ARANIDIPINE

Description

Aranidipine was launched in Japan as an antihypertensive agent. Its pharmacological effects are similar to other dihydropyridine derivatives, e.g., nefidipine, however, it is more potent and longer lasting. This is partially due to the fact that its initial metabolite (ketone reduction) is just as effective as the parent compound. Aranidipine exerts its activity by blocking Ca⁺² entry during depolarization via L-type voltagegated Ca channels. This causes decreased levels of intracellular Ca which leads to enhanced relaxation of smooth and cardiac muscle. It is a selective α₂-adrenoreceptor antagonist which inhibits vasoconstrictive responses. As a dihydropyridine derivative, it can be synthesized via a modified Hantsch synthesis. While sold as a racemate, the (S)-enantiomer is 150 times more active than the (R)- antipode.

Originator

Maruko Seiyaku (Japan)

Definition

ChEBI: Aranidipine is an organic molecular entity.

Manufacturing Process

100.0 mg of 50% sodium hydride was added to a mixture of 20.0 g of 2,2- ethylenedioxypropanol and 100 ml of benzene, and 20.0 g of diketene was added dropwise to the mixture while refluxing the mixture. After refluxing the mixture for 2 h, the solvent was distilled off and the resulting residue was distilled under reduced pressure to obtain 21.5 g (70% yield) of 2,2- ethylenedioxypropyl acetoacetate as a colorless oil, boiling point of 90°C (6 mm Hg).
Ammonia gas was passed through a mixture of 19.0 g of 2,2- ethylenedioxypropyl acetoacetate and 100 ml of methanol for 2.5 h under icecooling while stirring. The solvent was then distilled off and the residue was distilled under reduced pressure to obtain 16.0 g (84% yield) of 2,2- ethylenedioxypropyl 3-aminocrotonate as a pale yellow oil, boiling point of 120°C (5 mm Hg).
A mixture of methyl 2'-nitrobenzylidene acetoacetate, 2,2-ethylenedioxypropyl 3-aminocrotonate and ethanol was refluxed for 10 h. The resulting reaction solution was allowed to stand overnight, and the precipitated crystals were collected by filtration and recrystallized from ethanol to obtain methyl 2,2- ethylenedioxypropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5- dicarboxylate.
Methyl 2,2-ethylenedioxypropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate was refluxed in an ethanol solution containing 10% hydrochloric acid for 6 h. The solvent was then distilled off and the residue was crystallized from diethyl ether to give methyl 2-oxopropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate as yellow prisms, melting point 155°C (recrystallized from a mixture of ethyl acetate and hexane).

brand name

Bec/Sapresta

Therapeutic Function

Antihypertensive