EP1670551A1 - Combinaison d'amides de l'acide phenylcarboxylique avec des bloquants des recepteurs beta-adrenergiques et leur utilisation dans le traitement d'arythmies atriales - Google Patents

Combinaison d'amides de l'acide phenylcarboxylique avec des bloquants des recepteurs beta-adrenergiques et leur utilisation dans le traitement d'arythmies atriales

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Publication number
EP1670551A1
EP1670551A1 EP04764792A EP04764792A EP1670551A1 EP 1670551 A1 EP1670551 A1 EP 1670551A1 EP 04764792 A EP04764792 A EP 04764792A EP 04764792 A EP04764792 A EP 04764792A EP 1670551 A1 EP1670551 A1 EP 1670551A1
Authority
EP
European Patent Office
Prior art keywords
phenyl
atoms
atenolol
compounds
sulfonylamino
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Withdrawn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
EP04764792A
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German (de)
English (en)
Inventor
Klaus Wirth
Joachim Brendel
Heinz Goegelein
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.)
Sanofi Aventis Deutschland GmbH
Original Assignee
Sanofi Aventis Deutschland GmbH
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Filing date
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Application filed by Sanofi Aventis Deutschland GmbH filed Critical Sanofi Aventis Deutschland GmbH
Publication of EP1670551A1 publication Critical patent/EP1670551A1/fr
Withdrawn legal-status Critical Current

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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

Definitions

  • the invention relates to the combination of one or more ⁇ -adrenoceptor blockers (abbreviated to "beta blocker”), such as atenolol, carvedilol, nadolol, pindolol, acebutolol, metoprolol, oxprenolol, propranolol, alprenoiol, pindolol, bisoprolol, esmolol, carteolol, Bupranolol, mepindolol, penbutolol, celiprolol or talinol, and one or more Kv1.5 blockers, in particular phenylcarboxamides of the formulas Ia and / or Ib
  • Atrial fibrillation (AF) and atrial flutter are the most common persistent cardiac arrhythmias. The incidence increases with age and often leads to fatal consequences, such as brain stroke. AF affects approximately 1 million Americans annually, leading to more than 80,000 strokes each year
  • class III antiarrhythmic agents for example, dofetilide, ibutilide, almokalant
  • IK r rapidly activating potassium channel
  • IK r and IK S which also occur in the human ventricle, the IK ur plays an important role in the human atrium, but not in the
  • Antiarrhythmic drugs that act via a selective blockade of the IK ur current or Kv1.5 channel are not yet available on the market.
  • some patent applications describe compounds that act as atrial-selective antiarrhythmic drugs because of their blocking effect on the Kv1.5 channel. For example, that describes
  • Patent application WO 0125189 inter alia biphenylcarbonamides as Kv1.5 blocker.
  • the applications WO 02088073 and WO 02100825 describe anthranilic acid amides as Kv1.5 blockers for the treatment of arrhythmias.
  • Kv1.5-blockers such as, for example, compounds of the formulas Ia and Ib
  • a beta-blocker can be significantly enhanced by concomitant administration of a beta-blocker.
  • Betabiockers does not fail more than that of a substance alone. If the effect of the Betabiockers would be based on the refractory period on a beta-adrenergic stimulation of the IK ur, this effect would already be blocked by a Kv1.5 blockers and be expected no additional antiarrhythmic effect of Betabiockers. The cause of the over-additive effect of the combination of IK ur and
  • Betabiocker on the atrial refractory period remains to be studied.
  • beta blocker The advantage of using a beta blocker is its good compatibility and its recognized effect on the overall cardiovascular mortality. Patients with atrial fibrillation often have concomitant coronary heart disease or
  • Beta blockers show beneficial effects in coronary heart disease in the sense of an antianginal effect, reduce the
  • Beta blockers are already used successfully in the prevention and treatment of atrial fibrillation. In addition, they serve to control the frequency of the ventricle, ie they protect the ventricle from its effect on the AV node before the high frequencies of the atrium, when the sinus rhythm can not be restored or held. Betabiockers are considered to be well tolerated and very effective cardiovascular medications: Patients with atrial fibrillation are often already suffering from other cardiovascular diseases for the therapy of a betabiocker therapeutically useful. A combination of a beta blocker with an effective one Kv1.5-Blocker is therefore particularly useful in terms of the Vorhofflimmem as well as the cardiac disease.
  • the combinations of Kv1.5 and beta blockers described here can therefore be used as highly effective antiarrhythmics with a particularly advantageous safety profile.
  • the compounds are useful in the treatment of supraventricular arrhythmias, for example, atrial fibrillation or atrial flutter.
  • the combinations can be used to terminate existing atrial fibrillation or flutter to regain the sinus rhythm (cardioversion).
  • the significantly enhanced effect of the combination can cardiovert even patients with persistent fibrillation, who were previously inaccessible to drug treatment.
  • the combinations reduce the susceptibility to the emergence of new flicker events (preserving the sinus rhythm, prophylaxis).
  • the invention relates to the combination of one or more beta blockers and one or more compounds of the formula la and / or Ib
  • R alkyl having 3, 4 or 5 C atoms or quinolinyl
  • R (2) is alkyl having 1, 2, 3 or 4 C atoms or cyclopropyl
  • R (4), R (5), R (6) and R (7) independently of one another are hydrogen, F, Cl, CF3, OCF3, CN, alkyl having 1, 2 or 3 C atoms, alkoxy having 1, 2 or 3 C atoms;
  • R (8) alkyl having 2 or 3 C atoms, phenyl or pyridyl, wherein phenyl and pyridyl are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3, alkyl with 1, 2 or 3 C atoms and alkoxy having 1, 2 or 3 C atoms; R (9).
  • beta-blockers are selected from the group atenolol, carvedilol, nadolol, pindolol, acebutolol, metoprolol, Oxprenolol, Propranolol, Alprenoiol, Pindolol, Bisoprolol, Esmolol, Carteolol, Bupranolol, Mepindolol, Penbutolol,
  • beta-blockers and one or more compounds of the formula Ia and / or Ib and / or physiologically compatible salts thereof, wherein the beta-blockers are selected, is particularly preferred the group atenolol, carvedilol, nadolol, pindolol, acebutolol, metoprolol, oxprenolol, propranolol, alprenoiol, pindolol, for example atenolol.
  • beta-blockers are selected from the group atenolol, carvedilol, nadolol,
  • beta blockers Especially preferred are the following combinations of beta blockers and
  • Atenolol 2- (butyl-1-sulfonylamino) -N- (cyclopropyl-pyridin-3-yl-methyl) -5-methyl-benzamide and
  • R alkyl having 3, 4 or 5 C atoms or quinolinyl
  • R (2) is alkyl having 1, 2, 3 or 4 C atoms or cyclopropyl
  • R (3) is phenyl or pyridyl, wherein phenyl and pyridyl are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3, alkyl
  • R (4), R (5), R (6) and R (7) independently of one another are hydrogen, F, Cl, CF3, OCF3, CN, alkyl having 1, 2 or 3 C atoms, alkoxy having 1, 2 or 3 C atoms;
  • R (8) is alkyl having 2 or 3 C atoms, phenyl or pydidyl, where phenyl and pyridyl are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3, alkyl having 1, 2 or 3 C atoms and alkoxy having 1, 2 or 3 C atoms; R (9) C (O) OR (10) or COR (10); R (10) -C x H 2x -R (11); x 0, 1 or 2; R (11) phenyl, where phenyl is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF 3, OCF 3, alkyl having 1, 2 or 3 C atoms and alkoxy having 1, 2 or 3 C atoms atoms; and / or their pharmaceutically acceptable salts.
  • betablockers together with one or more compounds of the formula Ia and / or Ib and / or a physiologically tolerable salt thereof for the preparation of a medicament for therapy or
  • the beta blockers being selected from the group of atenolol, carvedilol, nadolol, pindolol, acebutolol, metoprolol, oxprenolol, propranolol, alprenoiol, pindolol, bisoprolol, esmolol, carteolol, bupranolol, mepindolol, penbutolol, celiprolol, Talinol.
  • beta-blockers together with one or more compounds of formula Ia and / or Ib and / or a physiologically acceptable salt thereof for the manufacture of a medicament for the therapy or prophylaxis of atrial fibrillation or atrial flutter, wherein the beta-blockers are selected from the group Atenolol, Carvedilol, Nadolol, Pindolol,
  • beta-blockers together with one or more compounds of the formula Ia and / or Ib and / or a physiologically tolerable salt thereof for the manufacture of a medicament for the therapy or prophylaxis of atrial fibrillation or atrial flutter
  • the beta-blockers are selected are from the group of atenolol, carvedilol, nadolol, pindolol, acebutolol, metoprolol, oxprenolol, propranolol, alprenoiol, pindolol, and wherein the compounds of formula Ia and / or Ib are selected from
  • Alkyl radicals and alkylene radicals can be straight-chain or branched. This also applies to the alkylene radicals of the formulas C n H 2n , C m H 2m and C x H 2x . Alkyl radicals and alkylene radicals can also be straight-chain or branched if they are substituted or are contained in other radicals, for example in an alkoxy radical. Examples of alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or n-pentyl. The divalent radicals derived from these radicals, for example Methylene, 1, 1-ethylene, 1, 2-ethylene, 1, 1-propylene, 1, 2-propylene, etc. are examples of
  • Pyridyl is both 2-, 3- and 4-pyridyl.
  • Quinolinyl includes 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, with the 8-quinolyl residue being preferred.
  • Monosubstituted phenyl radicals may be substituted in the 2-, 3- or 4-position, disubstituted in the 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5 -Position.
  • the substituents may be the same or different.
  • the compounds of the formula Ia or Ib contain one or more acidic or basic groups or one or more basic heterocycles, the corresponding physiologically or toxicologically acceptable salts are also part of the invention, in particular the pharmaceutically usable salts.
  • the compounds of the formula Ia can be deprotonated on the sulfonamide group and, for example, as alkali metal salts, preferably sodium or potassium salts, or as
  • Compounds of formula Ia or Ib which contain a pyridine or quinoline substituent can also be used in the form of their physiologically acceptable acid addition salts with inorganic or organic acids, for example as hydrochlorides, phosphates, sulfates, methanesulfonates, acetates, lactates, maleinates, fumarates, malates , Gluconates, etc.
  • beta blockers can be used in the form of their physiologically acceptable salts.
  • the compounds of formula I can be present in stereoisomeric forms with appropriate substitution. Contain the compounds of formula Ia or Ib one or more centers of asymmetry, they may independently have the S configuration or the R configuration.
  • the invention includes all possible stereoisomers, for example enantiomers or diastereomers, and mixtures of two or more stereoisomeric forms, for example enantiomers and / or diastereomers, in any desired ratios.
  • Enantiomers for example, thus belong in enantiomerically pure form, both as left- and as dextrorotatory antipodes, and also in the form of mixtures of the two enantiomers in different ratios or in the form of racemates to the invention.
  • the preparation of individual stereoisomers can be carried out by separating a mixture by customary methods or, for example, by using isomerically pure synthesis building blocks.
  • beta blockers for example, the substances listed in Table 1 can be used.
  • Table 1 Names and Structural Formulas of Exemplary Beta Block Name Structure
  • the compounds of the formulas Ia and Ib used according to the invention and / or their physiologically tolerable salts can thus advantageously be used together with one or more beta-blockers on animals, preferably on mammals, and especially on humans, as medicaments, in particular for the treatment of atrial arrhythmias.
  • the combination of the two active ingredients can be such that active ingredients of the formula la and / or Ib and one or more beta blockers are administered together in a drug or that a drug containing one or more active ingredients of the formula la and / or Ib and a separate Drug containing one or more beta blockers may be administered simultaneously or sequentially in any order.
  • Administration one at a time also includes a combination in which the individual drugs are administered at different times and in different ways for a better effect achieve. However, it may also be expedient first to administer a suitable dose of the one drug and then to administer the other drug, for example by infusion, until the desired combination effect, for example cardioversion into the sinus rhythm, has occurred. Depending on the circumstances of the individual case, it may be cheaper, or the
  • the invention thus relates, for example, to a product comprising a combination of one or more beta-blockers and one or more compounds of the formula Ia and / or Ib and / or physiologically compatible salts thereof for simultaneous, separate or time-graduated
  • the weight ratio of the active ingredients of the formulas Ia and / or Ib to the beta blocker (s) in the combinations according to the invention is usually in the range from 1000: 1 to 1: 10000, preferably between 50: 1 and 1: 250.
  • the present invention also provides the use of compounds of the formulas Ia and / or Ib and / or a physiologically acceptable salt thereof and one or more beta blockers for the preparation of pharmaceutical preparations which contain one or more of the compounds Ia and / or Ib and one or more the beta blocker as effective components in addition to usual, pharmaceutical and their use as a medicament for the treatment of, for example, atrial arrhythmias.
  • compositions which as active ingredient an effective
  • the pharmaceutical preparations normally contain 0.1 to 90% by weight of the compounds of the formulas Ia and / or Ib and / or their physiologically tolerable salts and of the beta-blocker and / or their physiologically tolerable salts.
  • the preparation of the pharmaceutical preparations can be carried out in a manner known per se.
  • the active compounds and / or their physiologically acceptable salts are brought together with one or more solid or liquid galenic carriers and / or excipients in a suitable dosage form or dosage form, which can then be used as a medicament in human medicine or veterinary medicine.
  • suitable dosage form or dosage form which can then be used as a medicament in human medicine or veterinary medicine.
  • Medicaments containing combinations according to the invention of compounds of the formulas Ia and / or Ib and / or their physiologically tolerated salts and of one or more beta-blockers and / or their physiologically tolerated salts or the individual components used in combination may be administered orally, parenterally, administered intravenously, rectally, by inhalation or topically, the preferred application depending on the individual case.
  • Claimed are in particular combination preparations of compounds of the formula Ia and / or Ib and / or their physiologically tolerable salts and one or several beta blockers and / or their physiologically acceptable salts for the treatment of atrial arrhythmias such as atrial fibrillation and atrial flutter.
  • excipients are suitable for the desired drug formulation is familiar to the person skilled in the art on the basis of his specialist knowledge.
  • solvents for example, antioxidants, dispersants, emulsifiers, defoamers, flavoring agents, preservatives, solubilizers, means for obtaining a depot effect, buffer substances or dyes may be used.
  • the active compounds with the appropriate additives such as carriers, stabilizers or inert diluents, mixed and brought by the usual methods in the appropriate dosage forms, such as tablets, dragees, capsules, aqueous, alcoholic or oily solutions.
  • inert carriers for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch may be used. It can. the preparation is carried out both as dry and as wet granules.
  • Suitable oily carriers or as solvents are, for example, vegetable or animal oils, such as sunflower oil or cod liver oil.
  • a solvent for aqueous or alcoholic or oil are examples of vegetable or animal oils, such as sunflower oil or cod liver oil.
  • Solutions are, for example, water, ethanol or sugar solutions or mixtures thereof, into consideration.
  • Further auxiliaries are, for example, polyethylene glycols and polypropylene glycols.
  • the active compound for subcutaneous, intramuscular or intravenous administration, the active
  • Suitable solvents are, for example, water, physiological saline or alcohols, for example ethanol, propanol, glycerol, in addition to sugar solutions such as glucose or
  • Mannitol solutions or mixtures of the various solvents mentioned.
  • a pharmaceutical formulation for administration in the form of aerosols or sprays are suitable, for example, solutions, suspensions or emulsions of the active ingredients or their physiologically acceptable salts in a pharmaceutically acceptable solvent, such as in particular ethanol or water, or a mixture of such solvents.
  • the formulation may also contain other pharmaceutical auxiliaries, such as surfactants, emulsifiers and stabilizers, as well as a propellant gas.
  • Such a preparation usually contains the active ingredient in a concentration of about 0.1 to 10, in particular from about 0.3 to 3 weight percent.
  • the dosage of the active ingredients to be administered according to the invention or of the physiologically tolerable salts thereof depends on the individual case and, as usual, must be adapted to the circumstances of the individual case for optimum action. Of course, it depends on the frequency of administration and on the potency and duration of action of each used for therapy or prophylaxis
  • the dosage of the Kv1.5-blocker of formula Ia and / or Ib can usually in
  • the dose may usually vary between 5 and 300 mg per day and human, preferably between 25 and 100 mg per day and human. But it can also be appropriate higher doses.
  • Blocker and / or Betabiocker and / or their physiologically acceptable salts are administered in lower doses than when administered only one of the two
  • Active ingredients can be administered at once or it can be divided into several, for example, two, three or four administrations.
  • Example 1 2 '- ⁇ [2- (4-Methoxy-phenyl) -acetylamino] -methyl ⁇ -biphenyl-2-carboxylic acid (2-pyridin-3-yl-ethyl) -amide
  • the resulting intermediate (40.7 g) was dissolved in 600 ml of methylene chloride and then 100 ml of trifluoroacetic acid was slowly added dropwise. After stirring overnight, the reaction mixture was concentrated in vacuo. The residue was treated with 250 ml of ethyl acetate and concentrated again to distill off excess trifluoroacetic acid. To the resulting crude product dissolved in 170 ml of methylene chloride, 72.8 ml (530 mmol) of triethylamine were added dropwise and 1 g of DMAP was added.
  • the compound was obtained according to the synthesis instructions given in WO 0125189.
  • the compound was obtained according to the synthesis instructions given in WO 0125189.
  • Kv1.5 channels were expressed in Xenopus oocytes.
  • oocytes from Xenopus laevis were first isolated and defolliculated. Subsequently, in these oocytes in vitro synthesized Kv1.5 coding RNA was injected. After 1-7 days of Kv1.5 protein expression, Kv1.5 currents were measured on the oocytes using the two-microelectrode voltage-clamp technique.
  • the Kv1.5 channels were usually activated with 500 ms voltage jumps to 0 mV and 40 mV. The bath was filled with a solution of the following. Composition flushed :. NaCl 96 mM, KCl 2 mM, CaCl 2 1, 8 mM, MgCl 2 1 mM,
  • HEPES 5mM (titrated with NaOH to pH 7.4). These experiments were carried out at room temperature.
  • Geneclamp amplifiers Analog Instruments, Foster City, USA
  • MacLab D / A converters and software ADInstruments, Castle Hill, Australia
  • the substances according to the invention were tested by adding them to the bath solution in different concentrations.
  • the effects of the substances were calculated as percent inhibition of the Kv1.5 control current obtained when no substance was added to the solution.
  • the data were then extrapolated with the Hill equation to determine the inhibitory concentrations IC50 for the respective substances.
  • a left lateral thoracotomy was performed in the fifth intercostal space.
  • the lungs were retracted with sutures, the pericardium opened and held with sutures, allowing the heart to rock in this.
  • the tip of a MAP Pacing TM Electrophysiology Catheter (EP Technologies, Model 1675, Boston Scientific Corporation, 92257 La Garenne-Colombes Cedex, France) was then placed on the free wall of the left atrium in a right angle position and in a tripod under constant pressure on the left Atrium fixed.
  • the electric Stimulation was performed with an external heart stimulator from Biotronik (UHS 20, Universial heart stimulator, Biotronik GmbH, 12359 Berlin, Germany).
  • AERP Atrial Effective Refractory Period
  • Electrophysiology catheter was derived.
  • a conditioning stimulation cycle of 10 base intervals (S1) in a twofold stimulus threshold was followed by a diastolic, prematurely coupled extra-stimulus (S2, 1ms pulse duration, 200ms refractory period) with a 5ms decrement from a coupling interval 30ms above the expected effective refractory period (AERP) , The 5ms
  • Example 1 or 5 increases the refractory times to a stable level.
  • the compound of Example 1 was infused at a dose of 3 mg / kg / h. After 1 h infusion, on the
  • Plateau of the effect of the compound of Example 1, was 1 mg / kg atenolol as
  • Table 4 Refractory times in milliseconds following combined administration of the IKur blocker.
  • the compound of Example 5 was infused at a dose of 3 mg / kg / h. After 1 h of infusion, on the plateau of action of the compound of Example 5, 1 mg / kg of atenolol was used as

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Abstract

L'invention concerne la combinaison d'un ou de plusieurs bêtabloquants et d'un ou de plusieurs bloquants de Kv1.5, en particulier d'amides de l'acide phénylcarboxylique de formule (la) et/ou (lb) et/ou de sels pharmaceutiquement acceptables de ces derniers ainsi que l'utilisation de cette combinaison dans le traitement d'arythmies atriales.
EP04764792A 2003-09-08 2004-09-03 Combinaison d'amides de l'acide phenylcarboxylique avec des bloquants des recepteurs beta-adrenergiques et leur utilisation dans le traitement d'arythmies atriales Withdrawn EP1670551A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10341233A DE10341233A1 (de) 2003-09-08 2003-09-08 Kombination von Phenylcarbonsäureamiden mit beta-Adrenozeptoren-Blockern und deren Verwendung zur Behandlung von Vorhofarrhythmien
PCT/EP2004/009837 WO2005025674A1 (fr) 2003-09-08 2004-09-03 Combinaison d'amides de l'acide phenylcarboxylique avec des bloquants des recepteurs beta-adrenergiques et leur utilisation dans le traitement d'arythmies atriales

Publications (1)

Publication Number Publication Date
EP1670551A1 true EP1670551A1 (fr) 2006-06-21

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EP04764792A Withdrawn EP1670551A1 (fr) 2003-09-08 2004-09-03 Combinaison d'amides de l'acide phenylcarboxylique avec des bloquants des recepteurs beta-adrenergiques et leur utilisation dans le traitement d'arythmies atriales

Country Status (12)

Country Link
EP (1) EP1670551A1 (fr)
JP (1) JP2007505036A (fr)
AR (1) AR045601A1 (fr)
AU (1) AU2004271697A1 (fr)
BR (1) BRPI0414203A (fr)
CA (1) CA2538009A1 (fr)
DE (1) DE10341233A1 (fr)
IL (1) IL173919A0 (fr)
MX (1) MXPA06002103A (fr)
PE (1) PE20050373A1 (fr)
TW (1) TW200526580A (fr)
WO (1) WO2005025674A1 (fr)

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DE102005028862A1 (de) * 2005-06-22 2007-01-11 Sanofi-Aventis Deutschland Gmbh Substituierte Heterocyclen, ihre Verwendung als Medikament sowie sie enthaltende pharmazeutische Zubereitungen
TW200812962A (en) * 2006-07-12 2008-03-16 Astrazeneca Ab New compounds I/418
JP5685203B2 (ja) 2009-05-29 2015-03-18 ラクオリア創薬株式会社 カルシウムチャネル遮断薬またはナトリウムチャネル遮断薬としてのアリール置換カルボキサミド誘導体

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6194458B1 (en) * 1998-10-30 2001-02-27 Merck & Co., Inc. Benzamide potassium channel inhibitors
DE19947457A1 (de) * 1999-10-02 2001-04-05 Aventis Pharma Gmbh 2'-Substituierte 1,1'-Biphenyl-2-carbonamide, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament sowie enthaltende pharmazeutische Zubereitungen
DE10059418A1 (de) * 2000-11-30 2002-06-20 Aventis Pharma Gmbh Ortho, meta-substituierte Bisarylverbindungen, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament sowie sie enthaltende pharmazeutische Zubereitungen
DE10060807A1 (de) * 2000-12-07 2002-06-20 Aventis Pharma Gmbh Ortho, ortho-substituierte stickstoffhaltige Bisarylverbindungen, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament sowie sie enthaltende pharmazeutische Zubereitungen
DE10121003A1 (de) * 2001-04-28 2002-12-19 Aventis Pharma Gmbh Anthranilsäureamide, Verfahren zur Herstellung, ihrer Verwendung als Medikament sowie sie enthaltende pharmazeutische Zubereitungen
DE10128331A1 (de) * 2001-06-12 2002-12-19 Aventis Pharma Gmbh Anthranilsäureamide mit Heteroarylsulfonyl-Seitenkette, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltende pharmazeutische Zubereitungen

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005025674A1 *

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JP2007505036A (ja) 2007-03-08
MXPA06002103A (es) 2006-05-31
WO2005025674A1 (fr) 2005-03-24
TW200526580A (en) 2005-08-16
DE10341233A1 (de) 2005-03-24
PE20050373A1 (es) 2005-07-05
BRPI0414203A (pt) 2006-10-31
IL173919A0 (en) 2006-07-05
AR045601A1 (es) 2005-11-02
AU2004271697A1 (en) 2005-03-24

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