Calcium channel blockers benzothiazepine

Antianginal agents, 5 107-135, 110-lllt, 118-120t, 124-124t arylalkylamines and benzothiazepins (calcium channel blockers),... 

Benzothiazepines belong to the three classes of calcium channel blockers which are important cardiovascular drugs in the management of angina pectoris and hypertension. A diastereoselective one-pot synthesis of the trans-and ds-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-l,5-benzothiazepin-4-one nucleus, a key intermediate in the preparation of the calcium channel blocker Diltiazem, was carried out under microwave irradiation in an open vessel (Scheme 25). Control of the diastereoselectivity was achieved by vary-... 

Calcium carbonate (hmestone) slurry, in flue gas scrubbing, 11 717 Calcium channel blockers, 5 116-135 arylalkylamines and benzothiazepins, 5 116-117, 118-120t 1,4-dihydropyridines, 5 124-129t Calcium channels, 5 85-86... 

Calcium is involved in the contraction of cardiac and vascular smooth muscle cells, and in the auto-maticity of cardiac pacemaker cells. Actions of calcium channel blockers on vascular smooth muscle cells are described with the main account of these drugs in Chapter 23. Although the three classes of calcium channel blocker have similar effects on vascular smooth muscle in the arterial tree, their cardiac actions differ. The phenylalkylamine, verapamil, depresses myocardial contraction more than the others, and both verapamil and the benzothiazepine, diltiazem, slow conduction in the SA and AV nodes. 

Four categories of calcium channel blockers can be defined based on their chemical structures and actions diphenylalkylamines, benzothiazepines, dihydropyridines, and bepridil. Both diphenylalkylamines (verapamil) and benzothiazepines (diltiazem) exhibit effects on both cardiac and vascular tissue. With specificity for the heart tissue, these two types of calcium channel blockers can slow conduction through the AV node and are useful in treating arrhythmias. The dihydropyridines (nifedipine is the prototypical agent) are more potent peripheral and coronary artery vasodilators. They do not affect cardiac conduction, but can dilate coronary arteries. They are particularly useful as antianginal agents. Bepridil is unique in that it blocks both fast sodium channels and calcium channels in the heart. All calcium channel blockers, except nimodipine and bepridil, are effective in treating HTN. 

Cayl channels (L-type) are targets of calcium-channel blockers or calcium antagonists which decrease the influx of Ca + in cardiac and smooth muscle vascular cells dihy-dropyridines (nifedipine and analogs), phenylalkylamines (verapamil) and benzothiazepines (diltiazem), widely used as antihypertensive, antianginal and antiarrhythmic drugs. Cayl openers, like Bay K 8644, have been synthesized but have not found any therapeutic interest. 

Calcium channel blockers, such as amlodipine introduced in chapter 22, are used to treat angina and hypertension. Diltiazem 189 was introduced by the Tanabe company in 1984 and is a simple derivative of the benzothiazepine 192 having two adjacent chiral centres on the heterocyclic seven-membered ring. 

L-type or high-voltage-activated calcium channels carry the majority of the calcium inward current in smooth muscle cells. They start to activate at a high membrane potential (around -30 mV) with a maximum at slightly positive membrane potentials (around -f-10 mV), have a large conductance (20-25 pS with 110 mM Ba2+ as charge carrier), inactivate slowly, and are readily and specifically blocked by the classic organic calcium channel blockers nifedipine (a 1,4-dihydro-pyridine), verapamil (a phenylalkylamine), and dil-tiazem (a benzothiazepine) (see Hofmann etah, 1994). 

Microwave activation coupled with dry media technique as a green chemistry procedure has been applied to the synthesis of a series of 1,5-benzothiazepines [128-130], These compounds are well known cardiovascular drugs acting as calcium-channel blockers. The reaction using montmorillonite KSF as an inorganic solid was noticeably accelerated under the action of MW activation when results were compared with those obtained by classical heating under similar conditions (Eq. 43) ... 

Calcium-channel blockers in current clinical usage affect the slow L-type channel. They are usually classified by their chemical structure, which determines their selectivity for vascular smooth muscle over myocardium, and hence their potential to slow the heart rate (negative inotropic activity) see Table 23. T, (below). Interactions due to additive inotropic effects will therefore apply only to the benzothiazepine (diltiazem) and phenyla-Ikylamine-type (verapamil) calcium-channel blockers, and usually not to the dihydropyridine-type (e.g. nifedipine) calcium-channel blockers. All three types of calcium-channel blocker will have additive hypotensive effects with other drugs with blood-pressure lowering activity. 

A large number of diugs interfere with the smooth muscle contraction. These compounds lower blood pressure and are referred to as antihypertensive. In this section, only those coumpounds will be mentioned that have a direct effect on smooth muscle tone. Phenylephrine is an agonist on most smooth muscles and activates ax adrenoceptors. Carbachol is an agonist on some smooth muscles and activates contraction through muscarinic receptors. Blockers of the ax-adrenoceptors such as prazosin and urapidil are competitive inhibitors of the ax-receptor in vascular and bladder smooth muscle. Phenoxybenzamine is an ineversible blocker of ax receptors and phentol-amine blocks ax and a2 receptors. Ca2+ channel blockers such as the dihydropyiidines, phenylalkyla-mines and benzothiazepines lower smooth muscle tone by blocking the L-type calcium channel. 

Calcium-entry blockers include those agents that are selective for slow calcium channels in the myocardium (slow channel blockers) and consist of the following categories of substances benzothiazepines (diltiazem and dihydropy-ridines)—nifedipine, nicardipine, niludipine, nimodipine, nisoldipine, nitrendipine, ryosidine, amlodipine, azodipine, dazodipine, felodipine, flordipine, iodipine, isradipine, mesu-dipine, oxodipine, and riodipine and, phenylalkylamines— verapamil, gallopamil, anipamil, desmethoxyverapamil, emopamil, falipamil, and ronipamil. 

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