IBUTILIDE

Absorption

Rapid after intravenous injection

Toxicity

Acute overdose in animals results in CNS toxicity; notably, CNS depression, rapid gasping breathing, and convulsions. The intravenous median lethal dose in the rat was more than 50 mg/kg which is, on a mg/m2 basis, at least 250 times the maximum recommended human dose.

Originator

Corvert,Pharmacia and Upjohn,USA

The Uses of IBUTILIDE

Cardiac depressant (anti-arrhythmic).

Background

Ibutilide is a Class III antiarrhythmic agent available in intravenous formulations. It is indicated for the conversion of acute atrial flutter and recent onset atrial fibrillation to normal sinus rhythm (NSR).

Indications

Indicated for the rapid conversion of atrial fibrillation or atrial flutter of recent onset to sinus rhythm.

Definition

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

Manufacturing Process

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.

brand name

Inocor (Sterling Winthrop).

Therapeutic Function

Antiarrhythmic

General Description

Ibutilide, N-{4-[4-(ethylheptylamino)-1-hydroxybutyl]phenyl}methanesulfonamide (Corvert), aclass III antiarrhythmic belonging to the methanesulfonanilideclass of agents, is indicated for rapid conversion ofatrial fibrillation or atrial flutter to normal sinus rhythm.Unlike dofetilide, it is not highly specific for the delayedrectifier potassium currents (Ikr) and does have some affinityfor sodium channels.

Pharmacokinetics

Ibutilide prolongs the action potential duration and increases both atrial and ventricular refractoriness in vivo, i.e., class III electrophysiologic effects. Voltage clamp studies indicate that ibutilide, at nanomolar concentrations, delays repolarization by activation of a slow, inward current (predominantly sodium), rather than by blocking outward potassium currents, which is the mechanism by which most other class III antiarrhythmics act.

Clinical Use

Ibutilide (Corvert) is another methanesulfonanilide derivative , but unlike sotalol, it lacks any β-adrenergic blocking activity. Like sotalol, it exhibits electrophysiologic effects characteristic of Class III. Ibutilide is used only by intravenous infusion as its fumarate salt.

Metabolism

Primarily hepatic. Eight metabolites of ibutilide were detected in metabolic profiling of urine. These metabolites are thought to be formed primarily by o-oxidation followed by sequential b-oxidation of the heptyl side chain of ibutilide. Of the eight metabolites, only the o-hydroxy metabolite possesses class III electrophysiologic properties similar to that of ibutilide in an in vitro isolated rabbit myocardium model.