be employed in the form of a pharmaceutical composition in association with a human or veterinary pharmaceutical carrier, diluent and/or excipient, although the exact form of the composition will naturally depend on the mode of administration.
  • compositions are prepared by admixture and are suitably adapted for oral, parenteral or topical administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, pastilles, reconstitutable powders, injectable and infusable solutions or suspensions, suppositories and transdermal devices.
  • Orally administrable compositions are preferred, in particular shaped oral compositions, 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.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • Solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. 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.
  • 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, carboxymethyl cellulose, 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; preservatives, for example methyl or propyl ⁇ -hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate
  • 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 active 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 active compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active compound.
  • the composition may be in the form of a transdermal ointment or patch for systemic delivery of the compound and may be prepared in a conventional manner, for example, as described in the standard textbooks such as Oermatological Formulations' - B.W. Barry (Drugs and the Pharmaceutical Sciences - Dekker) or Harrys Cosmeticology (Leonard Hill Books).
  • compositions may contain further active agents such as anti-hypertensive agents and diuretics.
  • compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
  • pharmaceutically acceptable embraces compounds, compositions and ingredients for both human and veterinary use: for example the term 'pharmaceutically acceptable salt' embraces a veterinarily acceptable salt.
  • the present invention further provides a method for the treatment and/or prophylaxis of arrhythmia, especially cardiac arrhythmia such as ventricular arrhythmia, and also ischaemic rhythm disorders in a human or non-human mammal which comprises administering an effective, non-toxic, amount of a compound of the general formula (I), or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof to a human or non-human mammal in need thereof.
  • the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention.
  • the compound of the general formula (I), or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof may be taken in doses, such as those described above, one to six times a day in an amount in the range of from 0.01 mg/kg to 15 mg/kg, for example 0.1 mg/kg to 5 mg/kg, such that the total daily dose for a 70 kg adult will generally be in the range of from 0.7 to 6300 mg, and more usually about 7 to 2100 mg. Similar dosage regimens are suitable for the treatment and/or prophylaxis of non-human mammals.
  • the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of arrhythmia, especially cardiac arrhythmia such as ventricular arrhythmia, and also ischaemic rhythm disorders.
  • the aqueous layer was separated and successively washed with 10 ml of ethyl acetate, treated with 1 N aqueous NaOH, and extracted with 50 ml of ethyl acetate.
  • the organic layer was separated, washed with water, dried over magnesium sulfate, and concentrated in vacuo.
  • the obtained crude product was purified by flash chromatography (silica gel, CH2CI2 : MeOH 98:2 as eluent). 0.31 g of a pure compound was isolated after crystallisation in acetonitrile.
  • Guinea pigs (300-350 g) were anesthetized by intravenous injection of sodium pentobarbital (60 mg/kg). After thoracotomy the heart was rapidly excised and placed in oxygenated Tyrode solution. Papillary muscles were removed from the right ventricle. Preparations were then fixed to the silastic base of a 5 ml organ bath and supervised with oxygenated Tyrode solution maintained at 37 ⁇ 1°C.
  • the modified Tyrode solution (pH 7.35) contained the following (mM) : NaCl 125, KCl 4.0, MgCl 2 0.5, CaCl 2 1.8, NaHCO 3 24, NaH 2 PO 4 0.9 and glucose 5.5.
  • the solution was equilibrated with a gas mixture of 95% O2 - 5% CO2. After a stabilisation period (at least lh), transmembrane action potentials were recorded with conventional microelectrodes (10 MOhm) connected to a high input impedance amplifier (BIOLOGIC VF 180). External stimuli were delivered to the preparation with bipolar platinum electrodes placed at one end of the muscle. The pulse duration was 1 ms and the amplitude was twice threshold. The basic cycle length was 1000 ms (PULSAR 6i stimulator). The signals were monitored on a storage oscilloscope (GOULD 1602) and simultaneously recorded on a digital tape recorder (BIOLOGIC DTR 1200) for further analysis.

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Abstract

Composé de la formule (I) ou sel ou solvat de ce composé. Dans cette formule, A représente (CH2)n, n valant zéro ou représentant un entier choisi entre 1 et 2; B représente un groupe n-alkylène C2-C4 dans lequel chaque atome de carbone est éventuellement substitué par un groupe alkyle C1-C6; Z représente une liaison (CH2)m dans laquelle m représente un entier compris entre 1 et 4, ou X-CH2-CH2 dans lequel X représente O ou S; D représente CO, SO2, NH-CO, NH-SO2, -CH=CH- ou P(O)(OR4), R4 représentant alkyle C1-C6; Q représente aryle, aralkyle, aralcényle ou aralcynyle, la fraction aryle étant substituée ou non par 1 à 5 substituants choisis dans la liste composée de nitro, halogène, alkylsulfonamide, 1-imidazo, alkyle ou haloalkyle, ou Q représente furanyle substitué, thiényle substitué, ou: pyranyle, thiazolyle, imidazolyle, triazolyle ou les équivalents benzo-fusionnés de furanyle, pyranyle, thiényle, thiazolyle, imidazolyle ou triazolyle, indolyle, oxoindolyle, indényle, isoindényle, indazolyle, indolizinyle ou pyridinyle ou cycloalkyle éventuellement fusionné à un groupe aryle, tous substitués ou non substitués; R1, R2 et R3 représentent chacun indépendamment H, alkyle, OH ou alcoxy, ou, s'ils sont accolés à des atomes de carbone adjacents, n'importe quels deux éléments parmi R1, R2 et R3 peuvent former, avec les atomes de carbone auxquels ils sont accolés, un noyau hétérocyclique fusionné de quatre à six atomes, parmi lesquels un à trois des atomes sont des atomes d'oxygène ou d'azote; et Ar représente aryle substitué ou non substitué, les éventuels substituants étant R1, R2 et R3 définis ci-dessus, ou Ar représente un groupe hétéroaryle substitué ou non substitué. L'invention se rapporte également à un procédé de préparation de ces composés, à des compositions pharmaceutiques les comprenant ainsi qu'à leur utilisation dans le domaine médical.
PCT/EP1994/001704 1993-05-26 1994-05-24 Nouveaux composes WO1994027967A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP7500224A JPH09501404A (ja) 1993-05-26 1994-05-24 新規化合物
AU69717/94A AU6971794A (en) 1993-05-26 1994-05-24 Novel compounds
EP94918376A EP0700385A1 (fr) 1993-05-26 1994-05-24 Nouveaux composes

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
FR9306290A FR2705674B1 (fr) 1993-05-26 1993-05-26 Nouveaux composés et leur procédé de préparation et leur utilisation en tant que médicaments.
FR93/06290 1993-05-26
FR9309326A FR2708607A1 (fr) 1993-07-29 1993-07-29 Nouveaux composés, leur procédé de préparation et leur utilisation en tant que médicaments.
FR93/09326 1993-07-29

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WO1999043658A1 (fr) * 1998-02-27 1999-09-02 Warner-Lambert Company Agents d'aniline heterocyclique substituee bloquant les canaux de calcium
WO2000006559A1 (fr) * 1998-07-30 2000-02-10 Warner-Lambert Company Analogues de dipeptides reduits utilises comme antagonistes des canaux calciques
EP0991753A1 (fr) * 1997-05-08 2000-04-12 Smithkline Beecham Corporation Inhibiteurs de proteases
WO2001081308A2 (fr) * 2000-04-20 2001-11-01 Nps Allelix Corp. Aminopiperidines
US6323217B2 (en) * 2000-01-13 2001-11-27 Adir Et Compagnie Piperidine-4 sulphonamide compounds
WO2003035645A1 (fr) * 2001-10-09 2003-05-01 Kyorin Pharmaceutical Co., Ltd. Nouvelles 4-(2-furoyl)aminopiperidines, intermediaires utilises dans la synthese de ces dernieres, leur procede de production et leur utilisation medicale
US6756393B2 (en) 2000-03-06 2004-06-29 Acadia Pharmaceuticals, Inc. Azacyclic compounds
US6903085B1 (en) 1999-08-24 2005-06-07 Astrazeneca, Ab Substituted piperidine compounds useful as modulators of chemokine receptor activity
EP1559428A1 (fr) * 2002-11-06 2005-08-03 Takeda Pharmaceutical Company Limited Regulateur de recepteur
US6958350B2 (en) 2001-02-19 2005-10-25 Astrazeneca Ab Chemical compounds
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WO2005103042A1 (fr) * 2004-04-20 2005-11-03 Glaxo Group Limited Composes presentant des groupes morpholinyle et piperidinyle destines a etre utilises en tant qu'inhibiteurs de glyt1
US7192973B2 (en) 2001-11-15 2007-03-20 Astrazeneca Ab Piperidine derivatives and their use as modulators of chemokine receptor activity (especially CCR5)
US7217719B2 (en) 2001-12-28 2007-05-15 Acadia Pharmaceuticals Inc. Spiroazacyclic compounds as monoamine receptor modulators
US7253186B2 (en) 2002-06-24 2007-08-07 Carl-Magnus Andersson N-substituted piperidine derivatives as serotonin receptor agents
US7294636B2 (en) 2003-05-09 2007-11-13 Astrazeneca Ab Chemical compounds
WO2008096189A2 (fr) 2005-09-23 2008-08-14 M's Science Corporation Dérivés de pipéridine et de pipérazine
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US7790899B2 (en) 2004-09-27 2010-09-07 Acadia Pharmaceuticals, Inc. Synthesis of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms
US7820695B2 (en) 2004-05-21 2010-10-26 Acadia Pharmaceuticals, Inc. Selective serotonin receptor inverse agonists as therapeutics for disease
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US10512644B2 (en) 2007-03-12 2019-12-24 Inheris Pharmaceuticals, Inc. Oligomer-opioid agonist conjugates
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US10953000B2 (en) 2016-03-25 2021-03-23 Acadia Pharmaceuticals Inc. Combination of pimavanserin and cytochrome P450 modulators
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US10981871B2 (en) 2015-07-20 2021-04-20 Acadia Pharmaceuticals Inc. Methods for preparing N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form C
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US11464768B2 (en) 2016-12-20 2022-10-11 Acadia Pharmaceuticals Inc. Pimavanserin alone or in combination for use in the treatment of Alzheimer's disease psychosis

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EP0379441A1 (fr) * 1989-01-20 1990-07-25 Rhone-Poulenc Sante Nouveaux dérivés du benzopyranne, leur preparation et les compositions pharmaceutiques qui les contiennent
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US6369077B1 (en) 1997-05-08 2002-04-09 Smithkline Beecham Corporation Protease inhibitors
EP0991753A1 (fr) * 1997-05-08 2000-04-12 Smithkline Beecham Corporation Inhibiteurs de proteases
EP0991753A4 (fr) * 1997-05-08 2001-07-11 Smithkline Beecham Corp Inhibiteurs de proteases
US6251918B1 (en) 1997-08-11 2001-06-26 Warner-Lambert Company Aniline derivatives as calcium channel blockers
WO1999007689A1 (fr) * 1997-08-11 1999-02-18 Warner-Lambert Company Derives d'aniline utilises en tant qu'inhibiteurs calciques
US6495715B2 (en) 1997-08-11 2002-12-17 Warner-Lambert Company Calcium channel blockers
WO1999043658A1 (fr) * 1998-02-27 1999-09-02 Warner-Lambert Company Agents d'aniline heterocyclique substituee bloquant les canaux de calcium
WO2000006559A1 (fr) * 1998-07-30 2000-02-10 Warner-Lambert Company Analogues de dipeptides reduits utilises comme antagonistes des canaux calciques
US6316440B1 (en) 1998-07-30 2001-11-13 Warner-Lambert Company Reduced dipeptide analogues as calcium channel antagonists
US6903085B1 (en) 1999-08-24 2005-06-07 Astrazeneca, Ab Substituted piperidine compounds useful as modulators of chemokine receptor activity
US6323217B2 (en) * 2000-01-13 2001-11-27 Adir Et Compagnie Piperidine-4 sulphonamide compounds
CN1298705C (zh) * 2000-01-31 2007-02-07 瑟维尔实验室 新的哌啶－4－磺酰胺化合物、其制备方法和含有它们的药物组合物
US6756393B2 (en) 2000-03-06 2004-06-29 Acadia Pharmaceuticals, Inc. Azacyclic compounds
US6815458B2 (en) 2000-03-06 2004-11-09 Acadia Pharmaceuticals, Inc Azacyclic compounds
US9296694B2 (en) 2000-03-06 2016-03-29 Acadia Pharmaceuticals Inc. Azacyclic compounds
US9765053B2 (en) 2000-03-06 2017-09-19 Acadia Pharmaceuticals Inc. Methods of treatment using selective 5-HT2A inverse agonists
WO2001081308A2 (fr) * 2000-04-20 2001-11-01 Nps Allelix Corp. Aminopiperidines
WO2001081308A3 (fr) * 2000-04-20 2002-04-04 Nps Allelix Corp Aminopiperidines
US6958350B2 (en) 2001-02-19 2005-10-25 Astrazeneca Ab Chemical compounds
US6960602B2 (en) 2001-03-22 2005-11-01 Astrazeneca Ab Piperidine derivatives as modulators of chemokine receptors
WO2003035645A1 (fr) * 2001-10-09 2003-05-01 Kyorin Pharmaceutical Co., Ltd. Nouvelles 4-(2-furoyl)aminopiperidines, intermediaires utilises dans la synthese de ces dernieres, leur procede de production et leur utilisation medicale
US7375115B2 (en) 2001-10-09 2008-05-20 Kyorin Pharmaceutical Co., Ltd. 4-(2-furoyl) aminopiperidines, intermediates in synthesizing the same, process for producing the same and medicinal use of the same
US7192973B2 (en) 2001-11-15 2007-03-20 Astrazeneca Ab Piperidine derivatives and their use as modulators of chemokine receptor activity (especially CCR5)
US7217719B2 (en) 2001-12-28 2007-05-15 Acadia Pharmaceuticals Inc. Spiroazacyclic compounds as monoamine receptor modulators
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US7511053B2 (en) 2001-12-28 2009-03-31 Acadia Pharmaceuticals, Inc. Spiroazacyclic compounds as monoamine receptor modulators
US7253186B2 (en) 2002-06-24 2007-08-07 Carl-Magnus Andersson N-substituted piperidine derivatives as serotonin receptor agents
US7476682B2 (en) 2002-06-24 2009-01-13 Acadia Pharmaceuticals, Inc. N-substituted piperidine derivatives as serotonin receptor agents
US7538222B2 (en) 2002-06-24 2009-05-26 Acadia Pharmaceuticals, Inc. N-substituted piperidine derivatives as serotonin receptor agents
US7498326B2 (en) 2002-06-26 2009-03-03 Glaxo Group Limited Compounds
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US7294636B2 (en) 2003-05-09 2007-11-13 Astrazeneca Ab Chemical compounds
WO2005103042A1 (fr) * 2004-04-20 2005-11-03 Glaxo Group Limited Composes presentant des groupes morpholinyle et piperidinyle destines a etre utilises en tant qu'inhibiteurs de glyt1
US7875632B2 (en) 2004-05-21 2011-01-25 Acadia Pharmaceuticals, Inc. Selective serotonin receptor inverse agonists as therapeutics for disease
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US7923564B2 (en) 2004-09-27 2011-04-12 Acadia Pharmaceuticals, Inc. Synthesis of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy) phenylmethyl)carbamide and its tartrate salt and crystalline forms
US7868176B2 (en) 2004-09-27 2011-01-11 Acadia Pharmaceuticals, Inc. Salts of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-y1)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and their preparation
US7732615B2 (en) 2004-09-27 2010-06-08 Acadia Pharmaceuticals Inc. N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms
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EP0700385A1 (fr) 1996-03-13
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