Calcium Channel Blockers

clinically used doses, calcium channel blockers relax the smooth musculature of arteries while having little effect on veins. It is necessary to point out that the process of excitation-contraction in cardiac myocytes depends more on the flow of sodium ions into the cell than calcium ions. Consequently, calcium channel blockers have relatively little effect on contractibility of the heart in doses that relax smooth muscle.

Diltiazem: Diltiazem, 5-[2-(diethylamino)ethyl]-cii-2,3-dihydro-3-hydroxy-2-(4-methoxy-phenyl)-1,5-benzothiazepin-4(5#)-one (19.3.10), is synthesized in the following manner. The condensation of 4-methoxybenzaldehyde with methylchoroacetate in the presence of sodium methoxide in Darzens reaction conditions gives methyl ester of 3-(4-methoxyphenyl)-glycidylic acid (19.3.5). Reacting it with 2-aminothiophenol with the opening of epoxide ring gives methyl ester of 2-hydroxy-3-(2'-aminophenylthio)-3- (4''-methoxyphenyl)propionic acid (19.3.6). Hydrolysis of the resulting compound with alkali leads to the formation of the corresponding acid (19.3.7) in the form of a racemic mixture, which when on interaction with (+)-a-phenylethylamine gives threo-(+)-2-hydroxy-3-(2' -aminophenylthio)-3-(4''-methoxyphenylpropionic acid (19.3.8). Boiling this in a mixture of acetic anhydride/dimethylformamide/pyridine system brings to cyclization to the thiazepine ring and simultaneously acylates the hydroxyl group, forming (+)-a's-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepin-4-(5H)-one (19.3.9). Alkylation of the resulting product with 2,2-dimethylaminoethylchloride forms diltiazem (19.3.10) [8-15].

n(ch3)2

Diltiazem reduces the transmembrane influx of calcium ions into cells of cardiac muscle and smooth musculature of vessels. It causes dilation of coronary and peripheral vessels, increases coronary blood flow, and prevents development of coronary artery spasms. It lowers elevated arterial pressure and reduces tachycardia.

It is used for stable and nonstable angina pectoris (including after myocardial infarctions) as well as in arterial hypertension. Universally accepted synonyms of this drug are cardizem, dilacor, tiazac, iproventaril, and others.

Verapamil: Verapamil, 5-[(3,4-dimethoxyphenethyl)methylamino]-2-(3,4-dimethoxy-phenyl)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-dimethoxypheny-lacetonitrile 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

ch3-o

Was this article helpful?

0 0
Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

Get My Free Ebook


Post a comment