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WO2001010216A1 - Composes antiarythmiques - Google Patents

Composes antiarythmiques Download PDF

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Publication number
WO2001010216A1
WO2001010216A1 PCT/US2000/021538 US0021538W WO0110216A1 WO 2001010216 A1 WO2001010216 A1 WO 2001010216A1 US 0021538 W US0021538 W US 0021538W WO 0110216 A1 WO0110216 A1 WO 0110216A1
Authority
WO
WIPO (PCT)
Prior art keywords
dihydro
oxo
bistrifluoromethylphenyl
phenyl
acetamide
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.)
Ceased
Application number
PCT/US2000/021538
Other languages
English (en)
Inventor
John W. Butcher
David A. Claremon
Nigel J. Liverton
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.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
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 Merck and Co Inc filed Critical Merck and Co Inc
Priority to AU68950/00A priority Critical patent/AU6895000A/en
Publication of WO2001010216A1 publication Critical patent/WO2001010216A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines

Definitions

  • Arrhythmias often occur as complications to cardiac diseases such as myocardial infarction and heart failure. In a serious case, arrhythmias give rise to ventricular fibrillation and can cause sudden death.
  • antiarrhythmic agents of Class I according to the classification of Vaughan- Williams, which cause a selective inhibition of the maximum velocity of the upstroke of the action potential (Vmax) are inadequate for preventing ventricular fibrillation.
  • Vmax maximum velocity of the upstroke of the action potential
  • they have problems regarding safety, namely, they cause a depression of the myocardial contractility and have a tendency to induce arrhythmias due to an inhibition of the impulse conduction.
  • Beta-adrenergic receptor blocking agent which belong to Class II are of limited value since their effects are either limited to a certain type of arrhythmia or are contraindicated because of their cardiac depressant properties in certain patients with cardiovascular disease. Their safety, however, is higher than that of the antiarrhythmic agents of Class I.
  • Antiarrhythmic agents of Class III are drugs which cause a selective prolongation of the duration of the action potential without a significant depression of the Vmax.
  • drugs in this class were limited to sotalol and amiodarone, both of which have been shown to possess Class III properties.
  • Sotalol also possesses Class II effects which may cause cardiac depression and be contraindicated in certain susceptible patients.
  • Amiodarone is severely limited by side effects.
  • Drugs of this class are expected to be effective in preventing ventricular fibrillations.
  • Pure Class III agents, by definition are not considered to cause myocardial depression or an induction of arrhythmias due to the inhibition of the action potential conduction as seen with Class I antiarrhythmic agents.
  • IKs antagonists In the treatment of arrhythmia, IKs antagonists have demonstrated effectiveness when delivered orally in amounts ranging from about 0.01 to about 1 mg per kg of body weight per day, in a single dose or in 2 to 4 divided doses.
  • the activity of the compounds described herein as antiarrhythmic agents is measured by their ability to block the IKs and iKr currents as determined by the following test protocol.
  • Outward potassium currents are measured in single guinea pig ventricular myocytes using a whole-cell voltage clamp technique described in detail elsewhere (Sanguinetti and Jurkiewicz, 1990, Two components of cardiac delayed rectifier K+ current: differential sensitivity to block by Class III antiarrhythmic agents. J. Gen Physiol. 96: 195-215).
  • Myocytes are isolated by enzymatic (collagenase and protease) digestion of Langandorf perfused hearts. Single cells are then voltage clamped using 1 mm square-bore pipettes filled with 0.5 M Kgluconate, 25 mM KC1, 5 mM K(2)ATP. Cells are bathed in a solution containing, in mN: 132 NaCl, 4KC1, 1.2 MgCl2, 10 HEPES, 10 glucose: pH 7.2, temp. 35°C.
  • Test depolarizations are applied as voltage ramps from -85 to -50 mV, and as steps to -10 mV (0.5 s) and +50 mV (1.0 s).
  • I ⁇ i s measured as peak outward current during the voltage ramp.
  • iRr is measured as tail currents upon repolarization from -10 mV to -50 mV.
  • IKs is measured as time-dependent current during the pulse to +50 mV. Currents are measured during control, then after exposure to drug at two different concentrations.
  • the compounds described herein as selective IKs channel antagonists have an IC50 of less than 100 nM as IKs antagonists.
  • the compounds of this invention are at least 10 times more potent in the blockade of IKs than of blockade of iKr-
  • Beta-adrenergic receptor blocking agents are a class of pharmaceutically active compounds which decrease the positive chronotropic, positive inotropic, bronchodilator and vasodilator responses caused by beta-adrenergic receptor agonists. The magnitude of this decreased response is proportional to the existing sympathetic tone and the concentration of beta-blocker at the receptor sites. Beta- adrenergic receptor blockage is said to reduce cardiac output in both healthy subjects and patients with heart disease. While the mechanism of antihypertension effects of beta-adrenergic receptor blocking agents has not been established, possible mechanisms of action include reduction in cardiac output, reduction in plasma renin activity, and central nervous system sympatholytic action.
  • beta-adrenergic receptor antagonists have been shown effective in reducing the incidence of mortality and sudden death in postinfarction patients (Yusaf et al., Prog Cardiovasc Dis 17: 335-371, 1985; Lau et al., N Eng J Med 327: 248-254, 1992). While both selective IKs channel blockers and beta- adrenergic receptor blocking agents have been proven effective when administered separately, it is considered to be in the best interest of the patient to reduce the amount of these compounds provided to the patient. Any reduction of one or the other compound would be considered helpful, but this is particularly true of beta-adrenergic receptor blocking agents which are known to have significant side effects in some humans.
  • lH-Benzo[e] [l,4]diazepin-2-one compounds of Formula I which are selective IKs antagonists useful for the treatment and prevention of cardiac arrhythmias, are presented. Also claimed herein is the method of treatment and prevention of cardiac arrhythmias, such as atrial, supraventricular and ventricular ectopy, tachycardia, flutter or fibrillation, including atrial, supraventricular and ventricular arrhythmias resulting from myocardial ischemic injury, and pharmaceutical compositions containing the compounds of Formula I useful for the same.
  • cardiac arrhythmias such as atrial, supraventricular and ventricular ectopy, tachycardia, flutter or fibrillation, including atrial, supraventricular and ventricular arrhythmias resulting from myocardial ischemic injury, and pharmaceutical compositions containing the compounds of Formula I useful for the same.
  • R 1 is: C 3 -C 4 -alkyl, straight or branched;
  • R is: C 3 -C 6 -cycloalkyl, or phenyl, unsubstituted or substituted with one, two or three substituents selected from the group consisting of: C ⁇ -C 4 -alkyl, trifluoromethyl, and halo;
  • R 3 is: optionally substituted (CH 2 ) n -phenyl, unsubstituted or substituted with one, two or three substituents selected from the group consisting of: C C 4 -alkyl, trifluoromethyl, and halo; and
  • n 0, 1 or 2.
  • This invention is meant to include the individual diastereomers where such exist and mixtures thereof and enantiomers and mixtures of the enantiomers.
  • Formulas I include the conventional non-toxic salts or the quarternary ammonium salts of the compounds of Formula I formed, e.g., from non- toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of Formula I which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
  • R is: Ca-C ⁇ -cycloalkyl, or phenyl, unsubstituted or substituted with one two or three substituents selected from the group consisting of: C 1 -C 4 -alkyl, trifluoromethyl, and halo;
  • R 3 is: optionally substituted (CH 2 ) n -phenyl, unsubstituted or substituted with one, two or three substituents selected from the group consisting of: C C -alkyl, trifluoromethyl, and halo; and
  • n 0, 1 or 2.
  • R is: cyclopropyl, or phenyl
  • R is: -CH 2 -phenyl substituted with two substituents selected from the group consisting of: methyl and trifluoromethyl.
  • R is: cyclopropyl, or phenyl
  • R is: -CH 2 -phenyl substituted with two substituents selected from the group consisting of: methyl and trifluoromethyl.
  • a compound of Formula I or a pharmaceutically acceptable salt, crystal form or hydrate thereof, selected from the group consisting of:
  • a method of treating cardiac arrhythmia which comprises the administration to a patient in need of such treatment of an effective amount of a selective Ij ⁇ g antagonist of Formula I as recited above.
  • a method of preventing cardiac arrhythmia which comprises the administration to a patient in need of such treatment of an effective amount of a selective Ij s antagonist of Formula I as recited above.
  • a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of Formula I, as recited above, or a pharmaceutically acceptable salt, crystal form or hydrate thereof.
  • the selective IKs blockers of the present invention have the pharmacological properties required for antiarrhythmic agents of Class III, namely they demonstrate prolongation of QTc-interval , and dose dependent increases in ventricular refractoriness. This is accomplished without effecting heart rate, mean arterial pressure and PR and QRS intervals. Modest increases in LV+dP/dt (left ventricular change in pressure with time) is observed. Further, these compounds suppress the induction of PVS (Programmed Ventricular Stimulation) induced ventricular tachyarrhythmias.
  • PVS Programmed Ventricular Stimulation
  • these compounds are effective in treating and preventing all types of arrhythmias including ventricular, atrial and supraventricular arrhythmias.
  • the compounds of the present invention are especially useful for controlling reentrant arrhythmias and prevent sudden death due to ventricular fibrillation. These compounds are also effective in treating and preventing impaired cardiac pump functions.
  • a selective IKs antagonist is administered in an amount ranging from about .0001 to about 10 mg per kg of body weight per day, preferably from about .0001 to about 2 mg per kg of body weight per day, and more preferably, when intravenous delivery of the compounds is employed, from about 0.0003 to about 0.3 mg per kg of body weight per day, or when given orally from about 0.01 to about 1 mg per kg of body weight per day, in a single dose or in 2 to 4 divided doses of each compound.
  • the beta- adrenergic receptor blocking agent is administered in an amount ranging from about 1 mg per day to about 300 mg poer day and more preferably from about 2 mg/day to about 250 mg per day.
  • the activity of the compounds described herein as antiarrhythmic agents is measured by their ability to block the IKs and iKr currents as determined by the following test protocol.
  • Outward potassium currents are measured in single guinea pig ventricular myocytes using a whole-cell voltage clamp technique described in detail elsewhere (Sanguinetti and Jurkiewicz, 1990, Two components of cardiac delayed rectifier K + current: differential sensitivity to block by Class III antiarrhythmic agents. J. Gen Physiol. 96: 195-215).
  • Myocytes are isolated by enzymatic (collagenase and protease) digestion of Langandorf perfused hearts. Single cells are then voltage clamped using 1 mm square-bore pipettes filled with 0.5 M Kgluconate, 25 mM KC1, 5 mM K(2)ATP. Cells are bathed in a solution containing, in mN: 132 NaCl, 4KC1, 1.2 MgCl2, 10 HEPES, 10 glucose: pH 7.2, temp. 35°C.
  • the compounds described herein as selective IKs blockers have an IC50 of less than 100 nM as IKs blockers.
  • the compounds of this invention are at least 10 times more potent in the blockade of IKs than of blockade of IKr-
  • Triisopropylphenylsulfonylazide (2.27 g, 0.0073 mol) in THF (20 ml) was added over 5 min. This was stirred for 10 min, acetic acid (1.9 ml, 0.032 mol) was added and the reaction warmed to 30°C for 2 hour. The reaction was concentrated the residue dissolved in dichloromethane (200 mL) and washed with satd. NaHCO ⁇ (200 ml). The aqueous layer was back extracted with dichloromethane (100ml). The organic layers were combined, dried with Na2SO and evaporated to a brown foam.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés 1H-Benzo[e][1,4]diazépine-2-un, de Formule (I) qui sont des antagonistes séléctifs IKs, qui servent à traiter et à prévenir les arythmies cardiaques. L'invention concerne également le procédé de traitement ou de prévention des arythmies cardiaques, telles que l'ectopie atriale, supraventriculaire et ventriculaire, la tachycardie, le flutter ou la fibrillation; et aussi les arythmies atriales, supraventriculaires et ventriculaires provoquées par une blessure ischémique myocardique, et des compositions pharmaceutiques contenant les composés de Formule (I) utilisées dans le même but.
PCT/US2000/021538 1999-08-09 2000-08-07 Composes antiarythmiques Ceased WO2001010216A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU68950/00A AU6895000A (en) 1999-08-09 2000-08-07 Antiarrhythmic compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14793199P 1999-08-09 1999-08-09
US60/147,931 1999-08-09

Publications (1)

Publication Number Publication Date
WO2001010216A1 true WO2001010216A1 (fr) 2001-02-15

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/021538 Ceased WO2001010216A1 (fr) 1999-08-09 2000-08-07 Composes antiarythmiques

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AU (1) AU6895000A (fr)
WO (1) WO2001010216A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011021726A3 (fr) * 2009-08-21 2011-06-16 Otsuka Pharmaceutical Co., Ltd. Composé contenant de l'azote et composition pharmaceutique
US8664217B2 (en) 2008-02-22 2014-03-04 Otsuka Pharmaceutical Co., Ltd. Benzodiazepine compound and pharmaceutical composition
US8796447B2 (en) 2009-08-21 2014-08-05 Otsuka Pharmaceutical Co., Ltd. Process for producing benzo[B][1,4]diazepine-2,4-dione compound

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997048686A1 (fr) * 1996-06-21 1997-12-24 Merck & Co., Inc. Nouveaux n-1 alkyl-2-oxo-2,3,4,5-tetrahydro-1h-1,5-benzodiazepin-3-yl)-3-amides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997048686A1 (fr) * 1996-06-21 1997-12-24 Merck & Co., Inc. Nouveaux n-1 alkyl-2-oxo-2,3,4,5-tetrahydro-1h-1,5-benzodiazepin-3-yl)-3-amides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS [online] SELNICK H. G. ET AL.: "Preparation of bezodiazepinylamides as antiarrhythmics", accession no. STN Database accession no. 1998:31294 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8664217B2 (en) 2008-02-22 2014-03-04 Otsuka Pharmaceutical Co., Ltd. Benzodiazepine compound and pharmaceutical composition
WO2011021726A3 (fr) * 2009-08-21 2011-06-16 Otsuka Pharmaceutical Co., Ltd. Composé contenant de l'azote et composition pharmaceutique
CN102482234A (zh) * 2009-08-21 2012-05-30 大塚制药株式会社 含氮化合物和药物组合物
JP2013502378A (ja) * 2009-08-21 2013-01-24 大塚製薬株式会社 窒素含有化合物及び医薬組成物
EP2727917A1 (fr) * 2009-08-21 2014-05-07 Otsuka Pharmaceutical Co., Ltd. Composés contenant de l'azote et leurs compositions pharmaceutiques pour le traitement de la fibrillation auriculaire
US8796447B2 (en) 2009-08-21 2014-08-05 Otsuka Pharmaceutical Co., Ltd. Process for producing benzo[B][1,4]diazepine-2,4-dione compound
US8822453B2 (en) 2009-08-21 2014-09-02 Otsuka Pharmaceutical Co., Ltd. Nitrogen-containing compounds and pharmaceutical compositions thereof for the treatment of atrial fibrillation
US8940889B2 (en) 2009-08-21 2015-01-27 Otsuka Pharmaceutical Co., Ltd. Process for producing benzo [b] [1,4] diazepine-2,4-dione compound
US9212187B2 (en) 2009-08-21 2015-12-15 Otsuka Pharmaceutical Co., Ltd. Nitrogen-containing compounds and pharmaceutical compositions thereof for the treatment of atrial fibrillation
CN102482234B (zh) * 2009-08-21 2016-04-13 大塚制药株式会社 含氮化合物及其用于治疗心房纤维性颤动的药物组合物

Also Published As

Publication number Publication date
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