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WO2005011690A1 - Utilisation de composes de 3,7-diazabicyclo[3,3,1]nonane pour traiter et/ou prevenir des evenements arythmiques chez des patients humains males - Google Patents

Utilisation de composes de 3,7-diazabicyclo[3,3,1]nonane pour traiter et/ou prevenir des evenements arythmiques chez des patients humains males Download PDF

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Publication number
WO2005011690A1
WO2005011690A1 PCT/EP2004/051532 EP2004051532W WO2005011690A1 WO 2005011690 A1 WO2005011690 A1 WO 2005011690A1 EP 2004051532 W EP2004051532 W EP 2004051532W WO 2005011690 A1 WO2005011690 A1 WO 2005011690A1
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WIPO (PCT)
Prior art keywords
diazabicyclo
carbon atoms
nonane
group containing
tedisamil
Prior art date
Application number
PCT/EP2004/051532
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English (en)
Inventor
Werner Cautreels
Claus Steinborn
Matthias Straub
Katrin Beckmann
Johannes Wilhelmus Catherine Maria Jansen
Original Assignee
Solvay Pharmaceuticals Gmbh
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 Solvay Pharmaceuticals Gmbh filed Critical Solvay Pharmaceuticals Gmbh
Priority to CA002533492A priority Critical patent/CA2533492A1/fr
Priority to JP2006520832A priority patent/JP2006528155A/ja
Priority to BRPI0412247-0A priority patent/BRPI0412247A/pt
Priority to MXPA06000796A priority patent/MXPA06000796A/es
Priority to EP04742001A priority patent/EP1648456A1/fr
Priority to AU2004260624A priority patent/AU2004260624A1/en
Publication of WO2005011690A1 publication Critical patent/WO2005011690A1/fr

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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • 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 present invention relates to a novel medicinal use of 3,7-diazabicyclo- [3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7-diazabicyclo[3,3J]-nonane compounds, and most preferably to a novel medicinal use of tedisamil, and of pharmaceutically acceptable acid addition salts and/or solvates of said compounds.
  • 9,9-Alkylene-3,7-diazabicyclononane compounds of formula I and their pharmacological activities are known from published European Patent No. EP 103,833 and the corresponding U.S. Pat. No. 4,550,112, and Finnish Patent No. FI 76,338.
  • Compounds of formula I are a sub-group of the 9,9-N,N'-tetra-substituted 3,7-diaza- bicyclo[3.3J]nonane compounds described in the aforementioned patent specifications and can be prepared by the methods described therein.
  • the aforementioned patent specifications disclose that the compounds have useful cardio-active properties, particularly oxygen-saving effects and effects on the heart rate and heart rhythm in general, and are distinguished by a high physiological tolerance.
  • the compounds show a satisfactory anti-arrhythmic action even at low doses.
  • the undesired negative effect on the contractile power of the heart is extremely low; i.e. the compounds have a particularly favourable ratio of a nti -arrhythmic or the refractory period of the heart prolonging activities, to negative inotropic secondary activities.
  • Another object of the invention is to provide new anti-arrhythmic pharmaceutical compositions having an improved activity profile for the use in male human patients.
  • the objects of the invention are achieved by surprisingly discovering that 3,7- diazabicyclo-[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7- diazabicyclo[3,3J]-nonane compounds, and most preferably tedisamil, and of pharmaceutically acceptable acid addition salts and/or solvates of said compounds are particularly suitable for the treatment and/or prophylaxis of anti-arrhythmic events in male human patients, preferably for conversion of recent onset of atrial fibrillation (Afib) or flutter to normal sinus rhythm (NSR) in male human patients.
  • Afib atrial fibrillation
  • NSR normal sinus rhythm
  • an anti -arrhythmic pharmaceutical composition comprising an anti-arrhythmic amount effective in male human patients of at least one anti-arrhythmic active 3,7-diaza-bicyclo[3,3J]nonane compound as described in the present invention.
  • the subject of the invention is therefore the use of the use of 3,7-diaza- bicyclo[3,3J]nonane compounds, its physiologically acceptable acid addition salts and/or solvates thereof for the production of a pharmaceutical preparation for the treatment and/or prophylaxis of anti-arrhythmic events in male human patients, preferably for conversion of recent onset of atrial fibrillation (Afib) or flutter to normal sinus rhythm (NSR) in male human patients.
  • Afib atrial fibrillation
  • NSR normal sinus rhythm
  • the compounds suitable for this novel medicinal use in male human patients are 3,7-diazabicyclo[3,3J]nonane compounds corresponding to the Formula I:
  • R1 represents an alkyl group containing from 1 to 6 carbon atoms, an alkylene group containing from 3 to 6 carbon atoms having a double bond which is not linked directly to the nitrogen atom, a cycloalkylalkyl group containing from 4 to 9 carbon atoms, or a benzyl group
  • R2 represents a lower alkyl group
  • R3 represents a lower alkyl group
  • R2 and R3 together form an alkylene chain containing from 3 to 6 carbon atoms
  • R4 represents an alkyl group containing from 1 to 6 carbon atoms, an alkenyl group containing from 3 to 6 carbon atoms having a double bond which is not linked directly to the nitrogen atom, a cycloalkylalkyl group containing from 4 to 9 carbon atoms, a group corresponding to the Formula a:
  • R5 represents hydrogen, halogen, lower alkyl or lower alkoxy
  • Z represents an alkylene chain containing from 1 to 3 carbon atoms or a propenylene chain having a double bond which is conjugated with the phenyl group, or a group corresponding to the Formula b:
  • R6 represents hydrogen, halogen, lower alkyl or lower alkoxy
  • R7 represents hydrogen, halogen, lower alkyl or lower alkoxy
  • Particularly suited compounds for the novel medicinal use in male human patients according to the invention are compounds of Formula I, wherein R1 represents an alkyl group containing from 1 to 6 carbon atoms or a cycloalkylalkyl group containing from 4 to 7 carbon atoms.
  • R1 represents an alkyl group containing from 1 to 6 carbon atoms or a cycloalkylalkyl group containing from 4 to 7 carbon atoms.
  • the substituent R4 represents an alkyl group containing from 1 to 6 carbon atoms, a cycloalkylalkyl group containing from 4 to 7 carbon atoms, or a group corresponding to Formula b.
  • Preferred compounds for the novel medicinal use in male human patients according to the invention are compounds of Formula I, wherein R1 represents an alkyl group containing from 3 to 6 carbon atoms or a cycloalkylalkyl group containing from 4 to 7 carbon atoms, and R4 represents an alkyl group containing from 3 to 6 carbon atoms or a cycloalkylalkyl group containing from 4 to 7 carbon atoms.
  • Said 3,7-diazabicyclo- [3,3,1]nonane compound may be a 9,9-alkylene-3,7-diazabicyclo[3.3J]nonane compound of Formula I wherein R2 and R3 together form an alkylene chain containing from 4 to 5 carbon atoms, and R1 and R4 independently of one another each denote a straight-chain or branched alkyl group of 3-4 carbon atoms or the cyclopropylmethyl group, and physiologically acceptable acid addition salts and/or solvates thereof.
  • Preferred salts for this group of compounds are fumaric acid salts of 9,9-alkylene-3,7- diazabicyclo[3.3J]nonane compounds containing 1.5 moles of fumaric acid per mole of compound of formula I.
  • Further preferred compounds for the novel medicinal use in male human patients according to the invention are compounds selected from the group consisting of N,N'- dicyclopropyl-methyl-9, 9-tetramethylen-3,7-diazabicyclo[3,3J]nonane (tedisamil), N- isobutyl-N'-isopropyl-9,9-pentamethylen-3,7-diazabicyclo[3,3J]nonane, and physiologically acceptable acid addition salts and/or solvates thereof.
  • Preferred salts for this group of compounds are fumaric acid salts of N,N'-dicyclopropyimethyl-9, 9- tetramethylene-3,7-diazabicyclo[3,3J]nonane (tedisamil) or of N-isobutyl-N'-isopropyl- 9,9-pentamethylene-3,7-diazabicyclo[3,3J]nonane containing 1.5 moles of fumaric acid per mole of said 9,9-alkylene-3,7-diazabicyclo[3.3J]-nonane compound.
  • hydrochloride salts are also very suitable for the novel medicinal use according to the present invention in male human patients.
  • Particularly preferred 3,7-diazabicyclo[3,3J]nonane compounds are the 9,9- alkylene-3,7-diazabicyclo[3.3J]nonane compound tedisamil and the physiologically compatible acid addition salts and/or solvates thereof, these are most preferably used as compounds for the production of pharmaceutical preparations for the treatment and/or prophylaxis of of antiarrhythmic male human patients, preferably in conversion of recent onset of atrial fibrillation (Afib) or flutter to normal sinus rhythm (NSR) in male human patients.
  • Afib atrial fibrillation
  • NSR normal sinus rhythm
  • a tedisamil acid addition salt it may preferably be used according to the invention in the form of tedisamil hydrochloride or in the form of tedisamil sesquifumarate for the treatment of male human patients.
  • Further pharmacologic-ally compatible acid addition salts of tedisamil are known from European Patent No. EP 103,833.
  • salts with inorganic acids e.g.
  • sulfuric acid or hydrohalic acids especially hydrochloric acid
  • organic acids for instance lower aliphatic monocarboxylic or dicarboxylic acids such as acetic acid, fumaric acid, tartaric acid, lactic acid, maleic acid, citric acid or salicylic acid
  • sulfonic acids for instance lower alkyl sulfonic acids such as methane sulfonic acid, or benzene sulfonic acids optionally substituted in the benzene ring by halogen or lower alkyl, such as p-toluene sulfonic acid, are suitable as physiologically acceptable acid addition salts of the compounds of Formula I.
  • the superior anti-arrhythmic effect of the compounds of Formula I in male human patients in particular in the conversion of recent onset of atrial fibrillation (Afib) or flutter to normal sinus rhythm (NSR) in male human patients, can be demonstrated by clinical test data with human patients which prove the surprising suitability of 3,7- diazabicyclo[3,3J]nonane compounds, e.g. of tedisamil and its acid addition salts, for the treatment and/or prophylaxis of anti-arrhythmic effects in male human patients, preferably for conversion of recent onset of atrial fibrillation (Afib) or flutter to normal sinus rhythm (NSR) in male human patients.
  • This first clinical study in humans was a Multi-Center, Double-Blind, Randomized, Placebo-Controlled, Sequential Ascending Dose Groups Study to evaluate the Efficacy and Safety of Intravenous Tedisamil in the Rapid Conversion to Normal Sinus Rhythm in Patients with Atrial Fibrillation or Flutter.
  • the active ingredient used was tedisamil dihydrochloride.
  • the study was designed as a phase II study and executed in 35 to 40 centers in 3 to 4 countries. Study duration: Screening: up to 48 hours; treatment (in- patient): single 30-minute infusion; safety follow up: 24 hours (in-patient) with continuous telemetry and 28 day safety follow up.
  • the primary efficacy objective of the study was to demonstrate the superiority of any dose of tedisamil to placebo in the termination of atrial fibrillation/flutter as measured by the percentage of human patients converted to normal sinus rhythm (NSR) (for at least 60 seconds) at any time within 2.5 hours after the start of infusion, in humans.
  • NSR normal sinus rhythm
  • Secondary efficacy objectives were to determine the percentage of human patients remaining in sinus rhythm at 2.5 hours after initiation of the intravenous infusion of tedisamil versus placebo; to determine the percentage of human patients remaining in sinus rhythm at 24 hours after initiation of the intravenous infusion of tedisamil versus placebo; to determine the time to conversion after the start of the infusion of tedisamil versus placebo; and to determine the dose- and plasma concentration-response relationships of tedisamil versus placebo.
  • Safety objective determining the safety and tolerability of tedisamil versus placebo.
  • a multi-center, double-blind, randomized, placebo-controlled, sequential ascending dose groups study to evaluate the efficacy and safety of intravenous tedisamil versus placebo.
  • the study drug was infused over 30 minutes, receiving half the dose within 10 minutes and half the dose within the remaining 20 minutes
  • the first patient group received 0.4 mg/kg bodyweight (bw), infused as 0.2 mg/kg bw within 10 minutes, continued with 0.2 mg/kg bw infused within 20 minutes.
  • the next higher dose 0.6 mg/kg bw (0.3 mg/kg bw infused within 10 min, continued with 0.3 mg/kg bw infused within 20 minutes) was only administered after the initial dose has been assessed (blinded) and found to be safe.
  • a third stage may be added with a higher dose. Tedisamil blood concentrations were assessed during the infusion (at 10 and 30 minutes), at conversion to normal sinus rhythm, at recurrence and 24 hours after start of infusion.
  • Planned number of human subjects 330 randomized (110 patients per dose group)
  • Atrial fibrillation or flutter with a duration of > 3 hours and ⁇ 48 hours, occurring as a first or recurrent episode.
  • Placebo (vehicle) administered as a 30-minute intravenous infusion.
  • the total infusion time is 30 minutes, with half the dose infused within 10 minutes, and half the dose infused within the remaining 20 minutes.
  • Primary efficacy the percentage of human patients converted to normal sinus rhythm (for at least 60 seconds) at any time within 2.5 hours after the initiation of the infusion of study drug.
  • the percentage of conversion to normal sinus rhythm (at any time within 2.5 hours after the initiation of the infusion) in the placebo group is equal to 20% and the clinically relevant difference is 20%.
  • the percentage of conversion to normal sinus rhythm in the placebo group is equal to 10% and the clinically relevant difference is 40%.
  • Interim analyses for efficacy was performed halfway the first and second stages by an external statistician. The purpose is to terminate a stage when the tedisamil dose used in that stage is inefficacious.
  • each interim analysis was a predictive power calculation for the comparison of tedisamil and placebo with respect to the primary efficacy variable.
  • Blinded safety reviews were performed at the same time as the efficacy analyses and, in addition, at the end of the each stage (if applicable).
  • the analysis of a second study in humans confirmed the finding of the first study, e.g. that there is a gender difference related to efficacy, e.g. that male human patients show a higher conversion rate compared to women when treated with tedisamil.
  • the active ingredient used was tedisamil sesqifumarate.
  • the study was designed as a phase II study and executed in 30 to 40 centers in 5 countries. Study duration: Screening: up to 48 hours; treatment (in-patient): single 30-minute infusion; safety follow up: 24 hours (in-patient) with continuous telemetry and 28 day safety follow up.
  • the primary efficacy objective of the study in humans was to demonstrate the superiority of any dose of tedisamil sesquifumarate to placebo in the rapid conversion to normal sinus rhythm (for at least 60 seconds), as measured by the percentage of subjects converted at any time within 2.5 hours after the start of infusion.
  • Secondary efficacy objectives were to determine the percentage of subjects converting to normal sinus rhythm at any time within 2.5 hours after start of the intravenous infusion and in normal sinus rhythm at 2.5 hours after initiation of the infusion of tedisamil sesquifumarate versus placebo; to determine the percentage of subjects converting to normal sinus rhythm at any time within 2.5 hours after start of the intravenous infusion and in normal sinus rhythm at 24 hours after initiation of the infusion of tedisamil sesquifumarate versus placebo; to determine the percentage of human subjects converting to normal sinus rhythm at any time within 2.5 hours after start of the intravenous infusion and in normal sinus rhythm at hospital discharge; to determine the time to conversion to normal sinus rhythm after the start of the infusion of tedisamil sesquifumarate versus placebo; to determine the dose- and concentration -response relationships of tedisamil sesquifumarate versus placebo; and to determine the energy required for DC cardioversion of tedisamil sesquifumarate versus placebo.
  • Safety objective
  • the study drug was infused over 30 minutes, receiving half the dose within 10 minutes and half the dose within the remaining 20 minutes.
  • Subjects were randomly assigned to receive either: - 0.32 mg tedisamil free base per kg bodyweight (bw) (0J6 mg/kg bw within 10 minutes, followed by 0J6 mg/kg bw within 20 minutes); or - 0.48 mg tedisamil free base per kg bw (0.24 mg/kg bw within 10 min, followed by 0.24 mg/kg bw within 20 minutes); or - 0.64 mg tedisamil free base per kg bw (0.32 mg/kg bw within 10 min, followed by 0.32 mg/kg bw within 20 minutes); or - a 30 minute placebo infusion.
  • Atrial fibrillation or flutter with a duration of > 3 hours and ⁇ 45 days, occurring as a first or recurrent episode.
  • Test Product, Dose and Mode of Administration - Tedisamil free base 0.32 mg/kg body weight (equivalent to 0.51 mg/kg tedisamil sesquifumarate and to 0.4 mg/kg tedisamil dihydrochloride - Tedisamil free base 0.48 mg/kg body weight (equivalent to 0.77 mg/kg tedisamil sesquifumarate and to 0.6 mg/kg tedisamil dihydrochloride - Tedisamil free base 0.64 mg/kg body weight (equivalent to 1.02 mg/kg tedisamil sesquifumarate and to 0.8 mg/kg tedisamil dihydrochloride
  • Placebo (vehicle) administered as a 30-minute intravenous infusion similar to tedisamil infusion.
  • the total infusion time is 30 minutes, with half the dose infused within 10 minutes, and half the dose infused within the remaining 20 minutes.
  • Secondary efficacy percentage of human subjects in normal sinus rhythm at any time within 2.5 hours and at 24 hours after start of infusion, as well as at hospital discharge, time to conversion, dose- and concentration-response relationships and DC cardioversion energy.
  • Percentages of conversion will be compared among treatment groups using the (Pearson) chi-square statistics. Times to conversion will be compared among treatment groups using the log-rank test. Dose-response and concentration-response relationships and the energy required for DC conversion will be examined using descriptive statistics. Subjects with atrial fibrillation and atrial flutter will be separately analyzed. In addition, both populations will be pooled for analysis. All analyses involving the atrial flutter subject population will be considered as exploratory. Table I: Conversion of recent onset of atrial fibrillation (Afib) to NSR Conversion to NSR at any time within 2.5 hrs after start of infusion. ITT human patient sample; human patients with DC cardioversion are excluded.
  • Table II Conversion of recent onset of atrial fibrillation (Afib) to NSR Conversion to NSR at any time within 2.5 hrs after start of infusion. Human patients with atrial fibrillation ITT human patient sample; human patients with DC cardioversion are excluded.
  • Table III Conversion of recent onset of atrial fibrillation (Afib) to NSR Conversion to NSR at any time within 2.5 hrs after start of infusion. ITT human patient sample; human patients with DC cardioversion are excluded.
  • 3,7-diazabicyclo-[3,3J]nonane compounds preferably of 9,9-alkylene-3,7-diazabicyclo[3,3J]-nonane compounds, and most preferably of tedisamil, and of pharmaceutically acceptable acid addition salts and/or solvates, may be contained according to the invention, together with conventional pharmaceutical auxiliaries and/or carriers, in solid or liquid pharmaceutical preparations dedicated to the administration in humans.
  • solid preparations are preparations which can be administered orally, such as tablets, coated tablets, capsules, powders or granules, or alternatively suppositories.
  • compositions may contain conventional pharmaceutical inorganic and/or organic carriers, such as talcum, lactose or starch, in addition to conventional pharmaceutical auxiliaries, for example lubricants or tablet disintegrating agents.
  • Liquid preparations such as suspensions or emulsions of 3,7-diazabicyclo- [3,3J]nonane compounds, preferably of 9,9-alkylene-3,7-diazabicyclo[3,3,1]-nonane compounds, and most preferably of tedisamil, and of pharmaceutically acceptable acid addition salts and/or solvates thereof, may contain the usual diluents such as water, oils and/or suspension agents such as polyethylene glycols and the like.
  • Other auxiliaries may additionally be added, such as preservatives, taste correctives and the like.
  • the 3,7-diazabicyclo-[3,3J]nonane compounds preferably of 9,9-alkylene-3,7- diazabicyclo[3,3J]-nonane compounds, and most preferably tedisamil, and pharmaceutically acceptable acid addition salts and/or solvates thereof, can be mixed and formulated with the pharmaceutical auxiliaries and/or carriers in known manner.
  • 3,7-diazabicyclo- [3,3,1]nonane compounds preferably of 9,9-alkylene-3,7-diazabicyclo[3,3,1]-nonane compounds, and most preferably tedisamil, and pharmaceutically acceptable acid addition salts and/or solvates thereof, can for example be mixed with the auxiliaries and/or carriers in conventional manner and can be wet or dry granulated.
  • the granules or powder can be poured directly into capsules or be pressed into tablet cores in conventional manner. These can be coated in known manner if desired.
  • Examples 1 to 3 describe pharmaceutical preparations according to the invention which contain an active substance of Formula I, and also the production of such pharmaceutical preparations.
  • the following examples explain the production of pharmaceutical preparations containing tedisamil dihydrochloride.
  • Pharmaceutical preparations containing tedisamil sesquifumarate may be obtained in an analogous manner.
  • Example 1 Tablets Composition:
  • the active substance was mixed with corn starch and finely powdered lactose in a mixer.
  • the resulting mixture was thoroughly moistened with a 20% solution of polyvinylpyrrolidone ("Kollidon 25", from BASF) in deionized water. If necessary, additional deionized water was added.
  • the moist granules were passed through a 2 mm sieve, dried on trays at 40 DEG C. and then passed through a 1 mm sieve (Frewitt machine). After the granules had been mixed with magnesium stearate and talcum, tablets weighing 115 mg were pressed therefrom, so that each tablet contained 20 mg of the active substance.
  • Example 2 Capsules Composition
  • the active substance was mixed with corn starch and finely powdered lactose in a mixer.
  • the resulting mixture was thoroughly moistened with a 20% solution of polyvinylpyrrolidone ("Kollidon 25", from BASF) in deionized water. If necessary, deionized water was added.
  • the moist granules were passed through a 1.6 mm sieve (Frewitt machine), dried on trays at 40 DEG C, and then passed through a 1 mm sieve (Frewitt).

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Abstract

La présente invention concerne l'utilisation de composés de 3,7-diazabicyclo[3,3,1]nonane, de préférence des composés de 9,9-alkylène-3,7-diazabicyclo[3,3,1]nonane, et, encore mieux, l'utilisation de tedisamil, ainsi que les sels d'addition acide et/ou les solvates de ceux-ci, acceptables d'un point de vue physiologique, pour traiter et/ou prévenir des événements anti-arythmiques chez des patients humains mâles, de préférence pour faire passer un événement de fibrillation auriculaire (Afib) ou de flutter qui vient d'apparaître à un rythme sinusal normal (NSR) chez des patients humains mâles.
PCT/EP2004/051532 2003-07-21 2004-07-19 Utilisation de composes de 3,7-diazabicyclo[3,3,1]nonane pour traiter et/ou prevenir des evenements arythmiques chez des patients humains males WO2005011690A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
CA002533492A CA2533492A1 (fr) 2003-07-21 2004-07-19 Utilisation de composes de 3,7-diazabicyclo[3,3,1]nonane pour traiter et/ou prevenir des evenements arythmiques chez des patients humains males
JP2006520832A JP2006528155A (ja) 2003-07-21 2004-07-19 ３，７−ジアザビシクロ［３．３．１］ノナン化合物の、ヒト男性患者の抗不整脈事象治療及び／又は予防のための使用
BRPI0412247-0A BRPI0412247A (pt) 2003-07-21 2004-07-19 uso de compostos 3,7-diazabiciclo[3.3.1]nonano para o tratamento e/ou profilaxia de episódios arrìtmicos em doentes humanos do sexo masculino
MXPA06000796A MXPA06000796A (es) 2003-07-21 2004-07-19 Uso de los compuestos 3,7-diazabiciclo [3,3,1]nonano para el tratamiento y/o profilaxis de eventos antiarritmicos en pacientes humanos varones.
EP04742001A EP1648456A1 (fr) 2003-07-21 2004-07-19 Utilisation de composes 3,7-diazabicyclo¬3,3,1|nonane pour le traitement et/ou la prophylaxie d'incidents arythmiques chez des patients males
AU2004260624A AU2004260624A1 (en) 2003-07-21 2004-07-19 Use of 3,7-diazabicyclo`3, 3,1 !nonane compounds for the treatment and/or prophylaxis of anti-arrhythmic events in male human patients

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EP03102243.7 2003-07-21
EP03102243 2003-07-21

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JP (1) JP2006528155A (fr)
CN (1) CN1822833A (fr)
AU (1) AU2004260624A1 (fr)
BR (1) BRPI0412247A (fr)
CA (1) CA2533492A1 (fr)
MX (1) MXPA06000796A (fr)
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014134419A1 (fr) * 2013-03-01 2014-09-04 Gilead Sciences, Inc. Utilisation de bloqueurs ikach pour le traitement de maladies cardiaques
US9403782B2 (en) 2011-05-10 2016-08-02 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9598435B2 (en) 2011-07-01 2017-03-21 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9695192B2 (en) 2011-07-01 2017-07-04 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators

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US9403782B2 (en) 2011-05-10 2016-08-02 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9682998B2 (en) 2011-05-10 2017-06-20 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9598435B2 (en) 2011-07-01 2017-03-21 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9676760B2 (en) 2011-07-01 2017-06-13 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9695192B2 (en) 2011-07-01 2017-07-04 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
WO2014134419A1 (fr) * 2013-03-01 2014-09-04 Gilead Sciences, Inc. Utilisation de bloqueurs ikach pour le traitement de maladies cardiaques

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