- Synthesis of unsymmetrical 1, 4-dihydropyridine derivatives in ionic liquid and inference on the formation mechanism of furopyridines
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Aromatic aldehydes, methyl acetoacetate, ethyl acetoacetate, ammonium acetate, ethyl 4-chloroacetoacetate as materials, eight unsymmetrical 1, 4-dihydropyridine derivatives were synthesized in ionic liquid [Bmim]OH in short time with the 60%-90% yield, and the ionic liquid could be utilized for 5 times repeatedly with the no decrease of the yield, four of products [3(a-d)] (see in Table-1) were synthesized through Knoevenagel and Michael addition reaction, and another four Furopyridines [3(e-h)] (see in Table-2) through one-pot synthesis whose formation mechanism being different from that of [3(a-d)] was first inferred.
- Zhang, Jian,Jin, Long Fei
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experimental part
p. 916 - 921
(2012/02/16)
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- Antagonism of 4-substituted 1,4-dihydropyridine-3,5-dicarboxylates toward voltage-dependent L-type Ca2+ channels CaV1.3 and CaV1.2
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L-type Ca2+ channels in mammalian brain neurons have either a CaV1.2 or CaV1.3 pore-forming subunit. Recently, it was shown that CaV1.3 Ca2+ channels underlie autonomous pacemaking in adult dopaminergic neurons in the substantia nigra pars compacta, and this reliance renders them sensitive to toxins used to create animal models of Parkinson's disease. Antagonism of these channels with the dihydropyridine antihypertensive drug isradipine diminishes the reliance on Ca2+ and the sensitivity of these neurons to toxins, pointing to a potential neuroprotective strategy. However, for neuroprotection without an antihypertensive side effect, selective CaV1.3 channel antagonists are required. In an attempt to identify potent and selective antagonists of CaV1.3 channels, 124 dihydropyridines (4-substituted-1,4-dihydropyridine-3,5-dicarboxylic diesters) were synthesized. The antagonism of heterologously expressed CaV1.2 and CaV1.3 channels was then tested using electrophysiological approaches and the FLIPR Calcium 4 assay. Despite the large diversity in substitution on the dihydropyridine scaffold, the most CaV1.3 selectivity was only about twofold. These results support a highly similar dihydropyridine binding site at both CaV1.2 and CaV1.3 channels and suggests that other classes of compounds need to be identified for CaV1.3 selectivity.
- Chang, Che-Chien,Cao, Song,Kang, Soosung,Kai, Li,Tian, Xinyong,Pandey, Prativa,Dunne, Sara Fernandez,Luan, Chi-Hao,Surmeier, D. James,Silverman, Richard B.
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supporting information; experimental part
p. 3147 - 3158
(2010/07/08)
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- Synthesis and in vitro pharmacology of new 1,4-dihydropyridines. 1. 2-(ω-Aminoalkylthiomethyl)-1,4-dihydropyridines as potent calcium channel blockers
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The synthesis and in vitro calcium channel blocking activities and binding of 2-(ω-aminoalkylthiomethyl)-4-(substituted)phenyl-1,4- dihydropyridines, by determination of the displacement of [3H]nitrendipine from the calcium channel binding sites on rat cortex have been discussed. It has been shown that increasing the alkyl chain length on the 2-position of the 1,4-dihydropyridine ring from ethyl to pentyl does not affect the calcium channel blocking activity of 3-nitrophenyl substituted dihydropyridines, measured on K+-depolarisation induced contractile responses in rat aorta strips. It did not seem to be important whether the 1,4-dihydropyridines bore 2 identical or different ester moieties on the 3- and 5-position of the 1,4-dihydropyridine ring.
- Christiaans,Windhorst,Groenenberg,Van der Goot,Timmerman
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p. 859 - 867
(2007/10/02)
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- Studies on nilvadipine. I. Synthesis and structure-activity relationships of 1,4-dihydropyridines containing novel substituents at the 2-position
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The synthesis of new 1,4-dihydropyridine derivatives containing novel substituent at the 2-position of the nucleus via the key intermediate 2-formyl-1,4-dihydropyridines (X), is described. The aldehydes (X) were prepared by hydrolysis of the acetals (IX) which were obtained from aryl aldehyde (V) and alkyl 4,4-dialkoxyacetoacetate (VI) by the Knoevenagel reaction and treatment with alkyl 3-aminocrotonate (VIII) according to the modified Hantzsch method. The formyl group of the aldehydes (X) was reactive enough to be converted to a variety of functional groups such as hydroxymethyl, cyano, substituted iminomethyl, carbamoyl, semicarbazone, substituted vinyl, ethynyl, and so on. In all of the novel compounds we prepared, 2-hydroxymethyl- and 2-cyano-1,4-dihydropyridines (IV and XXII) were found to possess potent activities in preliminary biological evaluations on hypotension in normotensive rats and on an increase in coronary blood flow in pentobarbital-anesthetized dogs. Optimization research in order to obtain a more potent compound was accomplished in the 2-hydroxymethyl- and 2-cyano-1,4-dihydropyridine series. We selected isopropyl 2-cyano-3-methoxycarbonyl-4-(3-nitrophenyl)-6-methyl-1,4-dihydropyridin e-5-carboxylate (XXIIj) as a candidate compound for further biological evaluation studies. Fortunately, XXIIj (nilvadipine) has been accepted in clinical use for the treatment of hypertension.
- Satoh,Ichihashi,Okumura
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p. 3189 - 3201
(2007/10/02)
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- SYNTHESIS OF 2-CHLOROMETHYL-1,4-DIHYDROPYRIDINES
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The title compounds were prepared by condensation of aldehydes with alkyl 3-aminocrotonate and 4-chloroacetoacetate.
- Cupka, Pavol,Svetlik, Jan
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p. 529 - 534
(2007/10/02)
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