Description
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.
Description
(±)-Ibutilide is a class III antiarrhythmic agent. It inhibits the rapidly activating delayed-rectifier potassium current (I
Kr) in AT-1 myocytes with an IC
50 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.
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.
