azimilide Property

storage temp. 

2-8°C

solubility 

DMSO: soluble1mg/mL, clear (warmed)

form 

powder

color 

white to beige

Safety

Hazard Codes 

T

Risk Statements 

25

Safety Statements 

45

RIDADR 

UN 2811 6.1 / PGIII

WGK Germany 

3

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Danger

Hazard statements

H301Toxic if swalloed

Precautionary statements

P264Wash hands thoroughly after handling.

P264Wash skin thouroughly after handling.

P270Do not eat, drink or smoke when using this product.

P301+P310IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.

P405Store locked up.

P501Dispose of contents/container to..…

azimilide Chemical Properties,Usage,Production

Originator

Stedicor,Procter and Gamble

Uses

Azimilide Dihydrochloride is an oral type III potassium channel blocker agent that blocks both the rapid activating component and the slow activating component of the delayed rectifier potassium current. Both preclinical and clinical studies have demonstrated the efficacy of azimilide and its safety in the treatment of supraventricular and ventricular tachyarrhythmia. Azimilide also is being studied in a worldwide multicenter trial for prevention of sudden cardiac death in patients after myocardial infarction.

Uses

Azimilide dihydrochloride may be used in the electrophysiology experiments with human ether-a-go-go-related gene 1a (HERG1a) subunit.

Manufacturing Process

1-Phenylmethylenamino-3-(4-chlorobutyl)-2,4-imidazolidinedione dihydrochloride is prepared by adding 60% sodium hydride in mineral oil (7.8 g, 0.1944 mole) over 1 h to a stirred solution o f 1- (benzy1ideneamino)hydantoin [prepared as described by J. Gut, A Novacet, and P. Fiedler, Coll. Czech. Chern. Comrnun., Vol. 33, pp. 2087-2096, No. 71, 1968] (39.5 g , 0.1944 mole) in dimethyl formamide (1000 ml). After complete addition, the solution is heated at steam bath temperature (approximately 100°C) for 1.5 h. The resulting mixture is allowed to cool to room temperature (30°C).
While stirring at room temperature, 1-bromo-4-chlorobutane (100 g ,0.5832 mole, 3 eq.) is added in one portion. The mixture becomes exothermic reaching around 35°C in approximately 30 min. The near-solution is heated a t approximately 80°C by steam bath for 4 h, cooled and stirred for approximately 8 h at room temperature (30°C). The cloudy mixture is filtered, removing a small amount of insoluble solid. The filtrate is concentrated under reduced pressure to a semi-solid residue. This residue is triturated with H2O (400 ml), collected, recrystallized from acetonitrile, and then air-dried to give 43.1 g (0.1467 mole) of 1-phenylmethyleneamino-3-(4-chlorobutyl)-2,4- imidazolidinedione.
A mixture of 1-phenylmethyleneamino-3-(4-chlorobutyl)-2,4- imidazolidinedione (43.1 g, 0.1467 mole), acetone (1200 ml) and sodium iodide (48.4 9, 0.3227 mole) is heated to reflux. Reflux is maintained for 5 h. The mixture is filtered, collecting the insoluble. The filtrate is recharged with sodium iodide (10.0 g) and reflux is resumed and is maintained for 15 h. After cooling to room temperature, the mixture is filtered, removing the insoluble NaCl (total recovery, 9.5 g, 110%). The filtrate is poured into H2O (2000 ml) while stirring. After stirring for 30 min, the solid is collected and air-dried to yield 51.5 g (0.1337 mole) of 1-phenylmethyleneamino-3-(4-iodobutyl)-2,4- imidazolidinedione.
A solution of 1-phenylmethyleneamino-3-(4-iodobutyl)-2,4-imidazolidinedione (10.0 g, 0.0260 mole), dimethylformamide (150.0 mg) and 1- methylpiperazine (11.5 ml, 10.4 9, 0.1040 mole) is heated to reflux. Reflux is maintained for 3 h. After cooling to approximately 40°C, the solution is concentrated under reduced pressure by rotary evaporator to an oily-solid residue. This residue is dissolved in H2O (200 ml) then made basic with saturated NaHCO3 (200 ml). The resulting mixture is stirred for 2 h. The solid is collected and air-dried, and is next dissolved in absolute ethanol (150 ml), next filtered, then made acidic to wet litmus with EtOH/HCl. After cooling several hours, the solid is collected and air-dried to give 8.04 g (0.0187 mole) of 1-phenylmethyleneamino-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4- imidazolidinedione dihydrochloride.
A mixture of 1-phenylmethyleneamino-3-[4-(4-methyl-1-piperazinyl)butyl]- 2,4-imidazolidinedione dihydrochloride (8.04 g, 0.0187 mole), 2 N HCl (125 ml) and 5% Pd/C: 50% H2O (1.5 g) is subjected to hydrogen on a Parr apparatus at 40 psi at room temperature. After 2 h, the catalyst is removed by filtration. The filtrate is divided into two equal portions. Each is concentrated under reduced pressure on a rotary 10 evaporator to an oily residue of 1-amino-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4-imidazolidinedione hydrochloride.
A solution of 1-amino-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4- imidazolidinedione hydrochloride (0.0094 mole), dimethylformamide (75 ml) and 5-(4-chlorophenyl)-2-furancarboxaldehyde [prepared as described in U.S. Patent No. 20 4,882,354, to Huang et al., assigned to Norwich Eaton Pharmaceuticals, Inc., issued November 21, 1984, see Cols. 7 and 8] (1.94 g , 0.0094 mole) is stirred at room temperature for 72 h. The mixture is filtered, collecting the solid. Recrystallization from absolute ethanol/H2O and air-drying gives 2.63 g (0.0050 mole) of 1-[[[5-(4-chlorophenyl)-2- furanyl]methylene]amino]3-[4-(4-methyl-1-piperazinyl)butyl]-2,4- imidazolidinedion hydrochloride.
1-[[[5-(4-Chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(4-methyl-1- piperazinyl)butyl]-2,4-imidazolidinedione hydrochloride, (6.56 g, 0.0124 mole) is dissolved in H2O (300 ml) and washed with (1x100 ml). The aqueous phase is made basic with saturated NaHCO3 solution. The resulting mixture is extracted with CH2Cl2 (4x100 ml). The extract is washed with saturated NaCl (2x50 ml), dried over MgSO4 (activated charcoal), filtered and concentrated under reduced pressure to a solid residue. This solid is triturated in anhydrous ether, collected and air-dried. Recrystallization once from absolute EtOH and then from toluene (activated charcoal), next washing with anhydrous ether and air drying gives 2.05 g (0.0045 mole) of 1-[[[5-(4-chlorophenyl)-2- furanyl]methylene]amino]-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4- imidazolidinedione.

Therapeutic Function

Antiarrhythmic

Biochem/physiol Actions

Azimilide is an inhibitor of human ether-a-go-go-related gene (HERG) channel. It displays a decrease in inhibitory effect in acidic pH conditions.

storage

Store at -20°C