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EP0700389A1 - Anti-arrhythmic n-substituted 3-benzazepines or isoquinolines - Google Patents

Anti-arrhythmic n-substituted 3-benzazepines or isoquinolines

Info

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Withdrawn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
German (de)
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/en
Application filed by SmithKline Beecham Laboratoires Pharmaceutiques filed Critical SmithKline Beecham Laboratoires Pharmaceutiques
Publication of EP0700389A1 publication Critical patent/EP0700389A1/en
Withdrawn legal-status Critical Current

Links

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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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A compound of formula (I) or a salt thereof, or a solvate thereof, wherein A represents CH2, (CH2)2, CO, COCH2, CH2CO, CSCH2 or CH=CH; B represents CH2 or CO; Z represents a bond, CH2, (CH2)2 or X-CH2-CH2 wherein X represents O or S; D represents CO, SO2, NH-CO, NH-SO2, CH=CH or P(O)OR6 wherein R6 is C1-6 alkyl; 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; R1, R2, R3, R4 and R5 each independently represent H, alkyl, OH or alkoxy or, if attached to adjacent carbon atoms, any two of R1, 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 R6; a process for preparing such compounds, pharmaceutical compositions comprising such compounds and the use of such compounds in medicine.

Description

ANTI-ARRHYTHMIC N-SUBSTITUTED 3-BENZAZEPI ES OR ISOQUINOLINES
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.
Because 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.
However, due to their mechanism of action, i.e. a concentration dependent increase in the cardiac action potential duration, higher doses of class UI 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.
United Kingdom Patent Applications, Publication Numbers 2099425 and 2130213 disclose certain benzazepines and benzodiazines which are stated to have heart rate lowering activity. It has now been discovered that certain novel N-substituted benzocyclic amine derivatives induce a self-limiting increase of the cardiac action potential duration, related to a dual blockade of cardiac potassium and calcium channels. Consequently, they are considered to be useful anti-arrhythmic agents having an improved pharmacological profile over pure class III 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.
Accordingly, the invention relates to a compound of formula (I) :
(I) or a salt thereof, or a solvate thereof, wherein A represents CH2, (CH^, CO, COCH2,CH2CO, CSCH2 or CH=CH; B represents CH2 or CO;
Z represents a bond, CH , (CH2)2 or X-CH2-CH2 wherein X represents O or S;
D represents CO, SO2, NH-CO, NH-SO2,CH=CH or P(O)OR6 wherein Rg is Cι_6 alkyl;
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
Suitably, A represents CH2, (CH2)2, CH2CO or CH=CH.
Preferably, A represents (CH2)2. Suitably, B represents CH2.
Suitably, Z represents a bond, CH or (CH2)2.
Preferably, Z represents a bond.
Suitably, D represents CO, SO2, NH-CO or -CH=CH-.
Suitably, D represents CO or SO , preferably CO. Suitably, 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.
Suitably, 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.
Suitably, Q represents cycloalkyl optionally fused to an aryl group, for example bicyclo[4.2.0]octa- 1 ,3,5-triene. Favourably, Q represents aryl, such as phenyl.
Favourably, Q represents substituted furanyl, substituted thienyl or substituted or unsubstituted pyranyl.
Favourably, Q represents the benzo fused equivalents of furanyl or pyranyl; or indolyl. Favourably, Q represents pyridinyl.
An example of a substituent for Q is a nitro group, a halogen, a methylsulphonamide group or a 1 -imidazo group.
Examples of Q include phenyl, 3-nitrophenyl, 4-nitrophenyl, furanyl 5-nitro- 2-furanyl, thienyl and bicyclo[4.2.0]octa-l,3,5-triene. In a preferred aspect, Q is phenyl or substituted phenyl, most preferably nitrophenyl such as 3- or 4-nitrophenyl, preferably 4-nitrophenyl.
Suitably, one or both of R and R2 represents alkoxy, for example methoxy. Suitably, one or two of R3, R4 and R5 represents alkoxy, for example methoxy, and the remaining members represent H. Suitably, E represents CH2CH2CH2.
As used herein, the term "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. As used herein, the term "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.
As used herein, the term "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. As used herein the term "aryl" includes phenyl and naphthyl, preferably phenyl.
Unless otherwise specified, 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.
In particular, 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.
As used herein, the term "cycloalkyl" includes C3-g preferably C4.6 cycloalkyl groups.
As used herein "halogen" includes fluorine, chlorine or bromine. As used herein, the term "alkylsulfonamido" includes a radical of the formula
O H II — N— S — R
11
O
wherein Rx is an alkyl group. As used herein, the term "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, α-keto-glutaric, α-glycerophosphoric, and glucose- 1- phosphoric acids. Preferably the acid addition salt is a hydrochloride. Pharmaceutically acceptable salts also include quaternary salts. Examples of quaternary salts include such compounds quatemised by compounds such as Rv-T wherein RY is C 1.5 alkyl, phenyl-Cι_6 alkyl or C5.7 cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable examples of Rv include methyl, ethyl and n- and iso- propyl; and benzyl and phenethyl. Suitably 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.
The 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):
(II)
wherein A, B, Z, E, R R2, R3, R4 and R5 are as defined in relation to formula (I) with a reagent of formula (III):
QL 1
(III)
wherein Q is as defined in relation to formula (I) and (a) for compounds of formula (I) wherein D is CO or SO2 ^ represents COX or SO2X respectively wherein X is a leaving group such as a halogen, and (b) for compounds of formula (I) wherein D is NHCO, Ll is N=C=O; and thereafter, if required, carrying out one or more of the following optional steps: (i) converting a compound of formula (I) into a further compound of formula (I); (ii) preparing a salt of the compound of formula (I) and/or a pharmaceutically acceptable solvate thereof.
The 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.
The compounds of formula (II) may be prepared by reducing a compound of formula (IV)
(IV) wherein Z, Ri, R2, R3, R4 and R5 are as defined in relation to formula (I), Ai represents A or a protected form thereof, B represents B or a protected form thereof, and Ei represents a C2-3 n-alkylene chain wherein each carbon atom may be optionally substituted with a Ci.g alkyl group; and thereafter if necessary removing any protecting group.
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 compound of formula (IV) may be prepared by reacting a compound of formula (V):
(V) wherein Z, E\, R3, R4 and R5 are as defined in relation to formula (IV), and L2 is a leaving group or atom such as a mesyl group or a halogen atom, with a compound of formula (VI):
(VI)
wherein A Bj, Rj and R2 are as defined in relation to the compound of formula
(IN).
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 (CH2) and B s CH - is suitably prepared by the method illustrated in Scheme I:
Scheme I catalytic chemical
reduction reduction
(VIII) (VII) (VI)
The synthesis of compounds of formula (VIII) is described in the literature, for example in J.Med.Chem., 1990, 33, 1496-1504.
The key intermediate for the synthesis of benzazepinone derivative of formula (H) (i.e. B = CO; A (CH2)2), is best illustrated by Scheme II
Scheme II
Compound (UA) is then submitted to an acylation as described in the conversion of the compounds of formula (II) to the compounds of formula (I).
As mentioned above the compounds of the invention are indicated as having useful therapeutic properties: 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.
More particularly, 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 J2eχ S£ 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. However, 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. At the above described dosage range, no toxicological effects are indicated for the compounds of the invention.
In such treatment, the compound may be administered by any suitable route, e.g. by the oral, parenteral or topical routes. For such use, 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.
For parenteral administration, 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. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, 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. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active compound.
For topical administration, 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. Baπy (Drugs and the Pharmaceutical Sciences - Dekker) or Harrys Cosmeticology (Leonard Hill Books).
In addition such compositions may contain further active agents such as anti-hypertensive agents and diuretics. As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
As used herein 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.
Conveniently, the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention. In the treatment and/or prophylaxis of arrhythmia and/or ischaemic arrhythmia disorders 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. In a further aspect 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 following Examples illustrate the invention but do not limit it in any way.
Description 1 3-(2,3,4,5-Tetrahydro-7,8-dimethoxy- lH-3-benzazepin-3-yl)-N-[(3,4- dimethoxyphenyl)-propanamide
1.22 g (5 mmol) 3-chloro-N-(3,4-dimethoxyphenyl)-propanamide, 1.04 g (5 mmol) 2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepine and 0.61 g (6 mmol) triethylamine in 20 ml acetonitrile were refluxed for 15 hours. The solvent was evaporated and the residue taken up in water. The precipitate was filtered off, washed with water and dried under vacuum to afford 1.7 g (72.4%) of the desired compound, m.p : 117°C
NMR (DMSO-d^) : δ = 2.55-3.15 (broad band,12H,6CH2); 3.71 (s,12H,4CH O); 6.79 (s,2H,Ar); 6.87 (d,lH,J=8.7Hz,Ar); 7.09 (dd,lH,J=8.7Hz,J'=2.1Hz,Ar); 7.30 (d,lH,J'=2.1Hz r); 10.04 (s,lH,exch D2O,NH) ppm.
Description 2 3-(2,3,4,5-Tetrahydro-7,8-dimethoxy- lH-3-benzazepin-3-yl)-N-(3,4- dimethoxyphenyl) propanamine 2.0 g (4.8 mmol) 3-(2,3,4,5-Tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)-N-
[(3,4-dimethoxyphenyl)propanamide (Dl) and 0.28 g (7.5 mmol) of lithium aluminium hydride in 25 ml THF were refluxed for 5 hours. After cooling with ice water, 0.30 ml water then 0.30 ml 15% aqueous NaOH and 1 ml water were added dropwise. The reactional mixture was filtered through celite and concentrated to dryness. The residue was chromatographed on silica and eluted with ethyl acetate/triethylamine : 95/5 then crystallised from diisopropyl ether yielding 1.0 g
(52%) of the desired compound. m.p : 90°C
NMR (CDCI3) : δ = 1.83 (q,2HJ=6.3Hz,CH2); 2.05-2.67 (m,6H,3CH2); 2.86-2.90 (m,4H,2CH2); 3.18 (t,2HJ=6.3Hz,CH2); 3.84 (t,12H,4CH30); 6.16
(dd,lH,J=2.3HzJ'=8.5Hz,Ar); 6.25 (d,lH,J=2.3Hz,Ar); 6.65 (s,2H,Ar); 6.76
(d,lH,J'=8.5Hz r) ppm.
Description 3 4,5-Dihydro-7,8-dimethoxy-3-[3-[(3,4-dimethoxyphenyl)- (phenylmethyl)-amino]propyl]-lH-3-benzazepin-2(3H)-one
0.42g (1.4 mmol) 7,8-Dimethoxy-3-(3-chloropropyl)-l,3,4,5-tetrahydro-2H-3- benzazepin-2-one and 1.02 g (4.2 mmol) N-(3,4- dimethoxyphenyl)benzenemethanamine were heated at 100°C under stirring for 1.5 hours. The mixture was cooled and taken up in ethyl acetate. The organic solution was washed twice with 20 ml water then extracted three times with 20 ml of N aqueous hydrochloric acid. 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.
NMR (CDC13) : δ = 1.87 (m,2H,CH2); 2.98 (m, 2H,CH2); 3.32 (m,2H,CH2); 3.46 (m,2H,CH2); 3.62 (m,2H,CH2); 3.75 (s,3H,CH3O); 3.80 (s,3H,CH3O); 3.82
(s,3H,CH3O); 3.84 (s,3H,CH3O); 3.75-3.85(m,2H,CH2CO); 4.41(s,2H,ArCH2); 6.24 (d,lH,J=8.4Hz,Ar); 6.34 (s,lH,Ar); 6.52 (s,lH,Ar); 6.59 (s,lH,Ar); 6.73 (d,lH,Ar); 7.25 (m,5H,Ar) ppm.
Description 4 4,5-Dihydro-7,8-dimethoxy-3-[3-[(3,4-dimethoxyphenyl)- amino]propyl]-lH-3-benzazepin-2(3H)-one
1.6 g (3.2 mmol) 4,5-Dihydro-7,8-dimethoxy-3-[3-[(3,4-dimethoxyphenyl)- (phenylmethyl)-amino]propyl]-lH-3-benzazepin-2(3H)-one (D3) in 50 ml methanol and 6 ml acetic acid were hydrogenated at room temperature under one bar of hydrogen over 0.2 g of 10% palladium on charcoal. The catalyst was filtered off and the solvent evaporated under vacuum. The residue obtained was taken up in water, the aqueous mixture was basified with 30% aqueous sodium hydroxide then extracted twice with 100 ml ethyl acetate. The organic solution was washed with water, dried over MgSO4 and concentrated to dryness to afford 1.23 g (92.7%) of the desired compound.
NMR (CDCI3) : δ = 1.75-1.95 (m,2H,CH2); 2.95-3.15(m,4H,2CH2); 3.65-3.75 (t,2H,J=6.5Hz,CH2); 3.72 (t,2HJ=6.5Hz,CH2); 3.80-4.00(m,14H,4.00, CH2); 6.13 (dd,lHJ=2.5Hz,J'=8.5Hz,Ar); 6.25 (d,lHJ=2.5Hz,Ar); 6.55 (s,lH,Ar); 6.60 (s,lH,Ar); 6.72 (d,lH,J'=8.5Hz,Ar) ppm.
Description 5 3-(6,7-Dimethoxy- l,2,3,4,-tetrahydro-2-isoquinolinyl)-N-(3,4- dimethoxyphenyl)-propanamide
2.3 g (10 mmol) 6,7-Dimethoxy-l,2,3,4,-tetrahydro-2-isoquinoline, hydrochloride,
2.43 g (10 mmol) 3-chloro-N-(3,4-dimethoxyphenyl)-propanamide and 2.43 g (24 mmol) triethylamine in 40 ml acetonitrile were refluxed under stirring for 18 hours. The solvent was evaporated and the resulting residue taken up in water. The aqueous mixture was extracted with methylene chloride, the organic solution was washed with water, dried over MgSO4 and concentrated to dryness. The obtained residue was triturated in diethyl ether to afford 3.55 g (88.6%) of the desired compound. m.p : 131°C
NMR (CDCI3) : δ = 2.61 (t,2H,J=6.1Hz,CH2); 2.85-2.98 (broad band,6H,3CH2); 3.72 (s,5H,ArCH2 and CH3O); 3.81 (s,3H,CH3O); 3.85 (s,3H,CH3O); 3.87 (s,3H,CH3O); 6.56 (s,lH,Ar); 6.65 (s,lH,Ar); 6.72 (s,2H,Ar); 7.18 (s,lH,Ar); 11.07(s,lH,exch D2O,NH) ppm
Description 6 3-(6,7-Dimethoxy-l,2,3,4,-tetrahydro-2-isoquinolinyl)-N-(3,4- dimethoxyphenyl)-propanamine
3.4 g (8.5 mmol) 3-(6,7-Dimethoxy-l,2,3,4,-tetrahydro-2-isoquinolinyl)-N-(3,4- dimethoxyphenyl)-propanamide were added by small fractions to a suspension of 0.48 g (13 mmol) lithium aluminium hydride in 40 ml of dried tetrahydrofuran at room temperature and under stirring. The mixture was refluxed under stirring for 3 hours then cooled with ice water. 0.5 ml water then 0.5 ml of 15% aqueous sodium hydroxide then 1.5 ml water were successively added dropwise to destroy the hydride in excess. A precipitate was filtered off, wash with tetrahydrofuran and the resulting organic solution was concentrated to dryness. The residue obtained was chromatographed on silica and eluted with methylene chloride/triethylamine : 95/5 to afford 2.8 g (85.2%) of orange oil.
NMR (CDCI3) : δ = 1.90 (q,2H =6.6Hz,CH2); 2.45-3.05(broad band,lH,exch D2O,NH); 2.67(t,2H,J=6.6Hz,CH2); 2.75(d,2HJ=5.2Hz,CH2); 2.84(d,2H,J=5.2Hz,CH2); 3.20(t,2H,J=6.6Hz,CH2); 3.57(s,2H,ArCH2N); 3.77 (s,3H,CH3O); 3.79 (s,3H,CH3O); 3.83 (s,3H,CH3O); 3.85 (s,3H,CH3O); 6.11 (dd,lH,J=2.6Hz,J'=8.4Hz,Ar); 6.16 (d,lH,J=2.6Hz,Ar); 6.52 (s,lH,Ar); 6.61 (s,lH,Ar); 6.73 (d,lH,J'=8.4Hz,Ar) ppm.
Description 7 l,3-Dihydro-7,8-dimethoxy-3-[[2-[4-[2-(2- methyl)propyl]phenyl]ethylamino]propyl]-2H-3-benzazepin-2-one. The title compound was obtained by reacting 2-[4-[2-(2- methyl)propyl]phenyl]ethanamine with 3-(3-chloropropyl)- 1 ,3-dihydro-7,8- dimethoxy-2H-3-benzazepin-2-one, using a procedure similar to that described in description 3.
Description 8 l,3,4,5-Tetrahydro-7,8-dimethoxy-3-[[2-[4-[2-(2- methyl)propyl]phenyl]ethylamino]propyl]-2H-3-benzazepin-2-one. The title compound was obtained by submitting the compound of description 7 to catalytic reduction over Pd/C.
Description 9 2,3,4,5-Tetrahydro-7,8-dimethoxy-N-[2-[4-[2-(2- methyl)propyl]phenyl]ethyl]-lH-3-benzazepin-3-propanamine. The title compound was obtained by reduction of the compound of description 8, using lithium aluminium hydride and a procedure identical to that of description 2. Description 10 2,3,4,5-Tetrahydro-7,8-dimethoxy-N-[(3,5- dimethoxy)phenylmethyl]-lH-3-benzazepine-3-propan amine. The title compound was obtained in two steps, starting from 7,8-dimethoxy-2,3,4,5- tetrahydro-lH-3-benzazepine and l-chloro-N-[(3,4- dimethoxy)phenylmethyl]propanamide and following a reaction cascade similar to that described in descriptions 1 and 2.
Description 11 2,3,4,5-Tetrahydro-7,8-dimethoxy-N-[[2-(3,4- dimethoxy)phenoxy]ethyl] - 1 H-3-benzazepin-3-propanamine.
The title compound was obtained by reacting 3-[(3-chloro)propyl]-lH-3-benzazepine with [2-(3,4-dimethoxy)phenoxy]ethylamine using a procedure similar to that described in description 3.
Description 12 l,3-Dihydro-7,8-dimethoxy-3-[[(3,4- dimethoxy)phenyl]aminopropyl]-2H-3-benzazepine-2-one.
The title compound was obtained by reacting 3-(3-chloropropyl)-l,3-dihydro-7,8- dimethoxy-2H-3-benzazepin-2-one with (3,4-dimethoxy)benzeneamine using a procedure similar to that described in description 3
Example 1 N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy- lH-3-benzazepin-3-yl)propyl]- N-(3,4-dimethoxyphenyl)-4-nitrobenzamide, hydrochloride
0.26 g (1.43 mmol) 4-nitrobenzoyl chloride were added dropwise to a stirred solution of 0.5 g (1.25 mmol) 3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)-N- (3,4-dimethoxyphenyl) propanamine (D2) and 0.45 g (1.43 mmol) triethylamine in 15 ml methylene chloride cooled with ice water. The mixture was stirred for 3 hours at room temperature then washed with water and dried over MgSO4- The solvent was concentrated to dryness. The residue was chromatographed on silica and eluted with methylene chloride/methanol : 95/5 yielding 0.61 g of compound which was salified in methanol by adding 0.25 ml of a solution of hydrochloric acid in diethyl ether. The methanolic mixture was concentrated to dryness and the residue triturated in anhydrous diethyl ether to afford 0.62 g (84.6%) of the desired compound. m.p : 247°C
NMR (DMSO-d6) : δ = 2.03 (m,2H,CH2); 2.80-3.05 (m,4H,2CH2); 3.10-3.40
(m,4H,2CH2); 3.50-3.75 (m,2H,CH2); 3.68 (s,6H,2CH3O); 3.73 (s,6H,2CH3O); 3.90
(t,2H,CH2N-CO); 6.77 and 6.86 (2s,4H,Ar); 6.98 (s,lH,Ar); 7.56 (d,2H,J=8.5Hz,Ar);
8.08 (d,2H,J=8.5Hz,Ar); 10.76 (s,lH,exch D2O,NH) ppm.
Example 2 N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy- lH-3-benzazepin-3-yl)propyl]- N-(3,4-dimethoxyphenyl)-3-nitrobenzenesulfonamide, hydrochloride.
Starting from 138 mg (0.625 mmol) 3-nitrobenzenesulfonylchloride and 200 mg (0.50 mmol) 3-(2,3,4,5-tetrahydro-7,8-dimethoxy- lH-3-benzazepin-3-yl)-N-(3,4- dimethoxyphenyl) propanamine (D2) and following the method described in Example 1, 215 mg (68.1%) of the desired compound were obtained as yellow crystals. The compound was purified as a free base by chromatography on silica using methylene chloride/methanol : 99.5/0.5 as eluent. The hydrochloride was purified by trituration in diisopropyl ether. m.p : 214°C
NMR (DMSO-d6) : δ = 1.83 (m,2H,CH2); 2.84-3.00 (m,4H,2CH2); 3.19-3.24 (m,4H,2CH2); 3.61-3.77 (s,12H,4CH3O and m,4H,2CH2); 6.64 (d,lH,J=2Hz,Ar); 6.71 (dd,lH,J=2HzJ'=8.6Hz,Ar); 6.84 (s,2H,Ar); 6.94 (d,lH,J'=8.6Hz,Ar); 7.86-7.99 (m,2H,Ar); 8.26 (s,lH,Ar); 8.57 (d,lH,J'=7.6Hz,Ar); 10.65 (s,lH,exch D2O,NH+) ppm.
Example 3 N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy- lH-3-benzazepin-3-yl)propyl]- N-(3,4-dimethoxyphenyl)-5-nitro-2-furancarboxamide, hydrochloride.
Starting from 110 mg (0.625 mmol) 5-nitrofurancarbonyl chloride and 200 mg (0.5 mmol) 3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)-N-(3,4- dimethoxyphenyl) propanamine (D2) and following the method described in Example 1, 239 mg (68%) of the desired compound were obtained as yellow crystals. The compound was purified as a free base by chromatography on silica using methylene chloride/methanol : 95/5 as eluent. The hydrochloride was purified by trituration in diisopropyl ether, m.p = 235°C
NMR (DMSO-d6) : δ = 2.02 (m,2H,CH2); 2.86-2.94 (m,4H,2CH2); 3.10-3.40 (m,4H,2CH2); 3.55-3.90 (3s,12H,4CH3O and m,4H,2CH2); 5.82 (d,lH,J=3.5Hz,Ar); 6.85 (s,2H,Ar); 6.99 (s,2H,Ar); 7.12 (s,lH,Ar); 7.51 (d,lH,J=3.5Hz,Ar); 10.74 (s,lH,exch D2O,NH+) ppm.
Example 4 N-[3-(78-Dimethoxy-2,3,4,5-tetrahydro-lH-3-benzazepin-3-yl)propyl]- N-(3,4-dimethoxyphenyl-3-(2-thiophenyl)-3-propenecarboxamide hydrochloride
108 mg (0.625 mmol) 3-(2-Thienyl)-2-propenoyl chloride were added to 200 mg (0.50 mmol) 3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)-N-(3,4- dimethoxyphenyl) propanamine (D2) and 0.09 ml (65.7 mg, 0.65 mmol) triethylamine in 10 ml chloroform cooled with ice- water under stirring. The mixture was stirred for 48 hours at room temperature and the solvent was then concentrated to dryness. The residue was chromatographed on silica and eluted with methylene chloride/methanol 95/5 then crystallised by trituration in diisopropyl ether yielding 267 mg of white crystals. The obtained crystallised compound was salified in a mixture of methanol (2 ml) and methylene chloride (1 ml) by adding 0.090 ml of a solution of 5 N hydrochloric acid in diethyl ether. The solvent was concentrated to dryness and the residue triturated in diethyl ether then crystallised from ethyl acetate containing some methylene chloride to afford 155 mg (53%) of the desired compound. m.p = 242°C
NMR (DMSO-d6) : δ = 2.85-3.05 (m,2H,CH2); 3.80-4.05 (m,4H,2CH2); 4.05-4.30 (m,4H,2CH2); 4.45-4.70(m,4H,2CH2); 4.68 (s,6H,2CH3O); 4.74 (s,3H,CH3O); 4.77 (s,3H,CH3O); 7.01 (d,lH,J=15.3Hz, CH=); 7.80-7.95 (m,3H,Ar); 7.95-8.10 (m,3H,Ar); 8.31 (d,lH,J=3.2Hz,Ar); 8.51 (d,lHJ=5.0Hz, CH=); 8.62 (d,lH,J=15.3Hz,Ar); 11.45 (s,lH,exch D2O,NH+) ppm.
Example 5 N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)propyl]- N-(3,4-dimethoxyphenyl)-7-bicyclo[4.2.0]octa- 1 ,3,5-trienecarboxamide, hydrochloride.
Starting from 95 mg (0.57 mmol) bicyclo [4.2.0] octa-l,3,5-triene-7-carbonyl chloride and 200 mg (0.50 mmol) 3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3- benzazepin-3-yl)-N-(3,4-dimethoxyphenyl)propanamine (D2) and following the method described in Example 1, 230 mg (80%) of the desired compound were obtained as cream crystals.The compound was purified as a free base by chromatography on silica using methylene chloride/methanol : 95/5 as eluent. The hydrochloride was purified by trituration in diisopropyl ether. m.p = 217°C
NMR (CDCI3) : δ = 2.20-2.40 (m,2H,CH2); 2.65-2.90 (m,4H,2CH2); 3.00-3.50 (m,4H,2CH2); 3.60-4.00 (m,6H3CH2); 3.85 (s,6H,2CH3O); 3.91 (s,3H,CH3O); 4.00 (s,3H,CH3O); 4.21-4.24 (m,lH,CH-CO); 6.64 (s,2H,Ar); 6.95-7.21 (m,7H,Ar); 12.75 (s,lH,exch D2θ,NH+) ppm.
Example 6 N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy-2-oxo-lH-3-benzazepin-3- yl)propyl]-N-(3,4-dimethoxyphenyl)-4-nitrobenzamide
0.8 g (4.3 mmol) 4-nitrobenzoyl chloride in 5 ml chloroform was added dropwise to a stirred solution of 1.18 g (2.8 mmol) 4,5-dihydro-7,8-dimethoxy-3-[3-[(3,4- dimethoxyphenyl)amino]propyl]-lH-3-benzazepin-2(3H)-one (D4) and 0.32 g (3.1 mmol) triethylamine in 30 ml chloroform, cooled with ice water. The mixture was stirred for 4 hours at room temperature and 100 ml methylene chloride were then added. After washing twice with 50 ml N aqueous hydrochloric acid, twice with 50 ml N aqueous sodium hydroxide then twice with 50 ml water, -ihe organic solution was dried over MgSO4 and concentrated to dryness. The resulting residue was chromatographed on silica and eluted with methylene chloride/methanol : 98/2 to give 1.04 g of compound. The compound was then triturated in a mixture of 5 ml methanol and 50 ml diethyl ether then crystallised from methanol to afford 0.91 g (58%) of yellow crystals. m.p = 126°C
NMR (CDC13) : δ = 1.93 (q,2H,J=7.1Hz,CH2); 3.07 (m,2H,CH2); 3.56 (t,2H,J=7.1Hz,CH2); 3.73 (s,3H,CH3O); 3.81 (s,3H,CH3O); 3.83 (s,3H,CH3O); 3.85 (s,3H,CH3O); 3.73-3.85 (m,4H,2CH2); 3.92 (t,2H,J=7.1Hz,CH2); 6.55-6.68 (m,5H,Ar); 7.44 (d,2H,J=8.7Hz,Ar); 8.02 (d,2H,J=8.7Hz,Ar) ppm.
Example 7 N-3-(l ,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propyl]-N-(3,4- dimethoxyphenyl)-4-nitrobenzamide, hydrochloride
Starting from 1.43 g (7.7 mmol) 4-nitrobenzoyl chloride and 2.7 g (7 mmol) 3-(6,7- dimethoxy-l,2,3,4,-tetrahydro-2-isoquinolinyl)-N-(3,4-dimethoxyphenyl)- propanamine (D6) and following the method described in Example 1, 2.26 g (56.4%) of the desired compound were obtained as yellow crystals after crystallisation from 25 ml acetone. m.p = 229°C
NMR (DMSO-d6) : δ = 2.0-2.2 (broad band,2H,CH2); 2.87-2.94 (broad band,lH,CH2); 3.14-3.2 (broad band,2H,CH2); 3.2-3.35 (broad band,lH,CH2); 3.67 (s,3H,CH3O); 3.69 (s,3H,CH3O); 3.72(s,3H,CH3O), 3.74 (s,3H,CH3O); 3.67-3.74 (broad band,2H,CH2); 3.9-4.0 (broad band,2H,CH2); 4.1-4.3 (broad band,lH,CH2); 4.3-4.5 (broad band,lH,CH2); 6.78 (s,3H,Ar); 6.82 (s,lH,Ar); 7.00 (s,lH,Ar); 7.58 (d,2H,j=8.6Hz,Ar); 8.09 (d,2H,J=8.6Hz,Ar); 10.87 (s,lH,exch D2O,NH+) ppm.
The following compounds were prepared using methods analogous to those described hereinbefore:
Example 8 N-[3-(2,3,4,5-Tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)-propyl]- N-(3,4-dimethoxyphenyl)-N'-(4-nitrophenyl)-urea, hydrochloride, hemihydrate
Reacting 3-(2,3,4,5-tetrahydro-7,8-dimethoxy- 1 H-3-benzazepin-3-yl)-N-(3,4- dimethoxyphenyl)propanamine (D2) with 4-nitro-isocyanatobenzene in methylene chloride during one night, followed by a standart work-up, a purification by chromatography on silica gel and a salification by anhydrous hydrochloric acid following procedures similar to those of example 1, afforded the title compound. m.p. -160°C
Example 9 N-[3-(2,3,4,5-Tetrahydro-7,8-dimethoxy- lH-3-benzazepin-3-yl)propyl]- N-[2-[4-[2-[2-methylpropyl)]phenyl]ethyl]-4-cyanobenzamide, hydrochloride
Starting from 2,3,4,5-Tetrahydro-7,8-dimethoxy-N-[2-[4-[2-(2- methyl)propyl]phenyl]ethyl]-lH-3-benzazepin-3-propanamine (D9) and 4-cyano benzoyl chloride and following a method similar to that described in example 1 provided the title compound. m.p. 215 - 217°C Example 10 5-Bromo-N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3- yl)-propyl]-N-(3,4-dimethoxyphenyl)-3-pyridinecarboxamide, hydrochloride, hemihydrate
Starting from 3-(2,3,4,5-tetrahydro-7,8-dimethoxy- lH-3-benzazepin-3-yl)-N-(3,4- dimethoxyphenyl) propanamine (D2) and 5-bromo-3-piperidinecarbonyl chloride and following a method similar to that described in example 1 provided the title compound. m.p. 239°C
Example 11 N-[3-(2,3,4,5-Tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3- yl)propyl]-N-(3,4-dimethoxyphenyl)-2-oxo-2H-3-benzopyrancarboxamide, hydrochloride, hydrate
Starting from 3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)-N-(3,4- dimethoxyphenyl) propanamine (D2) and 3,4-dihydro-2-oxo-2H-benzopyran-3- carbonyl chloride and following a method similar to that described in example 1 provided the title compound. m.p. 252°C
Example 12 N-[3-(2,3,4,5-Tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3- yl)propyl]-N-[(3,5-dimethoxyphenyl)methyl]-4-methylsulphonylaπιinobenzamide, hydrochloride
Staπing from 2,3,4,5-Tetrahydro-7,8-dimethoxy-N-[(3,5-dimethoxy)phenylmethyl]- lH-3-benzazepine-3-propanamine (D10) and 4-(methylsulfonylamino)-benzoyl chloride and following a method similar to that described in example 1 provided the title compound. m.p. ~ 135°C
Example 13 N-[3-(2,3,4,5-Tetrahydro-7,8-dimethoxy- lH-3-benzazepin-3-yl)- propyl]-N-[2-(3,4-dimethoxyphenyl)oxy]ethyl]-4-(lH-imidazol-l-yl)benzamide, dihydrochloride, dihydrate
Starting from 2,3,4,5-Tetrahydro-7,8-dimethoxy-N-[[2-(3,4- dimethoxy)phenoxy]ethyl]-lH-3-benzazepin-3-propanamine (Dl 1) and 4-(lH- imidazo-l-yl)-benzoyl chloride and following a method similar to that described in example 1 provided the title compound. m.p. 150°C
Example 14 N-[3-(2,3,4,5-Tetrahydro-7,8-dimethoxy- lH-3-benzazeρin-3-yl)- propyl]-N-(3,4-dimethoxyphenyl)-2-benzofurancarboxamide, hydrochloride, hemihydrate
Starting from 3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)-N-(3,4- dimethoxyphenyl) propanamine (D2) and 2-benzofurancarbonyl chloride and following a method similar to that described in example 1 provided the title compound, m.p. 275°C Example 15 N-[3-(2,3,4,5-Tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)- propyl]-N-(3,4-dimethoxyphenyl)-5-indolecarboxamide, hydrochloride, monohydrate
Starting from 3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)-N-(3,4- dimethoxyphenyl) propanamine (D2) and lH-indol-5-carbonyl chloride and following a method similar to that described in example 1 provided the title compound. m.p. 165°C
Example 16 N-[3-(7,8-Dimethoxy-2,3-dihydro-2-oxo-lH-3-benzazepin-3- yl)propyl]-N-(3,4-dimethoxyphenyl)-4-nitrobenzamide, monohydrate
Starting from 1 ,3-Dihydro-7,8-dimethoxy-3-[[(3,4-dimethoxy)phenyl]aminopropyl]-
2H-3-benzazepine-2-one (D12) and 4-nitrobenzoyl chloride and following a method similar to that described in example 1 provided the title compound. m.p. 138°C
Example 17 N-3-(2,3,4,5-Tetrahydro-7,8-dimethoxy- lH-3-benzazepin-3-yl)propyl]- N-(3,4-dimethoxyphenyl)-3,4-dinitrobenzamide, hydrochloride, hemihydrate
Starting from 3-(2,3,4,5-tetrahydro-7,8-dimethoxy- lH-3-benzazepin-3-yl)-N-(3,4- dimethoxyphenyl) propanamine (D2) and 3,4-dinitrobenzoyl chloride and following a method similar to that described in example 1 provided the title compound, m.p. 210°C
Example 18 N-[3-(2,3,4,5-Tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3- yl)propyl]-N-(3,4-dimethoxyphenyl)-6-oxo-lH-pyran-3-carboxamide, hydrochloride, hemihydrate
Starting from 3-(2,3,4,5-tetrahydro-7,8-dimethoxy- lH-3-benzazepin-3-yl)-N-(3,4- dimethoxyphenyl) propanamine (D2) and 2-oxo-2H-pyran-5-carbonyl chloride and following a method similar to that described in example 1 provided the title compound. m.p. - 190°C
Example 19 N-[3-(2,3,4,5-Tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3- yl)propyl]-N-(3,4-dimethoxyphenyl)-4-pyridinecarboxamide, dihydrochloride, hydrate
Starting from 3-(2,3,4,5-tetrahydro-7,8-dimethoxy- lH-3-benzazepin-3-yl)-N-(3,4- dimethoxyphenyl) propanamine (D2) and 4-pyridinecarbonyl chloride and following a method similar to that described in example 1 provided the title compound. m.p. 192°C Example 20 4-Amino-N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy-2-oxo- 1H-3- benzazepin-3-yl)propyl]-N-(3,4-dimethoxyphenyl)benzamide, hydrochloride, hemihydrate
The title compound was obtained by reduction of the nitro radical of the compound of example 6, using SnCl2,H2θ in ethanol. m.p. - 135°C
Example 21 N-[3-(2,3,4,5-Tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3- yl)propyl]4-(lH-imidazol-l-yl)~N-(3,4-dimethoxyphenyl)-benzamide, dihydrochloride, dihydrate
Starting from 3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)-N-(3,4- dimethoxyphenyl) propanamine (D2) and 4- (1 H-imidazol- l-yl)benzoyl chloride and following a method similar to that described in example 1 provided the title compound. m.p. - 185°C
Example 22 N-[3-(2,3,4,5-Tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3- yl)propyl]-N-(3,4-dimethoxyphenyl)-lH-benzimidazole-5-carboxamide, dihydrochloride, hemihydrate
Starting from 3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)-N-(3,4- dimethoxyphenyl) propanamine (D2) and lH-benzimidazol-5-carbonyl chloride and following a method similar to that described in example 1 provided the title compound. m.p. - 190°C
Pharmacological data
Methodology
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, MgCl20.5, CaCl2 1.8, NaHCO3 24, NaH2PO 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 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.
Measurements were made of action potential amplitude (APA) and action potential durations at 30-and 90% repolarization (APD30 and APD90 respectively). Recordings were made after 30 min of equilibration for each concentration. Only recordings in which the same impalement was maintained throughout the entire experiment were used for analysis.
0.3 μM 1.0 μM 3.0 μM 10.0 lM
ΛPD30 APD90 ■—
Effect of compound of example 1 on action potential duration (APD) recorded in guinea-pig papillary muscle. Action potential duration was measured at 30% (APD30) and 90% (APD90) of repolarization.

Claims

Claims:
1. A compound of formula (I) :
(I) or a salt thereof, or a solvate thereof, wherein A represents CH2, (CH2)2, CO, COCH2,CH2CO, CSCH2 or CH=CH; B represents CH2 or CO;
Z represents a bond, CH , (CH )2 or X-CH2-CH wherein X represents O or S;
D represents CO, SO2, NH-CO, NH-SO2,CH=CH or P(O)OR6 wherein Rg is Cι_6 alkyl;
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;
Rj, R2, R3, R4 and R5 each independently represent H, alkyl, OH or alkoxy or, if attached to adjacent carbon atoms, any two of R\, 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
R6 -
2. A compound according to claim 1, wherein 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, alkylsulfonamido, 1 -imidazo, alkyl or haloalkyl.
3. A compound according to claim 1 or claim 2, wherein Q represents substituted aryl.
4. A compound according to any one of claims 1 to 3, wherein Q represents nitro phenyl.
5. A compound according to any one of claims 1 to 4, wherein D represents CO, SO2, NH-CO or -CH=CH-.
6. A compound according to any one of claims 1 to 5, wherein D represents CO.
7. A compound according to any one of claims 1 to 6, wherein A represents CH2CH2.
8. A compound according to any one of claims 1 to 7, wherein B represents represents CH2.
9. A compound according to any one of claims 1 to 8, wherein Z represents a bond.
10. A compound according to any one of claims 1 to 9, wherein R\, R2, R3 and R2 each independently represent methoxy and R5 represents hydrogen.
11. A compound according to any one of claims 1 to 10, wherein E represents CH2CH2CH2.
12. A compound according to claim 1, selected from the list consisting of:
N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)propyl]-N-(3,4- dimethoxyphenyl)- nitrobenzamide,
N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)propyl]-N-(3,4- dimethoxyphenyl)-3-nitrobenzenesulfonamide,
N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)propyl]-N-(3,4- dimethoxyphenyl)-5-nitro-2-furancarboxamide,
N-[3-(78-dimethoxy-2,3,4,5-tetrahydro-lH-3-benzazepin-3-yl)propyl]-N-(3,4- dimethoxyphenyl-3-(2-thiophenyl)-3-propenecarboxamide,
N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)propyl]-N-(3,4- dimethoxyphenyl)-7-bicyclo[4.2.0]octa- 1 ,3,5-trienecarboxamide, N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy-2-oxo-lH-3-benzazepin-3-yl)propyl]-N-(3,4- dimethoxyphenyl)-4-nitrobenzamide,
N-3-(l,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propyl]-N-(3,4- dimethoxyphenyl)-4-nitrobenzamide,
N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)-propyl]-N-(3,4- dimethoxyphenyl)-N'-(4-nitrophenyl)-urea,
N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)propyl]-N-[2-[4-[2- [2-methylpropyl)]phenyl]ethyl]-4-cyanobenzamide,
5-bromo-N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)-propyl]-N- (3,4-dimethoxyphenyl)-3-pyridinecarboxamide,
N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)propyl]-N-(3,4- dimethoxyphenyl)-2-oxo-2H-3-benzopyrancarboxamide,
N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)propyl]-N-[(3,5- dimethoxyphenyl)methyl]-4-methylsulphonylaminobenzamide,
N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)-propyl]-N-[2-(3,4- dimethoxyphenyl)oxy]ethyl]-4-(lH-imidazol-l-yl)benzamide,
N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)-propyl]-N-(3,4- dimethoxyphenyl)-2-benzofurancarboxamide,
N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)-propyl]-N-(3,4- dimethoxyphenyl)-5-indolecarboxamide,
N-[3-(7,8-dimethoxy-2,3-dihydro-2-oxo-lH-3-benzazepin-3-yl)proρyl]-N-(3,4- dimethoxyphenyl)-4-nitrobenzamide,
N-3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)propyl]-N-(3,4- dimethoxyphenyl)-3,4-dinitrobenzamide,
N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)proρyl]-N-(3,4- dimethoxyphenyl)-6-oxo- 1 H-pyran-3-carboxamide, N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)propyl]-N-(3,4- dimethoxyphenyl)-4-pyridinecarboxamide,
4-amino-N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy-2-oxo- 1 H-3-benzazepin-3- yl)propyl]-N-(3,4-dimethoxyphenyl)benzamide,
N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)propyl]4-(lH- imidazol-1-yl)— N-(3,4-dimethoxyphenyl)-benzamide,
N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)propyl]4-(lH- imidazol- 1 -yl)~N-(3,4-dimethoxyphenyl)-benzamide, and
N-[3-(2,3,4,5-tetrahydro-7,8-dimethoxy-lH-3-benzazepin-3-yl)propyl]-N-(3,4- dimethoxyphenyl)-lH-benzimidazole-5-carboxamide; or a salt thereof, or a solvate thereof.
13. A process for preparing a compound of formula (I) as defined in claim 1, or a salt thereof, or a solvate thereof, which process is characterised by reacting a compound of formula (II):
(ID
wherein A, B, Z, E, R , R2, R3, R4 and R5 are as defined in relation to formula (I) with a reagent of formula (III):
Q i
(III)
wherein Q is as defined in relation to formula (I) and (a) for compounds of formula (I) wherein D is CO or SO2, L* represents COX or SO2X respectively wherein X is a leaving group such as a halogen, and (b) for compounds of formula (I) wherein D is NHCO, L- is N=C=O; and thereafter, if required, carrying out one or more of the following optional steps:
(i) converting a compound of formula (I) into a further compound of formula (I); (ii) preparing a salt of the compound of formula (I) and/or a pharmaceutically acceptable solvate thereof.
14. A pharmaceutical composition comprising a compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.
15. A compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.
16. A compound of formula (I), as defined in claim 1 , or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of and/or prophylaxis of arrhythmia.
17. 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 and ischaemic rhythm disorders.
18. A method for the treatment and/or prophylaxis of arrhythmia and 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.
EP94918377A 1993-05-27 1994-05-24 Anti-arrhythmic n-substituted 3-benzazepines or isoquinolines Withdrawn EP0700389A1 (en)

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FR9306346 1993-05-27
FR9306346A FR2705675B1 (en) 1993-05-27 1993-05-27 New compounds, their preparation process and their use as medicaments.
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

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