Diltiazem group

The synthesis of calcium channel blockers of the diltiazem group, effective in lowering blood pressure, has been reported by Hoffmann-LaRoche (Scheme 23.6).51 A screening of several auxiliaries yielded acceptable ee, but it was found that the use of (7i ,2.S)-2-phenylcyclohcxanol (27) gave the required diastereoisomer 28 as the major isomer.52-54 The intermediate could be isolated readily, and the auxiliary could be recycled simply by base hydrolysis. Multi-kilogram quantities of enantiomerically pure naltiazem (29) and diltiazem (30) were produced by this method. 

A. Schwartz et al. synthesized several calcium channel blockers of the diltiazem group enantioselectively by using an auxiliary-induced asymmetric Darzens gtycidic ester condensation. The condensation of p-anisaldehyde with an enantiopure a-chloro ester afforded a pair of diastereomeric glycidic esters that possessed significantly different solubility. The major product was crystallized directly from the reaction mixture in 54% yield and in essentially enantiopure form. This major glycidic ester was then converted to diltiazem in a few more steps. 

Many dmgs such as verapamil, diltiazem, troleandomydn and erythromycin contain alkylamine groups and are able to form tightly bound complexes, in particular with CYP3A4 [49-53],... 

Calcium-channel blockers interfere with the inward movement of calcium ions through the cell membrane channels. This results in reduction of myocardial contractility (hence negative inotropes), reduction of cardiac output and arteriolar vasodilatation. The dihydropyridine group, such as nifedipine and amlodipine, which may be used in the management of hypertension, are very effective as arterial vasodilators, whereas diltiazem and verapamil are very effective in reducing atrioventricular conduction. 

Chemically, calcium channel blockers are synthesized up of a fairly diverse group of compounds, which testifies of the diverse receptive regions both on the cell membrane surface as well as within the cell. Verapamil, which can be viewed as a benzylcyanide derivative, is one of the oldest and most actively used compounds of this class up to the present day. Diltiazem is a thiodiazepine, while nifedipin and nicardipine are derivatives of dihydropyridine. 

The Multicenter Diltiazem Postinfarction Trial Reseach Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med 1998 319 385-92. 

Figure 2.5 Reported concentrations of various PPCPs in Wastewater effluents by several research groups. On the x axis are respective PPCPs that are primarily cosmetics (1 = HHCB, 2 = AHTN, 3 = acetophenone, 4 = camphor, 5 = isobomeol, 6 = skatol, 7 = celestolide, i.e., AHMI, 8 = Phantolide, i.e., AHMI), the lotion ingredient (9 = methyl salicylate), two disinfectants (10 = triclosan and 11 = trilocarban), antihypertensive (12 = dehydronifedipine, 13 = diltiazem, 14 = bezafibrate, and 15 = gemfibrozil), analgesics and anti-inflammatories (16 = naproxen, 17 = ibuprofen, 18 = codeine), antimicrobials (19 = chlortetracycline, 20 = erythromycin, 21 = novobiocin, 22 = oxytetracycline, 23 = sulfamethaxazole, 24 = thiabendazole, 25 = trimethoprim), anxiolytic sedative (26 = carbamazepine), antidiabetic (27 = metaformin), reproductive (28 = 17(3 estradiol, 29 = 17a-ethinyl estradiol), GIT (30 = cimetidine, 31 = ranitidine), and respiratory (32 = Albuterol). The concentrations were compiled from Boyd et al. (2003), Gagne et al. (2006), Glassmeyer et al. (2005), Halden and Pauli (2005), Huang and Sedlak (2001), Ricking et al. (2003), and Temes et al. (2003).

Verapamil, diltiazem, and the dihydropyridine family (amlodipine, felodipine, isradipine, nicardipine, nifedipine, and nisoldipine) are all equally effective in lowering blood pressure, and many formulations are currently approved for this use in the USA. Clevidipine is a newer member of this group that is formulated for intravenous use only. 

Goldstein RE, Boccuzzi SJ, Cruess D, Nattel S. Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction. The Adverse Experience Committee and the Multicenter Diltiazem Postinfarction Research Group. Circulation 1991 83 52-60,... 

There are two groups dihydropyridines and diltiazem/verapamil. Both groups are metabolized by the CYP3A family of isoenzymes (especially CYP3A4), which are the sites of many of the pharmacokinetic interactions involving this class. Some drugs are substrates for P-gp. 

Stone PH, Gibson RS, Glasser SP, DeWood MA, Parker JD, Kawanishi DT, Crawford MH, Messineo FC, Shook TL, Raby K, et al. Comparison of propranolol, diltiazem, and nifedipine in the treatment of ambulatory ischemia in patients with stable angina. Differential effects on ambulatory ischemia, exercise performance, and anginal symptoms. The ASIS Study Group. Circulation 1990 82(6) 1962-72. 

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