Ibutilide fumarate

Covert was launched in the US and UK for treatment of atrial fibrillation and flutter and can be synthesized in three steps from N-phenyl rnethanesulfonamide. While ibutilide has an asymmetric center, it has been determined that the racemate is equipotent with either enantiomer. The antiarrhythmic action is derived from the compounds ability to prolong the action potential duration and lengthen the refractory period of myocardial tissue. Class Ⅲ antiarrhythrnic agents accomplish this by blocking outward potassium channels, however, ibutilide elicits the same effect by activation of slow inward sodium channels. Recent evidence indicates that it also is a potent blocker of the rapidly acting delayed rectifier potassium current (l_kr)and may block the ATP-inhibited potassium channel.

(±)-Ibutilide is a class III antiarrhythmic agent. It inhibits the rapidly activating delayed-rectifier potassium current (I_Kr) in AT-1 myocytes with an IC₅₀ value of 20 nM. (±)-Ibutilide also enhances the late inward sodium current (I_Na) and increases the action potential duration in isolated guinea pig ventricular cells. It decreases ventricular fibrillation induced by the ATP-dependent potassium channel activator pinacidil in Langendorff isolated perfused rabbit hearts when used at concentrations ranging from 3 to 30 μM. (±)-Ibutilide (15 μg/kg, i.v.) increases the effective refractory period (ERP) of the left and right atrium in anesthetized pigs. It prevents rapid pacing-induced atrial flutter in dogs when administered orally at doses ranging from 0.25 to 5 mg/kg. Formulations containing ibutilide have been used in the treatment of atrial arrhythmias.

White to Off-White Solid

Pharmacia ＆ Upjohn (UK)

A methanesulfonanilide antiarrhythmic agent; prologns myocardial action potential duration, predominantly by activation of slow inward sodium current. Antiarrhythmic (class III).

ChEBI: Ibutilide fumarate is a member of benzenes and an organic amino compound.

A mechanically stirred solution of aniline (139.7 g, 1.5 mole) in pyridine (2 L), under N2 is cooled in an ice bath. Methanesulfonyl chloride (171.8 g, 1.5 mole) is added dropwise to this solution while the temperature is maintained at 15°-20°C, which results in a red-orange color change in the reaction mixture. After the addition is complete the ice bath is removed and the reaction is allowed to continue at room temperature. The reaction is complete after 2.5 h. The reaction mixture is concentrated in vacuo and the residue is combined with 700 ml of water which results in crystallization of a dark red material.
This material is filtered and washed several times with water. The filtered material is dissolved in CH2Cl2, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue is dissolved in hot ethyl acetate, treated with Darco (decolorizing carbon) and crystallized to yield methanesulfonanilide which had a melting point: 93°-94°C.
A mechanically stirred suspension of aluminum chloride (88.0 g, 0.66 moles) and 150 ml of carbon disulfide under N2 is cooled in an ice bath. Methanesulfonanilide (30.0 g, 0.175 mol) and succinic anhydride (17.5 g, 0.175 mol) are combined and added rapidly to the cooled reaction mixture. The ice bath is removed and the mixture is stirred at room temperature for 6 h. The reaction mixture is then heated to 55°C and allowed to continue for 18 h. The reaction mixture is separated into two layers the bottom of which solidifies.
The upper layer is decanted and the remaining solid layer is decomposed with ice. The resulting suspension is filtered and the solid is washed several times with methylene chloride and dissolved in a mixture of saturated sodium bicarbonate (500 ml) and water (500 ml). This solution is acidified (pH 2) with HCl and the resulting precipitate is collected by filtration, redissolved in NaHCO3 and reprecipitated with HCl. The solid, 4-[(methylsulfonyl)amino]-γ- oxobenzenebutanoic acid, is collected by filtration. Melting point 198°-200°C.
A stirred solution of 4-[(methylsulfonyl)amino]-γ-oxobenzenebutanoic acid (12.0 g, 0.044 mol) in DMF (100 ml) under N2 is cooled in an ice bath to 5°C and treated with 1-hydroxybenzotriazole (5.94 g, 0.044 mol) and N,N'- dicyclohexylcarbodiimide (9.08 g, 0.044 mol). After 1 hour, ethylheptylamine (6.3 g, 0.044 mol) is added, after an additional 30 min the ice bath is removed and the mixture is kept at room temperature for 18 h.
The reaction mixture is filtered over a Celite filter aid and the filtrate is concentrated under vacuum. The resulting material is dissolved in CH2Cl2, washed with dilute HCl, NaHCO3 and concentrated. The residue is chromatographed over silica gel (1.25 kg) with 5% MeOH : 1% NH4OH : CH2Cl2. The N-ethyl-N-heptyl-γ-oxo-4-[(methylsulfonyl)amino]benzenebutanamide thus obtained is crystallized from EtOAc to yield 10.77 g, melting point 100°-102°C.
To a N2 covered suspension of 0.29 g (7.57 mmol) of LiAlH4 in 10 ml of THF cooled in an ice bath is added a solution of 1.0 g (2.52 mmol) of N-ethyl-Nheptyl-γ-oxo-4-[methylsulfonyl)amino]benzenebutanamide in 10 ml of THF over 6 min. The ice bath is then removed and the mixture heated at reflux for 27 h and then stirred at room temperature for 2 days. The mixture is cooled in an ice bath and there is added dropwise 10 ml of aqueous sodium potassium tartrate followed by EtOAc and H2O to keep the mixture fluid.
The aqueous fraction is extracted once with EtOAc and the combined EtOAc fractions are washed in turn with H2O and concentrated in vacuo. The residue is chromatographed on a 200 ml silica gel column (elution with 6% MeOH : CH2Cl2 containing 0.5% NH4OH) and 9.7 ml fractions were collected and treated with Et2O and aqueous NaHCO3. The organic layer is concentrated in vacuo to yield N-[4-[4-(ethylheptylamino)-1-hydroxybutyl]phenyl] methanesulfonamide.
Preparation of fumarate (WO Patent 01/07417). To dichloromethane solution of 4-[4-N-[(Ethylheptylamino)-1-hydroxybutyl]phenyl]methanesulfonamide is added hemimolar quantities of fumaric acid and heated to reflux until a clear solution was obtained. Upon cooling the fumarate of 4-[4-N- [(Ethylheptylamino)-1-hydroxybutyl]phenyl]methanesulfonamide was obtained.

Inocor (Sterling Winthrop);Corvert.

Antiarrhythmic

Ibutilide hemifumarate salt is considered a new generation "pure" Class III antiarrhythmic agent. Ibutilide binds to and alters the activity of hERG potassium channels, delayed inward rectifier potassium (IKr) channels and L-type (dihydropyridine sensitive) calcium channels.

Ibutilide (Corvert) is a structural analog of sotalol and produces cardiac electrophysiological effects similar to those of the antiarrhythmic agents in class III.
Ibutilide is approved for the chemical cardioversion of recent-onset atrial fibrillation and atrial flutter. Ibutilide appears to be more effective in terminating atrial flutter than atrial fibrillation. It can also lower the defibrillation threshold for atrial fibrillation resistant to chemical cardioversion.

The major adverse effect associated with the use of ibutilide is the risk of torsades de pointes due to QT prolongation. Other reported adverse cardiovascular events (all 2%) include hypotension and hypertension, bradycardia and tachycardia, and varying degrees of A-V block. The incidence of noncardiac adverse events with the exception of nausea does not differ from that of placebo.

Ibutilide has significant drug interactions.

Store at RT

Contraindications to the use of ibutilide include baseline prolongation of the QT interval, use of other QTprolonging drugs, history of torsades de pointes, hypersensitivity to ibutilide, uncorrected hypokalemia or hypomagnesemia, and pregnancy or breast-feeding.