Description
Verapamil HCl (152-11-4) is a clinically useful L-type calcium channel blocker.1 It is also used as an inhibitor of drug efflux pump proteins.2
Chemical Properties
white to off-white powder
Originator
Isoptin,Knoll ,W. Germany ,1963
Uses
analgesic, antipyretic
Uses
Bromhexine metabolite, sodium channel blocker, decongestent secretolytic agent for respiratory diseases
Manufacturing Process
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.
Brand name
Calan
(Searle); Covera (Searle); Isoptin (FSC); Isoptin (Par);
Verelan (Elan).
Therapeutic Function
Coronary vasodilator, Antiarrhythmic
General Description
Pharmaceutical secondary standards for application in quality control, provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards.
Verapamil hydrochloride is a calcium channel blocker used commonly for the management of angina, supra-ventricular tachyarrhythmia, hypertension, migraine and atrial tachyarrhythmias.
Biological Activity
L-type calcium channel blocker. Vasodilator, adrenergic antagonist.
Biochem/physiol Actions
α1-adrenoceptor antagonist; L-type calcium channel blocker. Blocks L-type Ca2+ channels in smooth and cardiac muscle, induces apoptosis of human primary and metastatic colon adenocarcinoma cells in vitro. Drug resistance reversal agent acting on Pgp, e.g. decrease renal tubule elimination of digoxin. Increases basal ATPase activity of Pgp. Substrate of Cyp3A4 and CYP2C6.
References
1) Brgden and Benfield (1996) Verapamil: a review of its pharmacological properties and therapeutic use in coronary artery disease; Drugs, 51 792
2) Safa et al. (1987) Identification of the multidrug resistance-related membrane glycoprotein as an acceptor for calcium channel blockers; J. Biol. Chem., 262 7884
