Ibutilide fumarate CAS 122647-32-9
Introduction：Basic information about Ibutilide fumarate CAS 122647-32-9, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Ibutilide fumarate Basic information
| Product Name: | Ibutilide fumarate |
| Synonyms: | (±)-N-[4-[4-(Ethylheptylamino)-1-hydroxybutyl]phenyl]methanesulfonamide hemifumarate;Ibutibide Fumarate;IBUTILIDE FUMRTATE;Ibutilide fumarate;N-[4-[4-(ethyl-heptyl-amino)-1-hydroxy-butyl]phenyl]methanesulfonamide fumarate;Corvert (tn);D00648;Ibutilide fumarate (usan) |
| CAS: | 122647-32-9 |
| MF: | (C20H36N2O3S)2.C4H4O4 |
| MW: | 885.24 |
| EINECS: | 687-381-2 |
| Product Categories: | Aromatics;Intermediates & Fine Chemicals;Medicine intermediate;Pharmaceuticals;Sulfur & Selenium Compounds;Inhibitors;Antiarrhythmic;Cardiovascular APIs |
| Mol File: | 122647-32-9.mol |
Ibutilide fumarate Chemical Properties
| Melting point | 112-117?C |
| RTECS | PB0475700 |
| storage temp. | 2-8°C |
| solubility | H2O: >20mg/mL |
| form | solid |
| color | off-white to tan |
| Water Solubility | H2O: >20mg/mL |
| λmax | 267nm(EtOH)(lit.) |
| Merck | 14,4883 |
| InChIKey | PCIOHQNIRPWFMV-WXXKFALUSA-N |
| SMILES | C1(=CC=C(NS(=O)(=O)C)C=C1)C(O)CCCN(CC)CCCCCCC.C1(C(O)CCCN(CC)CCCCCCC)C=CC(NS(=O)(=O)C)=CC=1.C(/C(=O)O)=C\C(=O)O |
| CAS DataBase Reference | 122647-32-9(CAS DataBase Reference) |
Safety Information
| Hazard Codes | Xn |
| Risk Statements | 22 |
| WGK Germany | 1 |
| HS Code | 2935904000 |
| Storage Class | 11 - Combustible Solids |
| Hazard Classifications | Acute Tox. 4 Oral Repr. 2 |
| Toxicity | rat,LD,oral,> 500mg/kg (500mg/kg),Teratology, The International Journal of Abnormal Development. Vol. 49, Pg. 406, 1994. |
| Description | Covert was launched in the US and UK for treatment of atrial fibrillation andflutter and can be synthesized in three steps from N-phenyl rnethanesulfonamide.While ibutilide has an asymmetric center, it has been determined that the racemate isequipotent with either enantiomer. The antiarrhythmic action is derived from thecompounds ability to prolong the action potential duration and lengthen the refractoryperiod of myocardial tissue. Class Ⅲ antiarrhythrnic agents accomplish this byblocking outward potassium channels, however, ibutilide elicits the same effect byactivation of slow inward sodium channels. Recent evidence indicates that it also is a potent blocker of the rapidly acting delayed rectifier potassium current (lkr)and mayblock the ATP-inhibited potassium channel. |
| Description | (±)-Ibutilide is a class III antiarrhythmic agent. It inhibits the rapidly activating delayed-rectifier potassium current (IKr) in AT-1 myocytes with an IC50 value of 20 nM. (±)-Ibutilide also enhances the late inward sodium current (INa) 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. |
| Chemical Properties | White to Off-White Solid |
| Originator | Pharmacia ＆ Upjohn (UK) |
| Uses | A methanesulfonanilide antiarrhythmic agent; prologns myocardial action potential duration, predominantly by activation of slow inward sodium current. Antiarrhythmic (class III). |
| Definition | ChEBI: Ibutilide fumarate is a member of benzenes and an organic amino compound. |
| 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, 1.5mole) is added dropwise to this solution while the temperature is maintainedat 15°-20°C, which results in a red-orange color change in the reactionmixture. After the addition is complete the ice bath is removed and thereaction is allowed to continue at room temperature. The reaction is completeafter 2.5 h. The reaction mixture is concentrated in vacuo and the residue iscombined with 700 ml of water which results in crystallization of a dark redmaterial. This material is filtered and washed several times with water. The filteredmaterial is dissolved in CH2Cl2, washed with brine, dried (Na2SO4), andconcentrated in vacuo. The residue is dissolved in hot ethyl acetate, treatedwith Darco (decolorizing carbon) and crystallized to yield methanesulfonanilidewhich 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 6h. The reaction mixture is then heated to 55°C and allowed to continue for 18h. The reaction mixture is separated into two layers the bottom of whichsolidifies. The upper layer is decanted and the remaining solid layer is decomposed withice. The resulting suspension is filtered and the solid is washed several timeswith methylene chloride and dissolved in a mixture of saturated sodiumbicarbonate (500 ml) and water (500 ml). This solution is acidified (pH 2) withHCl and the resulting precipitate is collected by filtration, redissolved inNaHCO3 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°Cand 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 isremoved and the mixture is kept at room temperature for 18 h. The reaction mixture is filtered over a Celite filter aid and the filtrate isconcentrated under vacuum. The resulting material is dissolved in CH2Cl2,washed with dilute HCl, NaHCO3 and concentrated. The residue ischromatographed 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 THFcooled 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 THFover 6 min. The ice bath is then removed and the mixture heated at reflux for27 h and then stirred at room temperature for 2 days. The mixture is cooledin an ice bath and there is added dropwise 10 ml of aqueous sodiumpotassium tartrate followed by EtOAc and H2O to keep the mixture fluid. The aqueous fraction is extracted once with EtOAc and the combined EtOAcfractions are washed in turn with H2O and concentrated in vacuo. The residueis chromatographed on a 200 ml silica gel column (elution with 6% MeOH :CH2Cl2 containing 0.5% NH4OH) and 9.7 ml fractions were collected andtreated with Et2O and aqueous NaHCO3. The organic layer is concentrated invacuo to yield N-[4-[4-(ethylheptylamino)-1-hydroxybutyl]phenyl]methanesulfonamide. Preparation of fumarate (WO Patent 01/07417). To dichloromethane solutionof 4-[4-N-[(Ethylheptylamino)-1-hydroxybutyl]phenyl]methanesulfonamide isadded hemimolar quantities of fumaric acid and heated to reflux until a clearsolution was obtained. Upon cooling the fumarate of 4-[4-N-[(Ethylheptylamino)-1-hydroxybutyl]phenyl]methanesulfonamide wasobtained. |
| Brand name | Inocor(Sterling Winthrop);Corvert. |
| Therapeutic Function | Antiarrhythmic |
| Biochem/physiol Actions | 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. |
| Clinical Use | Ibutilide (Corvert) is a structural analog of sotalol andproduces cardiac electrophysiological effects similar tothose of the antiarrhythmic agents in class III. Ibutilide is approved for the chemical cardioversion ofrecent-onset atrial fibrillation and atrial flutter. Ibutilideappears to be more effective in terminating atrial flutterthan atrial fibrillation. It can also lower the defibrillation threshold for atrial fibrillation resistant to chemicalcardioversion. |
| Side effects | The major adverse effect associated with the use of ibutilideis the risk of torsades de pointes due to QT prolongation.Other reported adverse cardiovascularevents (all 2%) include hypotension and hypertension,bradycardia and tachycardia, and varying degreesof A-V block. The incidence of noncardiac adverseevents with the exception of nausea does not differfrom that of placebo. |
| Drug interactions | Ibutilide has significant drug interactions. |
| storage | Store at RT |
| Precautions | Contraindications to the use of ibutilide include baselineprolongation of the QT interval, use of other QTprolongingdrugs, history of torsades de pointes, hypersensitivityto ibutilide, uncorrected hypokalemia orhypomagnesemia, and pregnancy or breast-feeding. |
| References | [1] GUI-RONG LI Ming Q D. Pharmacology of cardiac potassium channels.[J]. Advances in pharmacology, 2010, 59: 93-134. DOI: 10.1016/s1054-3589(10)59004-5 [2] T YANG D M R D J Snyders. Ibutilide, a methanesulfonanilide antiarrhythmic, is a potent blocker of the rapidly activating delayed rectifier K+ current (IKr) in AT-1 cells. Concentration-, time-, voltage-, and use-dependent effects.[J]. Circulation, 1995, 91 6: 1799-1806. DOI: 10.1161/01.cir.91.6.1799 [3] LEE K S. Ibutilide, a new compound with potent class III antiarrhythmic activity, activates a slow inward Na+ current in guinea pig ventricular cells.[J]. Journal of Pharmacology and Experimental Therapeutics, 1992, 262 1: 99-108. [4] G S FRIEDRICHS. Antifibrillatory effects of ibutilide in the rabbit isolated heart: mediation via ATP-dependent potassium channels.[J]. Journal of Pharmacology and Experimental Therapeutics, 1993, 266 3: 1348-1354. [5] KARSTEN KNOBLOCH. Electrophysiological and antiarrhythmic effects of the novel I(Kur) channel blockers, S9947 and S20951, on left vs. right pig atrium in vivo in comparison with the I(Kr) blockers dofetilide, azimilide, d,l-sotalol and ibutilide.[J]. Naunyn-Schmiedeberg’s archives of pharmacology, 2002, 366 5: 482-487. DOI: 10.1007/s00210-002-0599-x |
Ibutilide fumarate Preparation Products And Raw materials
| Raw materials | Lithium Aluminum Hydride-->Aniline-->Potassium sodium tartrate-->Methanesulfonyl chloride-->Fumaric acid-->Succinic anhydride-->ethylheptylamine-->1-Hydroxybenzotriazole |
