1.4- Dihydropyridine derivatives

In Diels-Alder reactions a nitroolefin may function as an electron-deficient ene com-onent or a 1,2-dihydropyridine derivative may be used as a diene component. Both types of iactants often yield cyclic amine precursors in highly stereoselective manner (R.K. Hill, 1962 i. BOchi, 1965, 1966A). 

Another dideoxypyrimidine nucleoside active against human immunodeficiency vims is 3 -azido-2/3 -dideoxyuridine [84472-85-5] (AZDU or CS-87, 64) C H N O. Since its synthesis, (167) CS-87 has been identified as a promising antiHIV agent (168) and is currentiy undergoing phase I clinical trials in patients with AIDS and AIDS-related complex. It appears to be less potent than AZT against HIV in a peripheral blood mononuclear (PBM) cell screening system and in MT-4 cell lines. This lower activity in PBM cells appears to be related to a lower affinity of CS-87 for the enzyme responsible for its initial phosphorylation (169). However, CS-87 has significantly lower toxicity on bone marrow cells than AZT (170) and penetration of the CNS as a 5 -dihydropyridine derivative. 

ELECTROOXIDATION, QUANTUM CHEMICAL CALCULATIONS AND CHEMILUMINESCENT ANALYSIS OF DIHYDROPYRIDINES DERIVATIVES... 

A modihed Hantzsch synthesis has been utilized for the preparation of 1,4-dihydropyridines (Scheme 66). Thus, condensation of formylfurazans 116 with an acetoacetic ester and aminocrotonic acid ester in isopropanol at reflux led to 1,4-dihydropyridine derivatives 117 in about 70% yield (92AE921). Both isomeric furoxan aldehydes reacted in a similar way. 

Dihydropyridine receptor (DHPR) is a member of voltage-dqiendent Ca2+ channels (CaVi, L-type), which specifically binds to dihydropyridine derivatives, a group of the Ca2+ channel blockers. Cav 1.1 works as the voltage sensor for skeletal muscle contraction, and Cay 1.2, as Ca2+-influx channel for cardiac muscle contraction. 

This chapter will concentrate on the L-type or high voltage activated channels that are sensitive to dihydropyridine derivatives (see below for the description of their pharmacology). These channels are the most well characterized from many perspectives and a large amount of information has accumulated concerning the... 

N Bodor, E Shek, T Higuchi. Delivery of a quaternary pyridinium salt across the blood-brain barrier by its dihydropyridine derivative. Science 190 155-156, 1975. 

Another approach to the generation of an iminium cation suitable for cyclization is the protonation of dihydropyridine derivatives. One example can be found in Scheme 48, where treatment of compound 243 with acid induced its cyclization to indoloquinolizine 244, a precursor in the first total synthesis of (i)-tangutorine 245, an alkaloid isolated from a traditional Chinese medicinal plant <2001TL6593>. 

After its isolation, the structure of alkaloid deplancheine (7) was unambiguously proved by several total syntheses. In one of the first approaches (14), 1,4-dihydropyridine derivative 161, obtained by sodium dithionite reduction of A-[2-(indol-3-yl)ethyl]pyridinium salt 160, was cyclized in acidic medium to yield quinolizidine derivative 162. Upon refluxing 162 with hydrochloric acid, hydrolysis and decarboxylation took place. In the final step of the synthesis, the conjugated iminium salt 163 was selectively reduced to racemic deplancheine. 

Asymmetric reduction of ketones. Pioneering work by Ohno et al. (6, 36 7, 15) has established that l-benzyl-l,4-dihydronicotinamide is a useful NADH model for reduction of carbonyl groups, but only low enantioselectivity obtains with chiral derivatives of this NADH model. In contrast, this chiral 1,4-dihydropyridine derivative (1) reduces a-keto esters in the presence of Mg(II) or Zn(II) salts in >90% ee (equation I).1 This high stereoselectivity of 1 results from the beneficial effect... 

E. Pop, E. Shek, T. Murakami, N. S. Bodor, Improved Anticonvulsant Activity of Phen-ytoin by a Redox Brain Delivery System. I Synthesis and Some Properties of the Dihydropyridine Derivatives , J. Pharm. Sci. 1989, 78, 609 - 616. 

N. Ogawa, T. Hirose, K. Fukushima, T. Suwa, T. Satoh, GSH-Independent Denitration of the Nitrate Ester of a Dihydropyridine Derivative in Rabbit Hepatic Cytosol , Biochem. Pharmacol. 1995, 49, 141 -146 N. Ogawa, T. Flirose, K. Fukushima, T. Suwa, T. Satoh, Metabolism of a Nitrate Ester, Dihydropyridine Derivative in Rabbit Hepatic Microsomes and Cytosol , Xenobiotica 1995, 25, 283-290. 

The formation of a double bond during anodic oxidations can result from eliminations of protons, carbon dioxide or acylium cations. The electrooxi dative aromatization of dihydropyridine derivatives and heterocycles containing nitrogen atom (di-hydroquinoxalines, tetrahydrocinnolines) involves an ECE mechanism as previously... 

The electroreduction of deactivated pyridines or pyridinium salts affords selectively the corresponding 1,2- or 1,4-dihydropyridine derivatives according to the position of the substituents (Schemes 133 and 134) [243]. In the same experimental conditions a monoactivated pyridine is not reducible. 

Scheme 3.27 Hantzsch reaction for the synthesis of dihydropyridine derivatives (189) [287],...

One very unusual case of prototropic isomerization was revealed for anion-radicals of 1,4-dihydropyridine derivatives (Gavars et al. 1999). These anion-radicals transform into 4,5-dihydro-pyridine analogs through proton detachment and addition. 

Cycloaddition reaction of the l-acyl-l,2-dihydropyridine derivative 240 with methyl cyanodithioformate afforded adduct 241, which was converted by three steps to solenopsin A (Id) (Scheme 13) (399). This route constitutes a completely stereoselective synthesis of this alkaloid however, details are not available. 

An interesting case of the addition of ketone hydrazone is observed in the reaction of acetone dimethylhydrazone with DMAD, wherein the initial nucleophilic attack is through the imino nitrogen, leading to products such as dimethyl A-isopropylidine-lV-dimethylamino-2-aminomaleate (132) and the dihydropyridine derivative (133). A small amount of the dimethylhydrazone of oxaloacetic ester (134) has also been observed in this reaction (Scheme 20). ... 

Koike, H., Nishino, H., and Yoshimoto, M. (1988). Dihydropyridine derivatives, their preparation and their use, US 4,772,596 (to Sankyo Company Limited and Ube Industries Limited). 

Similar results are obtained from reaction of pyridine A-oxide derivatives with 146 and several transformations, including ring opening, have been described. Reaction of pyridinium salts and 146 gives the corresponding 4-substituted-1,4-dihydropyridine derivatives 212 (Scheme 7.65). 

The significance of 1,4-dihydropyridine derivatives in reduction of biological substrates involving the intermediacy of a radical cation has led to much interest in such species. Such radical cations (154) have been generated by electrolytic oxidation in aqueous acetonitrile... 

There are some methods that are specific to HCHO. For example, the Hantzsch reaction of HCHO, collected with a diffusion scrubber, with ammonium acetate, acetic acid, and acetylacetone to form diacetyldihydrolutidine, which is measured using its fluorescence at 470 nm, has been applied to air measurements (Dasgupta et al., 1988, 1990 Kleindienst et al., 1988a,b Lawson et al., 1990 Khare et al., 1997). Reaction with 1,3-cyclohexanedione and ammonium acetate to form a dihydropyridine derivative that is measured by fluorescence has been used in conjunction with a diffusion scrubber (Fan and Dasgupta, 1994). Enzymatic methods have been used in which formaldehyde dehydrogenase catalyzes the oxidation of HCHO to HCOOH in the presence of -nicotinamide adenine dinucleotide, NAD+, which is reduced to NADH. The latter is measured by fluorescence at 450 nm (Lazrus et al., 1988 Ho and Richards, 1990). 

Whereas heating 1,3-diketones with 68 in the absence of solvent gives 69, 1-amino-1,2-dihydropyridine derivatives 70 are formed when 68 is heated with 1,3-diketones in refluxing ethanol in the presence of organic base. When... 

Further extension of this approach involved297 the 1,4-singlet-oxy-gen adduct (510) of the 3-cyano-l,2-dihydropyridine derivative 484, which was transformed into methyl 5-aniino-5-N-henzoyl-5-deoxy-DL-... 

H-NMR Data for Organolithium-Pyridine Adducts and Some of Their 1-Deutero-1,2-Dihydropyridine Derivatives"... 

The utility of some of these products for side-chain modification has also been demonstrated. For example, 4-chloro-3-formylpyridine undergoes the Hantzsch reaction to give a 4-(3-chloropyridine)-l,4-dihydropyridine derivative (88%). (4-Chloro-3-pyridyl)diphenylmethanol affords aza-analogues (65-70%) of the antimycotic agent chlortrimazol by reaction with thionyl chloride and imidazole derivatives (88JHC81). 

In contrast, a low dose of the Ca2+ channel agonist BAY K 8644, a dihydropyridine derivative, antagonizes the antinociceptive effect of p-opioids. This is in agreement with results from Smith and Stevens (1995), who reported that Ca2+, when administered i.c.v., antagonizes morphine-induced antinociception in the mouse tail flick assay. The dose - response curve of morphine is shifted to the right by i.c.v. administration of calcium ions. 

Dihydropyridine derivatives (76) have been alkylated under PT conditions by Palecek and Kuthan136 in good yield. 

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. 

The chemistry of flavins is complex, a fact that is reflected in the uncertainity that has accompanied efforts to understand mechanisms. For flavoproteins at least four mechanistic possibilities must be considered.1533 233 (a) A reasonable hydride-transfer mechanism can be written for flavoprotein dehydrogenases (Eq. 15-23). The hydride ion is donated at N-5 and a proton is accepted at N-l. The oxidation of alcohols, amines, ketones, and reduced pyridine nucleotides can all be visualized in this way. Support for such a mechanism came from study of the nonenzymatic oxidation of NADH by flavins, a reaction that occurs at moderate speed in water at room temperature. A variety of flavins and dihydropyridine derivatives have been studied, and the electronic effects observed for the reaction are compatible with the hydride ion mecha-nism.234 236... 

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