Subject dihydropyridine

Dihydropyridines not only are intermediates for the synthesis of pyridines, but also are themselves an important class of N-heterocycles an example is the coenzyme NADH. Studies on the function of NADH led to increased interest in the synthesis of dihydropyridines as model compounds. Aryl-substituted dihy-dropyridines have been shown to be physiologically active as calcium antagonists. Some derivatives have found application in the therapy of high blood pressure and angina pectoris. For that reason the synthesis of 1,4-dihydropyridines has been the subject of intensive research and industrial use. The Hantzsch synthesis has thus become an important reaction. 

Despite these challenges, the area of K+ channel openers (PCOs) is emerging as an active area of drug design. Over the past 5-10 years, eight novel structural classes of PCOs have received systematic development benzopyrans (e.g., cromakalim, 7.27), cyanoguanidines (e.g., pinacidil, 7.28), thioformamides (e.g., aprikalim, 7.29), pyridyl nitrates (e.g., nicorandil, 7.30), benzothiadiazines (e.g., diazoxide, 7.31), pyrimidine sulphates (e.g., minoxidil sulphate, 7.32), tertiary carbinols, and dihydropyridines. These various classes have been subjected to analog preparation with compound optimization via structure-activity studies. 

The anodic oxidation of various dihydropyridine derivatives to the corresponding pyridinium or pyridine derivatives has been the subject of several investigations both in protic and aprotic solvents.229-237. The great interest in this process is because of the biological importance of the pyridinium-dihydropyridine redox system. 

A mixture of 4.98 g of acetoacetic acid N-benzyl-N-methylaminoethyl ester, 2.3 g of p-aminocrotonic acid methyl ester, and 3 g of m-nitrobenzaldehyde was stirred for 6 hours at 100°C in an oil bath. The reaction mixture was subjected to a silica gel column chromatography (diameter 4 cm and height 25 cm) and then eluted with a 20 1 mixture of chloroform and acetone. The effluent containing the subject product was concentrated and checked by thin layer chromatography. The powdery product thus obtained was dissolved in acetone and after adjusting the solution with an ethanol solution saturated with hydrogen chloride to pH 1-2, the solution was concentrated to provide 2 g of 2,6-dimethyl-4-(3 -nitrophenyl)l,4-dihydropyridine-3,5-dicarboxylic acid 3-methylester-5-p-(N-benzyl-N-methylamino)ethyl ester hydrochloride. The product thus obtained was then crystallized from an acetone mixture, melting point 136°C to 140°C (decomposed). 

The initial borohydride ion and proton attack seem to be subject to steric interference. 2-Substituted pyridinium ions form intermediate 1,6-dihydropyridines, and 3,5-disubstituted pyridinium ions are resistant to reduction past the dihydropyridine stage. The reduction of 1,3,5-trimethylpyridinium iodide (18) rapidly forms an intermediate dihydropyridine on reaction with sodium borohydride in alcohol however, the conversion to the tetrahydropyridine is much slower than that observed for 2-, 4-, or 6-substituted pyridinium ions. 

The diverse nature of these effects is illustrated by recounting the experience of clinical pharmacologists who studied the pharmacokinetics of felodipine, a dihydropyridine calcium channel antagonist (14). They designed a study to test the effects of ethanol on felodipine metabolism. To mask the flavor of ethanol from the subjects, they tested a variety of fruit juices, selecting double-strength grapefruit juice prepared from frozen concentrate as most effective. 

Some nucleophiles add to iV-fluoro-pyridinium salts to give dihydropyridines in which elimination of fluoride occurs in situ to give the 2-substimted pyridine. However, the preparation of the pyridinium salts requires the use of elemental fluorine (31.1) and also, some carbanions are subject to competitive reactions such as C-fluorination. However, silyl enol ethers do react efficiently stabilised heteronucleophiles (phenolate, azide) can also be used, and isonitriles produce picolinamides. ... 

Conducting the hydrogenolytic opening of the isoxazole ring on the bisketal 173 resulted in higher yields than when carried out on the corresponding bis-ketone. In the latter case the carbinolamine intermediate 176 is subject to dehydration to synthetically useless dihydropyridine type by-products. 

Shinkai and Bruice (21, 22) recently have described the first example of a zinc-ion-catalyzed reduction of aldehyde by NADH and NADH analogs in aqueous solution. They found that 3-hydroxypyridine-4-carboxaldehyde derivatives are reduced by 1,4-dihydropyridines in aqueous methanol (52% by weight) at 30°. Furthermore, this reaction is subject to catalysis by divalent metal ions, including Zn(II), Eq. (9). The following apparent relative order for metal ion effectivenes was observed Ni2+>Co2+>Zn2+>Mn2+>Mg2+>control. 

A similar correlation approach (but not as a cocktail ) was used to elucidate similar rate-limiting steps in the metabolism of dihydropyridine calcium channel blockers. Racemic felodipine, racemic nitrendipine and nifedipine were investigated in a randomized cross-over study in healthy subjects, using stereoselective enantiomers. The high correlations between the AUCs of all compounds strongly suggest the involvement of the same or very similar enzyme(s) in their primary oxidative metabolism, which in all cases involves aromatization of the dihydropyridine ring stmcture [22]. 

A similar profile to nitrendipine of S > R plasma concentrations was observed for another dihydropyridine calcium channel blocker, amlodipine (Table 7). In a study employing 18 subjects, in which two salt forms (besylate and maleate) of amlodipine were administered (20 mg racemate), stereoselectivity was noted (Table 7) in the plasma S R AUC ratio for both... 

Studies on the asymmetric reduction with 1,4-dihydronicotinamide derivatives that contain chiral centers within their amide moieties have been widely extended after the first report on this subject COhnishi et al. 1975a,b). To improve the optical yield and to obtain further insights into the stereochemical course of the reduction, a variety of model compounds have been synthesized and subjected to the reduction. Table 4 lists the optical yields from the reduction of methyl or ethyl benzoylformate which has frequently been used as a substrate for these 1,4-dihydropyridine derivatives. 

Kellogg (1979) synthesized a 1,4-dihydropyridine derivative having a chiral bridge between the 3 and 5 positions (19) and subjected the compound to the reduction of several substrates. As listed in Table 14, the optical yields of the products (with the predominancy of S -configurations) were good compared to those obtained from C2-... 

The effect of synthetic polymers on the asymmetric reduction by NAD(P)H model compounds was examined. Shinkai et al. (1981) synthesized chiral 1,4-dihydropyridine derivatives bound to polystyrene beads (27-29) and subjected them to the reduction of ethyl benzoylformate in acetonitrile in the presence of magnesium perchlorate. As shown in Table 21, the optical yields from the polymeric systems were low compared to those from homogeneous systems. The reductions in homogeneous systems with 30 and 31 gave optical yields of 47 and 51, respectively. 

This pharmacological class is one of the most complex since its members act on a variety of newly discovered calcium channels within the central nervous system with either synaptic or somatic localization and numerous functions. Little is known about the impact of calcium antagonists on chemical neurotransmission, neuronal functions and intracellular calcium homeostasis, particularly in neurones and glial cells. This wide area of research and the action of these drugs on cerebral vascularization have been the subject of a number of recent reviews [95, 128-130]. For dihydropyridines, it is also important to note the peripheral (cardiovascular) effects which in turn affect the central nervous system. 

Asymmetric 1,4-Dihydropyridines Instead of two equivalents of one p-ketocarbonyl compound, two different equimolar p-ketocarbonyl compounds with different reactivities can be subjected to the Hantzsch 1,4-dihydropyridine synthesis. The products of those reactions are asymmetric 1,4-dihydropyridines 579. 

A full paper has now appeared on the previously described thermal dimerization of the 1,6-dihydropyridine (57). The dimer (58) undergoes a further thermal rearrangement to give (59). It has been established, by the use of appropriately labelled substrates, that (59) itself is also subject to degenerate thermal rearrangement. 

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