EP0639973A1 - Diamines pour le traitement de l'arythmie - Google Patents

Diamines pour le traitement de l'arythmie

Info

Publication number
EP0639973A1
EP0639973A1 EP93909965A EP93909965A EP0639973A1 EP 0639973 A1 EP0639973 A1 EP 0639973A1 EP 93909965 A EP93909965 A EP 93909965A EP 93909965 A EP93909965 A EP 93909965A EP 0639973 A1 EP0639973 A1 EP 0639973A1
Authority
EP
European Patent Office
Prior art keywords
dimethoxyphenyl
alkyl
pharmaceutically acceptable
ethyl
formula
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Withdrawn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
EP93909965A
Other languages
German (de)
English (en)
Inventor
A. Smithkline Beecham Lab Pharm Un. Rech. Bril
J.-F. S. P. Smithkline Beacham Lab Pharm Faivre
M.-C. Smithkline Beecham Lab. Pharm. Forest
B. E. J. Smithkline Beecham Lab. Pharm. Gout
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
Application filed by SmithKline Beecham Laboratoires Pharmaceutiques filed Critical SmithKline Beecham Laboratoires Pharmaceutiques
Priority to EP98200466A priority Critical patent/EP0852142A1/fr
Publication of EP0639973A1 publication Critical patent/EP0639973A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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

Definitions

  • This invention relates to a novel treatment and in particular to a novel treatment for arrhythmia and to certain novel compounds and compositions used in such treatment .
  • Antiarrhythmic drugs have been grouped according to the pattern of electrophysiological effects they produce and/or their presumed mechanism of action. A classification in four groups has been originally proposed by Naughan Williams in 1970. At the molecular level, class I compounds act on ⁇ a + currents; class II compounds possess b-adrenoceptor blocking activity; class III drugs block K + channels; and class IV drugs target Ca ++ channels.
  • European Patent Application, Publication Number 0233762 discloses compounds of formula (I) therein which are stated to have cardiovascular activity, including use in the treatment of angina.
  • cardiodepressive activity in ischaemic myocardium are also considered to be effective against atrial fibrillation and flutter.
  • the present invention provides a method for the treatment of arrhythmia in human or non-human mammals, which method comprises the administration of an effective, non-toxic amount of a compound of formula (I):
  • R 1 and R 4 are independently phenyl optionally substituted by one, two or three of halogen, C 1-4 alkoxy, C 1-4 alkyl, cyano, hydroxy, nitro, NR 5 R 6 or O 2 SNR 5 R 6 wherein R 5 and R 6 are independently hydrogen or C 1-6 alkyl or together are C 3-6 polymethylene, or disubstituted at adjacent carbon atoms by C 1-2 alkylenedioxy and optionally further substituted by one of the above groups;
  • R 2 is selected from (CH 2 ) z CN where z is O or an integer from 1 to 4, C 1-12 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-4 alkyl, phenyl C 1 -4 alkyl, pyridyl, pyridyl C 1-4 alkyl, COR 7 , COCH 2 COR 7 , SO 2 R 7 , CO 2 R 7 , CONHR 7 and CSNHR 7 , where R 7 is selected from C ⁇ -12 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1 -4 alkyl, phenyl and phenyl C 1-4 alkyl, any alkyl moiety in R 7 optionally substituted by hydroxy or C 1-4 alkanoyloxy, any pyridyl or phenyl moiety in R 2 optionally substituted as defined for R 1 and R 4 and any cycloalkyl moiety in R 2 optionally
  • R 3 is hydrogen, C 2-6 alkyl, C 2-6 alkene or C 3-8 cycloalkyl
  • A represents C 2-5 alkylene
  • B represents C 1 -4 alkylene.
  • 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.
  • the invention further provides a pharmaceutical composition for the treatment of arrhythmia, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof and a pharmaceutically acceptable carrier therefore.
  • Arryhthmia particularly includes cardiac arrhythmia and ischaemic rhythm disorders, especially cardiac arrhythmia.
  • Suitable values for R 1 and R 4 include phenyl, phenyl di-substituted by methylenedioxy and optionally further substituted by chloro, or phenyl substituted by one of fluoro, chloro or bromo or by one, two or three of methoxy, ethoxy, n- or iso-propoxy. methyl, ethyl, n - or iso-propyl. cyano, hydroxy or amino optionally substituted by one or two methyl groups.
  • R 1 and R 4 are preferably the same group, most preferably
  • R 1 and R 4 are halophenyl, especially 4-halophenyl, dihalophenyl, especially 3,4-dihalophenyl, dialkylphenyl, especially 3,4-dialkoxyphenyl, (hydroxy, alkoxy )phenyl such as (3-alkoxy,4-hydroxy)phenyl and trialkoxyphenyl such as 3,4,5-trialkoxyphenyl.
  • R 1 and R 4 examples include 4-fluorophenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, (3-methoxy, 4-hydroxy)phenyl and 3,4,5-trimethoxyphenyl.
  • Phenyl moieties in R 2 include phenyl, 2-, 3- and 4-nitrophenyl,
  • Suitable values for alkylene moieties in R 2 include -CH 2 -, -CH(CH 3 )- -CH 2 CH 2 CH 2 - and -CH 2 CH 2 -. Suitable values for R 2 when alkyl include n-pentyl.
  • Suitable values for alkyl R 7 in R 2 includes C 1_6 alkyl, such as methyl, ethyl, n- and iso- C 3 H 7 , n-C 4 H 9 , n-C 5 H 11 , nC 6 H 13 , nC 7 H 15 , nC 8 H 17 and nC 11 H 23 .
  • Suitable values for pyridyl moieties in R 2 include 2-and 4 - pyridyl.
  • Suitable values for optional substituents on alkyl moieties in R 7 include acetoxy.
  • Suitable values for z in R 2 include 0 or 1.
  • Suitable values for C 1-4 alkyl groups in R 2 include methyl and ethyl.
  • Suitable values for R 3 include hydrogen, methyl, ethyl, n- and iso-propyl. and n, iso -, sec- and t-butyl.
  • R 3 is methyl
  • Suitable values for A and B include -(CH 2 ) 2 - and -(CH 2 ) 3 -.
  • A is -(CH 2 ) 3- .
  • B is -(CH 2 ) 2- .
  • R 2 1 is CONHR 7 or CSNHR 7 where R 7 is as defined in formula (I), and the remaining variables are as defined in formula (I).
  • R 2 2 is COR 7 where R 7 is as defined in formula (I), and the remaining variables are as defined in formula (I).
  • pharmaceutically acceptable salts thereof and/or a pharmaceutically acceptable solvate thereof are class III antiarrhythmic agents, and hence can be used as such, for example they are effective against ventricular fibrillation.
  • R 7 is optionally substituted phenyl, optional substituents being selected from one halogen atom, especially a chlorine atom, and one, two or three of cyano, hydroxy, nitro and NR 5 R 6 wherein R 5 and R 6 are independently hydrogen (especially)or C 1-6 alkyl; a preferred substituent is a nitro group, especially a 4-nitro group.
  • R 7 is optionally substituted phenyl, optional substituents being selected from one halogen atom, especially a chlorine atom, and one, two or three of cyano, hydroxy, nitro and NR 5 R 6 wherein R 5 and R 6 are independently hydrogen (especially)or C 1-6 alkyl, or pharmaceutically acceptable salts thereof and/or a pharmaceutically acceptable solvates thereof, are combined class III and class IV antiarrhythmic agents and hence can be used as such, for example they are particularly effective against ventricular fibrillation, they are also considered to be effective against atrial fibrillation and flutter.
  • the compound of formula (I) is that compound wherein R 1 represents 3,4-dimethoxyphenyl, R 2 represents a 4-nitrobenzoyl group, R 3 represents methyl, R 4 represents 3,4-dimethoxyphenyl, A represents (CH 2 ) 3 and B represents (CH 2 ) 2 : i.e.the compound of example 50 of EP 0233762.
  • the invention extends to all such stereoisometric 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 the usual methods or any given isomer may be obtained by stereospecific or asymmetric syntheses.
  • alkyl, alkene and alkylene includes straight- and
  • Pharmaceutically acceptable salts include acid addition salts with conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric and pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, a-keto-glutaric, a-glycerophosphoric, and glucose-1-phosphoric acids.
  • acid addition salt is a hydrochloride; this is conveniently prepared by treating the relevant compound with HCl in a solvent such as diethylether.
  • Pharmaceutically acceptable salts also include quaternary salts.
  • quaternary salts include such compounds quaternised by compounds such as R 8 -T wherein R 8 is C 1-6 alkyl, phenyl-C 1-6 alkyl or C 5-7 cycloalkyl, and T is a radical corresponding to an anion of an acid.
  • R 8 include methyl, ethyl and n- and iso- propyl; and benzyl and phenethyl.
  • Suitable T include 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 pharmaceutically acceptable salts may also form solvates with pharmaceutically acceptable solvates and the invention extends to these.
  • salts of the compounds of the formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the preparation of pharmaceutically acceptable salts of compounds of the formula (I) or the compounds of the formula (I) themselves, and as such form an aspect of the present invention.
  • R 1 , R 2 , A, B and R 4 are as defined in relation to formula (I), and R' 3 represents C 2-6 alkene or C 3-8 cycloalkyl.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (IC) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.
  • the invention also provides a compound of formula (IC) or a
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a Novel Compound or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.
  • the invention also provides a Novel Compound or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance, in particular for use in the treatment of arrhythmia.
  • Pharmaceutically acceptable salts include conventional salts such as those disclosed in EP-A-0233762, but in particular the hydrochloride:
  • Pharmaceutically acceptable solvates include hydrates.
  • the compounds of formula (I), pharmaceutically acceptable salts thereof and/or a pharmaceutically acceptable solvates thereof may be prepared according to known methods including those methods disclosed in EP-A-0233762.
  • the compound wherein R 1 represents 3,4-dimethoxyphenyl, R 2 represents a 4-nitrobenzoyl group, R 3 represents methyl, R 4 represents 3,4-dimethoxyphenyl, A represents (CH 2 ) 3 and B represents (CH 2 ) 2 may be prepared according to methods disclosed in Example 50 of EP-A-0233762.
  • EP-A-0233762 also discloses certain intermediates for preparing the compounds of formula (I) which intermediates have the formula (II):
  • R 1 - NH - A - NR 3 - B - R 4 (II) wherein R 1 , A, R 3 , B and R 4 are as defined in relation to formula (I).
  • the present invention also provides a pharmaceutical
  • composition comprising a compound of the above defined formula (II) and a pharmaceutically acceptable carrier therefor.
  • the invention also provides a compound of formula (II) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use as a therapeutically active compound.
  • the invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of arrhythmia.
  • the present invention provides a method for the treatment of arrhythmia in human or non-human mammals, which method comprises the administration of an effective, non-toxic amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof.
  • the invention also provides the use of a compound of formula (II) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of arrhythmia.
  • Active compounds 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 the active compounds , the particular nature of the pharmaceutically acceptable salt or pharmaceutically acceptable solvate chosen, the nature and severity of the disorders being treated and the weight of the mammal.
  • a unit dose will normally contain 0.1 to 500 mg for example 2 to 50 mg, of the compound of the invention.
  • Unit doses will normally be administered once or more than once a day, for example 2,3,4,5 or 6 times a day, more usually 2 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 0.1 to 2500 mg, more usually 50 to 2000 mg, for example 10 to 75mg, that is in the range of approximately 0.002 to 35 mg/kg/day, more usually 1 to 30 mg/kg/day, for example 0.15 to 1 mg/kg/day.
  • the active 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
  • 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,
  • non-aqueous vehicles which may include edible oils
  • preservatives for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle.
  • the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the 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 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 active compound and may be prepared in a conventional manner, for example, as described in the standard textbooks such as 'Dermatological Formulations' - B.W. Barry (Drugs and the Pharmaceutical Sciences - Dekker) or Harrys Cosmeticology (Leonard Hill Books).
  • compositions may contain further active agents such as anti-hypertensive agents and diuretics.
  • compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
  • the mixture was then cooled to room temperature and quenched with 0.30 ml water, then washed with 0.30 ml of 15% aqeous NaOH and 0.60 ml water, then diluted with
  • reaction mixture was concentrated to dryness. 200 ml of ethyl acetate were added and the solution was washed with 100 ml water.
  • the resulting crude product was purified by flash chromatography on silica gel using 95:5 methylene chloride:methanol, affording 1 g (12%) of an amorphous solid.
  • the product was then disolved in 5 ml of ethyl acetate and 5.5N anhydrous HCl in diethyl ether was added dropwise.
  • the resulting amorphous solid was triturated in anhydrous diethyl ether and afforded 0.9 g (85%) of the title compound as yellow cristals.
  • ⁇ 1.85-2.25 (m,2H,CH 2 ); 2.50-3.50 (m,13H,(CH 2 )x5,NCH 3 ); 3.50-3.85 (m,14H, (OCH 3 )x4,CH 2 ); 6.40-7.00 (m,6H,Ar); 7.30-7.65 (m,2H,Ar); 8.10-8.35 (m,2H,Ar); 10.45-10.75 (m,1H,exch.D 2 O,NH) ppm.
  • the compound was purified as free base twice by chromatography on silica gel using first 97/3, then 98/2 methylene chloride/methanol, and as hydrochloride by trituration in diethyl ether.
  • Surgical preparation Dogs were anesthetized using 30 mg/kg i.v. sodium pentobarbital. A tracheal cannula was placed for artificial respiration with room air (Harvard 613 pump). A catheter was inserted into the right femoral artery to measure the systemic arterial pressure (Statham P23 ID, GOULD). A 5F Millar microtip catheter pressure transducer was inserted into die left carotid artery and advanced into the left ventricular lumen to measure the left ventricular pressure (LVP) and its first positive derivative dP/dt. Peripheral venous and arterial catheters were placed for drug administration and blood samples collection, respectively. Electrocardiographic variables were measured via a standard lead II ECG.
  • a CV5RL precordial lead of ECG was measured as previously described (Koerner et al. J.,Cardiovascular Pharmacol. Vol. 16, p.383-393, 1990).
  • the heart was suspended in a pericardial cradle.
  • the left circumflex coronary artery (LCX) was isolated close to its origin and a silk suture was placed around it for later occlusion.
  • Ventricular arrhythmias were analyzed during die preischemic period, during ischemia and during die first hour of reperfusion.
  • Ventricular premature beats (VPBs) were defined as identifiable premature QRS complexes and salvos as more than 2 consecutive VPBs.
  • Ventricular tachycardia was defined as 4 or more consecutive VPBs.
  • Ventricular fibrillation (VF) was diagnosed when total irregularity of rhythm occurred and when a rate could no longer be measured. If defibrillation was required a DC shock was given.
  • Heart rate was calculated from the ECG.
  • Guinea pigs (300-350 g) were anesthetized by intravenous injection of sodium pentobarbital (60 mg/kg). After thoracotomy die heart was rapidly excised and placed in oxygenated Tyrode solution. Papillary muscles were removed from the right ventricle. Preparations were then fixed to die 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 die following (mM): NaCl 125, KCl 4.0, MgCl 2 0.5, CaCl 2 1.8, NaHCO 3 24, NaH 2 PO40.9 and glucose 5.5. The solution was equilibrated with a gas mixture of 95% O 2 - 5% CO 2 .
  • transmembrane action potentials were recorded witii conventional microelectrodes (10 MOhm) connected to a high input impedance amplifier (BIOLOGIC VF 180). External stimuli were delivered to die preparation with bipolar platinum electrodes placed at one end of die muscle. The pulse duration was 1 ms and die 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.
  • RMP resting membrane potential
  • APA action potential amplitude
  • APD30, APD50 and APD90 action potential durations at 30, 50 and 90% repolarization
  • Ischemia and reperfusion-induced arrhythmias The effects of Compound I (0.3 and 1 mgKg) were compared to those of D-sotalol (3 and 10 mg/kg). Ventricular arrhythmias were analyzed during ischemia, maintained for 45 min, and again during die first 60 min of die reperfusion period. The effects of Compound I and D-sotalol on the incidence of ventricular fibrillation observed during these period were summarized in figure 1. The results show that 66.7 % of the control dogs (8 out of 12 dogs) exhibited ventricular fibrillation during either ischemia (2 dogs) or reperfusion (4 dogs).
  • Table 1 Effect of Compound I and d-Sotalol on electrocardiographlc parameters measured in anesthetized dog. n Before drug After drug Ischemia reperfusion
  • RMP resting membrane potential, APA; action potential amplitude, APD30, APD50 and APD90; action potential durations at 30, 50 and 90 % of the repofarizatfon respectively.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Emergency Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)

Abstract

L'invention concerne un traitement de l'arythmie chez l'homme ou d'autres mammifères, consistant à administrer une dose efficace et non toxique d'un composé de la formule (I) ou un sel de celui-ci acceptable sur le plan pharmaceutique et/ou un solvate de celui-ci acceptable sur le plan pharmaceutique. Dans cette formule: R1 et R4 représentent indépendamment des groupes phényle, le cas échéant substitué par un, deux ou trois des éléments suivants: halogène, alcoxy(C1-C4), alkyle(C1-C4), cyano, hydroxy, nitro, NR5R6 ou O2SNR5R6, où R5 et R6 représentent indépendamment hydrogène ou alkyle(C1-C6), ou ils forment ensemble (C3-C6)polyméthylène ou ils sont di-substitués sur des atomes de carbone adjacents par alkylènedioxy(C1-C2) en étant en outre, le cas échéant, substitués par un des groupes ci-dessus; R2 est choisi parmi les groupes (CH2)zCN où z représente 0 ou un nombre entier entre 1 et 4, alkyle(C1-12), cycloalkyle(C3-C7), cycloalkyl(C3-C7)alkyle(C1-C4), phényl(C1-C4)alkyle, pyridyle, pyridyl(C1-C4)alkyle, COR7, COCH2COR7, SO2R7, CO2R7, CONHR7 ou CSNHR7, où R7 est choisi dans les groupes alkyle(C1-C12), cycloalkyle(C3-C7), cycloalkyle(C3-C7)alkyle(C1-C4), phényle et phényl(C1-C4)alkyle, toute fraction alkyle dans R7 pouvant le cas échéant être substituée par un hydroxy ou un alcanoyloxy(C1-C4), toute fraction pyridyle ou phényle dans R2 pouvant le cas échéant être substituée comme décrit pour R1 et R4 et toute fraction cycloalkyle dans R2 pouvant le cas échéant être substituée par un ou deux groupes alkyle(C1-C4); R3 représente un hydrogène ou un alkyle(C2-C6), un alcène(C2-C6) ou un cycloalkyle(C3-C8); A représente un alkylène(C2-C5); et B représente un alkylène(C1-C4). L'invention concerne également les composés et les compositions pharmaceutiques utilisés dans un tel traitement.
EP93909965A 1992-05-14 1993-05-14 Diamines pour le traitement de l'arythmie Withdrawn EP0639973A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP98200466A EP0852142A1 (fr) 1992-05-14 1993-05-14 Diamines pour le traitement de l'arythmie

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9205855 1992-05-14
FR9205855A FR2691064B3 (fr) 1992-05-14 1992-05-14 Nouveau medicament pour le traitement de l'arythmie.
PCT/EP1993/001177 WO1993023024A1 (fr) 1992-05-14 1993-05-14 Diamines pour le traitement de l'arythmie

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP98200466A Division EP0852142A1 (fr) 1992-05-14 1993-05-14 Diamines pour le traitement de l'arythmie

Publications (1)

Publication Number Publication Date
EP0639973A1 true EP0639973A1 (fr) 1995-03-01

Family

ID=9429783

Family Applications (2)

Application Number Title Priority Date Filing Date
EP98200466A Withdrawn EP0852142A1 (fr) 1992-05-14 1993-05-14 Diamines pour le traitement de l'arythmie
EP93909965A Withdrawn EP0639973A1 (fr) 1992-05-14 1993-05-14 Diamines pour le traitement de l'arythmie

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP98200466A Withdrawn EP0852142A1 (fr) 1992-05-14 1993-05-14 Diamines pour le traitement de l'arythmie

Country Status (14)

Country Link
EP (2) EP0852142A1 (fr)
JP (2) JP2779269B2 (fr)
KR (1) KR950701517A (fr)
AP (1) AP410A (fr)
AU (2) AU677190B2 (fr)
CA (1) CA2135612A1 (fr)
FR (1) FR2691064B3 (fr)
HU (1) HUT72634A (fr)
IL (1) IL105690A0 (fr)
MX (1) MX9302832A (fr)
SG (1) SG47098A1 (fr)
TW (1) TW366283B (fr)
WO (1) WO1993023024A1 (fr)
ZA (1) ZA933376B (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2691064B3 (fr) * 1992-05-14 1996-01-12 Beecham Laboratoires Nouveau medicament pour le traitement de l'arythmie.
FR2694557B1 (fr) * 1992-08-05 1994-09-23 Synthelabo Dérivés de tétrahydronaphtalène, leur préparation, et leur application en thérapeutique.
FR2710065B1 (fr) * 1993-09-13 1996-10-04 Smithkline Beecham Labo Pharma Nouveaux composés, leur procédé de préparation et leur utilisation en tant que médicaments.
AU1949795A (en) * 1995-03-08 1996-09-23 Smithkline Beecham Laboratoires Pharmaceutiques Heterocyclycarboxamides and other compounds for the treatment of the cardiac arrhythmias

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3242344A1 (de) * 1982-11-16 1984-05-17 Dr. Karl Thomae Gmbh, 7950 Biberach Neue alkylendiaminoderivate, ihre herstellung und diese verbindungen enthaltende arzneimittel
US4751327A (en) * 1985-06-28 1988-06-14 Xerox Corporation Photoconductive imaging members with unsymmetrical squaraine compounds
GB8603765D0 (en) * 1986-02-15 1986-03-19 Beecham Wuelfung Gmbh & Co Kg Compounds
CA2060326C (fr) * 1989-07-25 2003-10-21 Jackson Boling Hester, Jr. Amino-alcenyl-phenylalcanesulfonamides, agents antiarythmiques
US5051422A (en) * 1989-09-15 1991-09-24 Schering Ag 2-substituted-1(4)-aryl piperazines and the process for their preparation
FR2691064B3 (fr) * 1992-05-14 1996-01-12 Beecham Laboratoires Nouveau medicament pour le traitement de l'arythmie.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9323024A1 *

Also Published As

Publication number Publication date
AU1485197A (en) 1997-05-15
JPH07506824A (ja) 1995-07-27
SG47098A1 (en) 1998-03-20
AP9300527A0 (en) 1993-07-31
AU677190B2 (en) 1997-04-17
FR2691064A1 (fr) 1993-11-19
CA2135612A1 (fr) 1993-11-25
IL105690A0 (en) 1993-09-22
EP0852142A1 (fr) 1998-07-08
JP2779269B2 (ja) 1998-07-23
HUT72634A (en) 1996-05-28
TW366283B (en) 1999-08-11
KR950701517A (ko) 1995-04-28
MX9302832A (es) 1994-07-29
WO1993023024A1 (fr) 1993-11-25
ZA933376B (en) 1995-02-14
JPH09118635A (ja) 1997-05-06
FR2691064B3 (fr) 1996-01-12
AU4067093A (en) 1993-12-13
AP410A (en) 1995-09-28

Similar Documents

Publication Publication Date Title
EP0700385A1 (fr) Nouveaux composes
JPS60252461A (ja) 抗低酸素および虚血薬理組成物
AU668932B2 (en) Method of blocking sodium channels or neuronal tissue
WO1994027971A1 (fr) 3-benzazepines ou isoquinolines n-substituees a action antiarythmique
EP0852142A1 (fr) Diamines pour le traitement de l'arythmie
ITMI951930A1 (it) Derivati di diarilalchenilammina
RU2159227C2 (ru) Нитробензамиды, фармацевтическая композиция, способ ее получения и способ лечения и/или профилактики аритмий и ишемических нарушений ритма
SK281017B6 (sk) 3,4-dihydroizochinolínové deriváty, spôsob ich výroby, farmaceutický prostriedok s ich obsahom a ich použitie
AU2011288410B2 (en) Panthenyl docosahexaeneoate and its use for treating and preventing cardiovascular diseases
US5492933A (en) Methods and compositions for treating urinary incontinence and other disorders using optically pure R-terodiline and hydroxylated derivatives thereof
EP0719263B1 (fr) Derives heterocycliques de carboxamide ayant une activite antiarythmique
WO1996027595A1 (fr) Heterocyclylcarboxamides et autres composes utilises pour le traitement des arythmies cardiaques
RU2676328C2 (ru) Циклическое углеводородное соединение
JPH0374233B2 (fr)
JP2007505036A (ja) フェニルカルボキサミドとβ−アドレナリン性受容体遮断剤の組み合わせおよびそれらの心房性不整脈の処置のための使用
AU691075B2 (en) Antiarrhythmic (S)-enantiomers of methanesulfonamides
JPH09500631A (ja) 抗不整脈剤としてのアザリシクロオクタン誘導体
CA2386845A1 (fr) Hydrochlorure de benzamide n-¬3-¬¬2-(3,4-dimethexyphenyl)ethyl|amino|propyl|-4-nitro polymorphe
JP3023988B2 (ja) （Ｓ）−α−フェニル−２−ピリジンエタンアミンベンゾエートおよび医薬としてのその使用
Borham et al. EXPERIMENTAL STUDY OF SOME CENTRAL NERVOUS SYSTEM AND CARDIOVASCULAR EFFECTS OF A LONG ACTING AMINOAMIDE LOCAL ANAESTHETIC (ROPIVACAINE) IN COMPARISON WITH (BUPIVACAINE)
JPS61249957A (ja) Ｎ−メチル−ｎ−フエニルウレイドエチルアミン誘導体及び製造法

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19941109

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL PT

17Q First examination report despatched

Effective date: 19960311

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20010709

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1010098

Country of ref document: HK