52-53-9

Verapamil, the classic calcium antagonist, has a negative inotropic, anti-ischemic, and conduction-delaying effect on the heart , . Its antiarrhythmic effect is based primarily on a prolongation of impulse conduction time in theAVnode and a reduction of frequency of impulse generation in the SA node.

Isoptin,Knoll ,W. Germany ,1963

Vasodilator (coronary).

Verapamil is primarily used as an antiarrythmic for treating ventricular arrhythmias; however, currently it is being forced out gradually by adenosine.

Verapamil is used for preventing angina pectoris attacks, arterial hypertension, and treating and preventing supraventricular arrhythmia (paroxysmal supraventricular tachycardia, atrial fibrillation, atrial flutter, extrasystole).

ChEBI: A tertiary amino compound that is 3,4-dimethoxyphenylethylamine in which the hydrogens attached to the nitrogen are replaced by a methyl group and a 4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl group.

177.2 g (1 mol) of veratryl cyanide are dissolved in 1 liter of toluene in a three-neck flask. 42.9 g (1.1 mols) of pulverized sodium amide are added. The mixture is heated to boiling under reflux for one hour while stirring and excluding moisture. A solution of the base (N-methyl-N-homoveratryl)-γ- aminochloropropane, freshly prepared from 339.2 g (1.1 mols) of the hydrochloride, in 1.2 liters of toluene is added drop by drop into this boiling mixture within two hours while stirring vigorously. Heating and stirring are continued for four more hours. After cooling, the reaction mixture is poured into 3 liters of ice water while stirring, The mixture is acidified with 20% hydrochloric acid. The acidified aqueous layer is separated, neutralized by the addition of sodium hydroxide solution, and rendered alkaline by the addition of concentrated potassium carbonate solution. The precipitated oily base is taken up in benzene. On evaporating the solvent, 402 g of the crude base are obtained in the form of a reddish-brown, viscous oil.
The crude base is dissolved in a mixture of 550 ml of isopropanol and 650 ml of ethyl acetate; Gaseous hydrogen chloride is introduced into the solution until it is of weakly acidic reaction. On allowing the mixture to stand at 0°C, 365 g of α-[(N-methyl-N-homoveratryl)-γ-amino-propyl]-3,4-dimethoxyphenyl acetonitrile hydrochloride precipitate as a slightly yellowish crystal powder of the melting point 136°C to 139°C (corr.). Yield: 81% of the theoretical yield. The pure, white hydrochloride melting at 140°C to 142°C (corr.) is obtained on recrystallizing the crude salt twice from isopropanol with the addition of decolorizing carbon. The salt is very soluble in water. The base prepared from the hydrochloride in the form of an almost colorless, very viscous oil boils at 233°C to 235°C/0.01 mm Hg; nD25= 1.5532. Dioxalate, melting point: 123°C to 125°C (corr.), on recrystallization from acetone and isopropanol.
61.9 g (0.15 mol) of α-[(N-methyl-N-homoveratryl)-γ-aminopropyl]-3,4- dimethoxyphenyl acetonitrile are dissolved in 300 ml of toluene. The solution is heated to boiling under reflux with 8.5 g (1.45 x 0.15 mols) of pulverized sodium amide for one hour while stirring. Thereafter, a solution of 31.4 g (1.7 x 0.15 mols) of isopropyl bromide in 50 ml of toluene is added drop by drop thereto within 90 minutes and the mixture is kept boiling for four more hours while stirring. The cooled reaction mixture is allowed to run into 1.5 liters of ice water and the mixture is acidified with 20% hydrochloric acid. The aqueous layer is separated and is rendered alkaline by the addition of a solution of potassium carbonate. The base is taken up in warm benzene. The solvent is evaporated and the residue is distilled in a vacuum. 62.6 g of α- isopropyl-α-[(N-methyl-N-homoveratryl)-γ-aminopropy]-3,4-dimethoxyphenyl acetonitrile are obtained in the form of a light yellow, very viscous oil. Boiling point: 232°C to 235°C/0.01 mm Hg; n D 25 = 1.5460. Yield: 91.8% of the theoretical yield. Hydrochloride: melting point: 139.5°C to 140.5°C (corr.), on recrystallization from a mixture of isopropanol and ethyl acetate.

Coronary vasodilator, Antiarrhythmic

Verapamil, 5-[. Hemodynamically, verapamil causesa change in the preload, afterload, contractility, heart rate,and coronary blood flow. The drug reduces systemic vascularresistance and mean blood pressure, with minor effectson cardiac output.
Verapamil is a synthetic compound possessing slightstructural similarity to papaverine. It can be separated intoits optically active isomers, of which the levorotatory enantiomeris the most potent. It is absorbed rapidly after oraladministration. The drug is metabolized quickly and, as aresult, has low bioavailability. The liver is the main siteof first-pass metabolism, forming several products. Thepreferential metabolic step involves N-dealkylation, followedby O-demethylation, and subsequent conjugation ofthe product before elimination. The metabolites have no significantbiological activity. Verapamil has an eliminationhalf-life of approximately 5 hours.

Verapamil is used as an antiarrythmic drug in treating supraventricular arrythmia such as paroxysmal atrial tachycardia, and for controlling atrial fibrillation. By blocking entrance of Ca2+ in the cell, verapamil exhibits a negative inotropic effect, and therefore it cannot be combined with β-adrenoblockers or cynidine since that would lead to an increased inotropic effect.

Verapamil (Isoptin, Covera), in addition to its use as an antiarrhythmic agent, has been employed extensively in the management of variant (Prinzmetal’s) angina and effort-induced angina pectoris. It selectively inhibits the voltage-gated calcium channel that is vital for action potential genesis in slowresponse myocytes, such as those found in the sinoatrial and A-V nodes.
Verapamil is useful for slowing the ventricular response to atrial tachyarrhythmias, such as atrial flutter and fibrillation. Verapamil is also effective in arrhythmias supported by enhanced automaticity, such as ectopic atrial tachycardia and idiopathic left ventricular tachycardia.

Orally administered verapamil is well tolerated by most patients. Most complaints are of constipation and gastric discomfort. Other complaints include vertigo, headache, nervousness, and pruritus.

Verapamil, 5-[(3,4-dimethoxyphenethyl)methylamino]-2-(3,4-dimethoxyphenyl) isopropylvaleronitrile (19.3.15), is synthesized by a scheme using 3,4- dimethoxyphenylacetonitrile as the initial substance. The synthesis of the final product (19.3.15) is accomplished by alkylating 2-(3.4-dimethoxyphenyl)-3-methylbutyronitrile (19.3.11) with N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-3-(chloropropyl)-N-methylamine (19.3.14). The initial 2-(3.4-dimethoxyphenyl)-3-methylbutyronitrile (19.3.11) is synthesized by alkylating 3,4-dimethoxyphenylacetonitrile with isopropyl chloride in the presence of sodium amide. The alkylating agent, N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-3- (chloropropyl)-N-methylamine (19.3.14), is also synthesized from 3,4-dimethoxyphenylacetonitrile followed by reduction into 3,4-dimethoxyphenylethylamine (19.3.12), with subsequent methylation into N-methyl-N-3,4-dimethoxyphenylethylamine (19.3.13). Next, the resulting N-[2-(3,4-dimethoxyphenyl)-ethyl] -N-methylamine (19.3.12) is alkylated by 1-chloro-3-bromopropane into the desired N-[2-(3,4-dimethoxyphenyl)- ethyl]-N-3-(chloropropyl)-N-methylamine (19.3.14), which is alkylated by 2-(3.4- dimethoxyphenyl)-3-methylbutyronitrile (19.3.11) to give the final product, verapamil(19.3.15).

Verapamil must be used with extreme caution or not at all in patients who are receiving -adrenoceptor blocking agents. Normally, the negative chronotropic effect of verapamil will in part be overcome by an increase in reflex sympathetic tone. The latter is be prevented by simultaneous administration of a β-adrenoceptor blocking agent, which exaggerates the depressant effects of verapamil on heart rate, A-V node conduction, and myocardial contractility. The use of verapamil in children less than 1 year of age is controversial.