Calcium channel blockers 1-4 dihydropyridine derivatives

Drugs that may be affected by delavirdine include the following Clarithromycin, indinavir, amprenavir, benzodiazepines, cisapride, dihydropyridine calcium channel blockers, ergot derivatives, quinidine, sildenafil, warfarin, saquinavir, and didanosine. 

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. 

Dihydropyridines chemistry is of interest not only from the point of view of fundamental research on heterocyclic compounds [ref. 9], but specially because of expanding practical applications of 1,4-dihydropyridine derivatives as pharmaceuticals in the line of calcium channel blockers [ref. 10,11]... 

Three-component cyclocondensation of keto sulfone 172 (n — 1), enamino ester 169 (R = C02Me), and 2-nitrobenzaldehyde unexpectedly afforded hexahydrothieno [3,2-Z>]pyridine 173 (n — 1) instead of the 1,4-dihydropyridine derivative. Heating the latter led to its dehydration to thienopyridine 174 (n — 1), which serves as a calcium channel blocker with a broad spectrum of biological activities (2000Mil). 

The reaction of ethyl acetoacetate, benzaldehyde, and urea leads to ethyl 1,2,3,4-tetrahydro-6-methyl-2-oxo-4-phenyl-5-pyrimidinecarboxylate. This reaction (the so called Biginelli reaction) was discovered over 100 years ago [93T6937], Interest in these dihydropyrimidines has increased rapidly mainly due to their close structural relationship to the pharmacologically important dihydropyridine calcium channel blockers of the nifedipine-type [93T6937], The dibromo (51) and monobromo derivatives (55) of the most simple Biginelli compounds mentioned above are readily obtained by bromination [93T6937], and the reactions of these derivatives with sodium azide have been studied recently [90LA505] [91 JCS(P1)1342],... 

Felodipine is a dihydropyridine derivative with diuretic properties (1). Its diuretic properties are not unique but are shared by other dihydropyridines. Its vasodilator-related adverse effects include flushing, headache, and tachycardia (2,3). Reduced arterial oxygen saturation has been seen in patients given intravenous felodipine for pulmonary hypertension (4,5). Along with amlodipine, but unlike other calcium channel blockers, felodipine may be safer in severe chronic heart failure accompanied by angina or hypertension. 

Hantzsch s reaction is a multicomponent organic reaction between an aldehyde, a P-keto ester, and a nitrogen donor such as ammonium acetate or ammonia. It provides rapid access to dihydropyridine and polyhydroquinoline derivatives, which constitute an important class of calcium channel blockers. Zinc oxide nanoparticles have been used for one-pot four-component synthesis of Hantzsch s polyhydroquinolines (7) and 1,4-dihydropyridines (5) in higher yields and short reaction times by the condensation of aldehydes (1), dimedone (2), active methylene compounds (4,6), and ammonium acetate (3) under solvent-free conditions at room temperature (Kassaee et al. 2010) (Scheme 9.1). 

In carbon-14 chemistry, Knoevenagel-Michael sequences with alkyl acetoacetates have found widest application in the synthesis of labeled 1,4-dihydropyridines (Hantzsch dihydropyridine synthesis). 4-Aryl-l,4-dihydro[ C]pyridine derivatives constitute a class of calcium antagonists and calcium channel blockers that play an important role in the treatment of cardiovascular diseases. The basic sequence, depicted in Figure 6.90, involves first the Knoevenagel condensation of an aromatic aldehyde with an alkyl... 

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