Dofetilide CAS 115256-11-6
Introduction：Basic information about Dofetilide CAS 115256-11-6, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Dofetilide Basic information
| Product Name: | Dofetilide |
| Synonyms: | Tikosyn;beta-((p-Methanesulfonamidophenethyl)methylamino)methanesulfono-p-phenetidide;Methanesulfonamide, N-(4-(2-(methyl(2-(4-((methylsulfonyl)amino)phenoxy)ethyl)amino)ethyl) phenyl);Tikosym;Methyl[2-[4-(methylsulfonylamino)phenoxy]ethyl][4-(methylsulfonylamino)phenethyl]amine;N-[4-[2-[N-Methyl-2-(4-methylsulfonylaminophenoxy)ethylamino]ethyl]phenyl]methanesulfonamide;U-68798;N-[4-[2-[2-[4-(methanesulfonamido)phenyl]ethyl-methylamino]ethoxy]phenyl]methanesulfonamide |
| CAS: | 115256-11-6 |
| MF: | C19H27N3O5S2 |
| MW: | 441.56 |
| EINECS: | 638-817-5 |
| Product Categories: | Inhibitors;Pfizer compounds;Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds;Antiarrhythmic;Active Pharmaceutical Ingredients;Medicine intermediate;115256-11-6 |
| Mol File: | 115256-11-6.mol |
Dofetilide Chemical Properties
| Melting point | 147-1490C |
| Boiling point | 614.1±65.0 °C(Predicted) |
| density | 1.344±0.06 g/cm3(Predicted) |
| storage temp. | 2-8°C |
| solubility | DMSO: >20mg/mL |
| pka | 7.0, 9.0, 9.6(at 25℃) |
| form | powder |
| color | white to off-white |
| Stability: | Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months. |
| InChI | 1S/C19H27N3O5S2/c1-22(13-12-16-4-6-17(7-5-16)20-28(2,23)24)14-15-27-19-10-8-18(9-11-19)21-29(3,25)26/h4-11,20-21H,12-15H2,1-3H3 |
| InChIKey | IXTMWRCNAAVVAI-UHFFFAOYSA-N |
| SMILES | CN(CCOc1ccc(NS(C)(=O)=O)cc1)CCc2ccc(NS(C)(=O)=O)cc2 |
| CAS DataBase Reference | 115256-11-6(CAS DataBase Reference) |
Safety Information
| Hazard Codes | T,N |
| Risk Statements | 61-48/22-51 |
| Safety Statements | 53-22-36-57 |
| WGK Germany | nwg |
| HS Code | 2935904000 |
| Storage Class | 6.1C - Combustible acute toxic Cat.3 toxic compounds or compounds which causing chronic effects |
| Hazard Classifications | Aquatic Chronic 2 Repr. 1B STOT RE 2 |
| Hazardous Substances Data | 115256-11-6(Hazardous Substances Data) |
| Description | Dofetilide was launched in the US as a novel class III antiarrhythmic for treatment ofcardiac patients with highly symptomatic atrial fibrillation This bisarylsulfonamide can beobtained by a three step synthesis starting from 4-nitro-N-methylphenethylamine andinvolving simultaneous nitro reduction and mesylation on both aromatic amine functions. Incontrast to other class III antiarrhythmic agents such as amiodarone, dofetilide potentlyand selectively inhibits a single potassium channel, Ikr, the rapidly acting component of thedelayed rectifier potassium current, Accordingly, by blocking the open state of Ikr,dofetilide is able to prolong the effective refractory period (ERP) in both atrial andventricular myocardium and the monophasic action potential duration. Moreover, as it targets only one cardiac ion channel, it does not produce any effects on the sinus node,cardiac conduction system and other extracardiac organs, making it unique amongestablished class III agents. Several pharmacological studies with models using differentanimal species indicated that dofetilide was a potent and highly selective class IIIantiarrhythmic agent devoid of cardiodepressive effects. During clinical trials in patientswith paroxysmal atrial or supraventricular fibrillation, dofetilide was found to increase atrialand ventricular refractory periods without affecting conduction or sinus node function. Ifincreases in the QT/QTc interval after oral or intravenous dofetilide are expected, as forother class III antiarrhythmic agents, other electrocardiographic intervals are unaffected. |
| Chemical Properties | White Crystalline Solid |
| Originator | Pfizer (US) |
| History | Dofetilide was synthesized in the late 1980s by Pfizer’s medicinal chemistry group led by Michael R. Laufman as a methanesulfonanilide derivative designed to block the rapid component of the delayed rectifier potassium current (IKr) without ancillary sodium- or beta-receptor activity, and the key composition-of-matter patent (US 4959366) was filed on 28 November 1988 and granted on 25 September 1990, providing the intellectual-property foundation for subsequent clinical development. Between 1993 and 1997 the Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND) study randomised 1 518 patients with severe left-ventricular dysfunction to dofetilide or placebo, showing no excess mortality and a significant 26 % reduction in hospitalisation for worsening heart failure, data that underpinned the New Drug Application submitted to the FDA on 30 June 1998. After a 15-month review that included an advisory-panel recommendation for approval contingent on a risk-management programme, the agency granted marketing authorisation on 1 October 1999 for the acute conversion and chronic maintenance of sinus rhythm in highly symptomatic atrial fibrillation/flutter, launching the product as Tikosyn® through a restricted distribution system requiring physician certification and inpatient initiation because of the dose-dependent risk of torsade de pointes. Post-marketing requirements were fulfilled by the continued-access study that treated >3 000 additional subjects, and the Risk Evaluation and Mitigation Strategy (REMS) was progressively relaxed, finally being rescinded by the FDA in January 2016, thereby allowing unrestricted outpatient prescribing while preserving the core label warnings regarding renal dosing and QT monitoring. |
| Uses | Dofetilide (90%) , is a potassium channel blocker. Antidysrhythmic drug. |
| Definition | ChEBI: A tertiary amino compound that is N-ethyl-N-methylethanamine substituted by a 4-[(methylsulfonyl)amino]phenoxy and a 4-[(methylsulfonyl)amino]phenyl group at the terminal carbon atoms respectively. It is used as an ani-arrhythmia drug. |
| Manufacturing Process | To a solution of N-methyl-4-nitrophenethylamine (1.5 g) (J.O.C., [1956], 21,45) and 2-[4-nitrophenoxy]ethyl chloride (1.55 g) (C.A., [1955], 49, 3163e)in acetonitrile (50 ml) was added potassium carbonate (1.25 g) and sodiumiodide (1.2 g) and the suspension was stirred at reflux for 72 hours. Afterevaporation to dryness, the residual oily solid was partitioned between a 2 Naqueous sodium bicarbonate solution and ethyl acetate. After two furtherextractions with ethyl acetate, the organic portions were combined, washedwith a saturated aqueous brine solution, dried over magnesium sulfate,filtered and evaporated. The resultant orange solid (2.7 g) was crystallisedfrom ethanol to give 1-(4-nitrophenoxy)-2-[N-methyl-N-(4-nitrophenethyl)amino]ethane (1.9 g), m.p. 74°C. A solution of 1-(4-nitrophenoxy)-2-[N-methyl-N-(4-nitrophenethyl)amino]ethane (1.5 g) in ethanol (100 ml) was stirred for 16hours at room temperature under three atmospheres of hydrogen in thepresence of Raney nickel. The reaction mixture was filtered and evaporated todryness. The residual oil was re-dissolved in ether, filtered and evaporated togive a yellow solid (1.1 g), which was crystallised from ethylacetate/petroleum ether (b.p. 60-80°C) to give 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-N-methylamino]ethane (0.9 g), m.p. 73-74°C. A solution of 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-Nmethylamino]ethane (0.75 g) and methanesulphonic anhdyride (1.0 g) in drymethylene chloride (50 ml) was stirred at room temperature overnight. Afterevaporation, the resultant oil was partitioned between a 2 N aqueous sodiumbicarbonate solution and ethyl acetate. After two further extractions with ethylacetate, the organic portions were combined, dried over magnesium sulfate,filtered and evaporated. The resultant colourless solid (1.2 g) was crystallisedfrom ethyl acetate/methanol to give methanesulfonamide, N-(4-(2-(methyl(2-(4-((methylsulfonyl)amino)phenoxy)ethyl)amino)ethyl)phenyl)-, (0.6 g), m.p.147-149°C. |
| Brand name | Tikosyn (Pfizer). |
| Therapeutic Function | Antiarrhythmic |
| General Description | Dofetilide, N-[4-(3-{[2-(4-methanesulfonylaminophenyl)ethyl]methylamino}propoxy)phenyl]methane-sulfonamide (Tikosyn), acts by blocking thecardiac ion channel carrying the rapid component of thedelayed rectifier potassium currents (Ikr) and is used toterminate supraventricular arrhythmias, prevent the recurrenceof atrial fibrillation, and treat life-threatening ventriculararrhythmias. Unlike sotalol and ibutilide, whichare also methanesulfonanilides, it has no effect on adrenergicreceptors or sodium channels, respectively. Dofetilidehas high specificity for the delayed rectifier potassiumcurrents. |
| Biological Activity | Selective potassium channel blocker. Blocks hERG K + channels; inhibits the rapid delayed-rectifier K + current (I Kr ). Displays class III antiarrhythmic properties. |
| Biochem/physiol Actions | Dofetilide is a Class III antiarrhythmic and hERG channel blocker. Dofetilide selectively blocks the rapid component of the delayed rectifier outward potassium current (IKr). |
| Clinical Use | Dofetilide (Tikosyn) is a “pure” class III drug. It prolongsthe cardiac action potential and the refractory periodby selectively inhibiting the rapid component ofthe delayed rectifier potassium current (IKr). Dofetilide is approved for the treatment of atrial fibrillationand atrial flutter. Because of the lack of significanthemodynamic effects, dofetilide may be useful in patientswith CHF who are in need of therapy forsupraventricular tachyarrhythmias. Dofetilide is not indicatedfor use in the setting of ventricular arrhythmias. |
| Side effects | The incidence of noncardiac adverse events is not differentfrom that of placebo in controlled clinical trials.The principal cardiac adverse effect is the risk of torsadesde pointes due to QT prolongation.The risk is approximately3%, and most cases are observed in the first3 days of therapy.As such, initiation of therapy shouldbe performed with the patient in hospital. |
| Drug interactions | Verapamil increases serum dofetilide levels, as do drugsthat inhibit cationic renal secretion, such as ketoconazoleand cimetidine, raise serum levels. |
| Metabolism | Dofetlide is used orally to suppress atrialfibrillation and flutter. It is more potent and selective than other Class III methanesulfonanilides,including sotalol. Dofetilide is well absorbed from the gastrointestinal tract, with a bioavailability of96 to 100%. The bioavailability of oral dofetilide is not affected by food or antacids. Protein bindingis 60 to 70%. Dofetilide is metabolized by the hepatic CYP3A4 enzyme system via N-dealkylation andN-oxidation to inactive or minimally active metabolites. Of the approximately 80% of a dose excretedin urine, approximately 80% is excreted unchanged, with the other 20% as metabolites. |
| storage | Room temperature |
| Precautions | Contraindications include baseline prolongation ofthe QT interval, use of other QT-prolonging drugs;history of torsades de pointes; a creatinine clearance ofless than 20 mL/minute; simultaneous use of verapamil,cimetidine, or ketoconazole; uncorrected hypokalemia orhypomagnesemia; and pregnancy or breast-feeding. |
| References | [1] M GWILT. UK-68,798: a novel, potent and highly selective class III antiarrhythmic agent which blocks potassium channels in cardiac cells.[J]. Journal of Pharmacology and Experimental Therapeutics, 1991, 256 1: 318-324. [2] D J SNYDERS A C. High affinity open channel block by dofetilide of HERG expressed in a human cell line.[J]. Molecular Pharmacology, 1996, 49 6: 949-955. |
Dofetilide Preparation Products And Raw materials
| Raw materials | Magnesium sulfate-->2-N-BUTOXYETHYL METHACRYLATE-->Methanesulfonic anhydride-->Hydrogen-->Sodium iodide-->Potassium carbonate-->1-(2-Chloroethoxy)-4-nitrobenzene-->BenzeneethanaMine, N-Methyl-4-nitro--->Aluminium-nickel-->Dofetilide N`-Nitryl Impurity-->Dofetilide Impurity 7-->N-Methyl-N-(2-(4-aminophenoxy)ethyl)-2-(4-aminophenyl)ehtanamine-->4-Nitrophenylethylamine hydrobromide-->N-Methyl-N-(2-(4-nitrophenoxy)ethyl)-2-(4-nitrophenyl)ethanamine-->Methanesulfonamide-->Methanesulfonyl chloride |
