EP0700389A1 - Antiarrythmische n-substituierte 3-benzazepine oder isochinoline - Google Patents

Antiarrythmische n-substituierte 3-benzazepine oder isochinoline

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Publication number
EP0700389A1
EP0700389A1 EP94918377A EP94918377A EP0700389A1 EP 0700389 A1 EP0700389 A1 EP 0700389A1 EP 94918377 A EP94918377 A EP 94918377A EP 94918377 A EP94918377 A EP 94918377A EP 0700389 A1 EP0700389 A1 EP 0700389A1
Authority
EP
European Patent Office
Prior art keywords
dimethoxy
tetrahydro
benzazepin
dimethoxyphenyl
propyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP94918377A
Other languages
English (en)
French (fr)
Inventor
Guy Marguerite Marie Gérard SmithKline NADLER
Michel Jean Roger SmithKline Beecham MARTIN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Laboratoires Pharmaceutiques
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 FR9306346A external-priority patent/FR2705675B1/fr
Application filed by SmithKline Beecham Laboratoires Pharmaceutiques filed Critical SmithKline Beecham Laboratoires Pharmaceutiques
Publication of EP0700389A1 publication Critical patent/EP0700389A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system

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.
  • Anti-arrhythmic agents are classified according to their electrophysiological effects on the cardiac cell (Vaugham- Williams, 1970, 1989) : class I 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 III agents represent the most specific class to treat reentrant arrhythmias.
  • Torsade de Pointe represent the main adverse effect for all pure class III compounds currently in development.
  • the invention relates to a compound of formula (I) :
  • Z represents a bond, CH , (CH 2 ) 2 or X-CH 2 -CH 2 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, amino, 1-imidazo, alkyl or haloalkyl, or Q represents substituted or unsubstituted: furanyl, pyranyl, thienyl, 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-l, R2, R3, R4 and R5 each independently represent H, alkyl, OH or alkoxy or, if attached to adjacent carbon atoms, any two of Ri, R2, R3, R4 and R5 together with the carbon atoms to which they are attached may form a fused heterocyclic ring of four to six atoms wherein one, two or three of the said atoms are oxygen or nitrogen; and
  • E represents C2.4 n-alkylene group wherein each carbon is optionally substituted by
  • A represents (CH 2 ) 2 .
  • B represents CH 2 .
  • Z represents a bond, CH or (CH 2 ) 2 .
  • Z represents a bond
  • D represents CO or SO , preferably CO.
  • 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, amino, 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 cycloalkyl optionally fused to an aryl group, for example bicyclo[4.2.0]octa- 1 ,3,5-triene.
  • Q represents aryl, such as phenyl.
  • Q represents substituted furanyl, 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 examples include phenyl, 3-nitrophenyl, 4-nitrophenyl, furanyl 5-nitro- 2-furanyl, thienyl and bicyclo[4.2.0]octa-l,3,5-triene.
  • Q is phenyl or substituted phenyl, most preferably nitrophenyl such as 3- or 4-nitrophenyl, preferably 4-nitrophenyl.
  • R and R2 represents alkoxy, for example methoxy.
  • R3, R4 and R5 represents alkoxy, for example methoxy, and the remaining members represent H.
  • E represents CH2CH2CH2.
  • 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 alkylene 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 C3-g preferably C4.6 cycloalkyl groups.
  • halogen includes fluorine, chlorine or bromine.
  • alkylsulfonamido includes a radical of the formula
  • 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 E represents a branched alkylene group) and 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 quatemised by compounds such as R v -T wherein RY is C 1.5 alkyl, phenyl-C ⁇ _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 and/or solvates of the compounds of the formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the preparation of pharmceutically 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 (III) 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 a low to ambient temperature, preferably ambient and preferably in the presence of a base such as triethylamine.
  • an inert solvent such as methylene chloride
  • the compounds of formula (II) may be prepared by reducing a compound of formula (IV)
  • the reduction of the compound of formula (IV) 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 an elevated temperature such as the reflux temperature of the solvent.
  • a lithium hydride such as lithium aluminium hydride in an aprotic solvent such as tetrahydrofuran (THF)
  • THF tetrahydrofuran
  • a compound of formula (IV) may be prepared by reacting a compound of formula (V):
  • the compounds of formula (V) and (VI) are known compounds and may also be prepared according to procedures described in European Patent Application, Publication Number 0471388.
  • a compound of formula (VI) wherein A represents (CH 2 ) and B s CH - is suitably prepared by the method illustrated in Scheme I:
  • 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 J2e ⁇ S£ or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition
  • 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.
  • no toxicological effects are indicated for the compounds of the invention.
  • 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 p.-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 monoole
  • 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 'Dermatological Formulations' - B.W. Ba ⁇ y (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.
  • active agents such as anti-hypertensive agents and diuretics.
  • the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
  • the term '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 ischemic 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 phase was washed with ethyl acetate, basified with 30% aqueous sodium hydroxide and extracted three times with 20 ml ethyl acetate.
  • the resulting organic solution was washed with water, dried over MgSO4 and concentrated to dryness.
  • the residue obtained was chromatographed on silica and eluted with methylene chloride/methanol : 98/2 giving 0.28g (39.5%) of a brown oil.
  • the title compound was obtained by reduction of the nitro radical of the compound of example 6, using SnCl2,H2 ⁇ in ethanol. m.p. - 135°C
  • 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 superfused with oxygenated Tyrode solution maintained at 37 ⁇ 1°C.
  • the modified Tyrode solution (pH 7.35) contained the following (mM) : NaCl 125, KC1 4.0, MgCl 2 0.5, CaCl2 1.8, NaHCO 3 24, NaH 2 PO 0.9 and glucose 5.5.
  • the solution was equilibrated with a gas mixture of 95% O2 - 5% CO2.
  • transmembrane action potentials were recorded with conventional microelectrodes (10 MOh ) 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.
  • Action potential duration was measured at 30% (APD30) and 90% (APD90) of repolarization.

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EP94918377A 1993-05-27 1994-05-24 Antiarrythmische n-substituierte 3-benzazepine oder isochinoline Withdrawn EP0700389A1 (de)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
FR9306346 1993-05-27
FR9306346A FR2705675B1 (fr) 1993-05-27 1993-05-27 Nouveaux composés, leur procédé de préparation et leur utilisation en tant que médicaments.
FR9309327 1993-07-29
FR9309327 1993-07-29
PCT/EP1994/001705 WO1994027971A1 (en) 1993-05-27 1994-05-24 Anti-arrhythmic n-substituted 3-benzazepines or isoquinolines

Publications (1)

Publication Number Publication Date
EP0700389A1 true EP0700389A1 (de) 1996-03-13

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EP94918377A Withdrawn EP0700389A1 (de) 1993-05-27 1994-05-24 Antiarrythmische n-substituierte 3-benzazepine oder isochinoline

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EP (1) EP0700389A1 (de)
JP (1) JPH09501405A (de)
AU (1) AU6971894A (de)
WO (1) WO1994027971A1 (de)

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MXPA05000827A (es) 2002-07-19 2005-08-29 Memory Pharm Corp Inhibidores de fosfodiesterasa 4, incluyendo analogos de anilina y difenilamina n-sustituidos.
CN100381425C (zh) 2002-07-19 2008-04-16 记忆药物公司 作为磷酸二酯酶4抑制剂的6-氨基-1h-吲唑及其药物组合物和用途
CN100513397C (zh) 2002-11-19 2009-07-15 记忆药物公司 磷酸二酯酶4抑制剂
WO2007149728A2 (en) * 2006-06-20 2007-12-27 Alcon Research, Ltd. Aryl and heteroaryl tetrahydrobenzazepine derivatives and their use for treating glaucoma
FR2920773B1 (fr) * 2007-09-11 2009-10-23 Servier Lab Derives de 1,2,4,5-tetrahydro-3h-benzazepines, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
RU2764243C2 (ru) 2017-09-22 2022-01-14 ДЖУБИЛАНТ ЭПИПЭД ЭлЭлСи Гетероциклические соединения в качестве ингибиторов PAD
PT3697785T (pt) 2017-10-18 2023-04-03 Jubilant Epipad LLC Compostos de imidazopiridina como inibidores de pad
KR20200085836A (ko) 2017-11-06 2020-07-15 주빌런트 프로델 엘엘씨 Pd1/pd-l1 활성화 억제제로서의 피리미딘 유도체
PT3704120T (pt) 2017-11-24 2024-07-03 Jubilant Episcribe Llc Compostos heterocíclicos como inibidores de prmt5
BR112020018610A2 (pt) 2018-03-13 2020-12-29 Jubilant Prodel LLC Compostos de fórmula i, fórmula ii, fórmula iii, fórmula iv, fórmula v, fórmula vi, ou seus polimorfos, estereoisômeros, tautômeros, profármacos, solvatos e sais farmaceuticamente aceitáveis dos mesmos e uso dos mesmos; processo de preparação; composição farmacêutica; e método para o tratamento e/ou prevenção de várias doenças, que incluem câncer e doenças infecciosas

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AU6971894A (en) 1994-12-20
JPH09501405A (ja) 1997-02-10
WO1994027971A1 (en) 1994-12-08

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