Description
Lacidipine is a new second-generation dihydropyridine calcium antagonist introduced
as a once a day treatment for mild to moderate hypertension. It is reported to have high
selectivity for vascular smooth muscle and also a long duration of action. The use of
lacidipine as an antiatherosclerotic agent is currently under investigation.
Chemical Properties
White-to-Off-White Crystalline Solid
Originator
Glaxo (United Kingdom)
Uses
A dihydropyridine calcium channel blocker. Antihypertensive
Uses
antihypertensive;dihydropyridinr calcium channel blocker
Definition
ChEBI: Lacidipine is a cinnamate ester and a tert-butyl ester.
Brand name
Lacipil; Lacirex; Viapres
Biochem/physiol Actions
Lacidipine is a long-acting calcium antagonist that is used in the management of hypertension. Lacidipine is a L-type Ca(2+) channel blocker belonging to 1,4-dihydropyridine class. Also, Lacidipine inhibits ryanodine receptors on the ER membrane that enhances folding, trafficking and lysosomal activity of ERAD (ER-associated degradation) misfolded lysosomal glucocerebrosidase (GS).
Synthesis
1. 18 liters of dichloromethane were added to the reactor, followed by 5 kg of tert-butoxycarbonylmethyltriphenylphosphonium bromide (prepared with reference to Example 1).
2. 2.05 kg of o-phthalaldehyde was added, followed by 1 liter of dichloromethane, and the mixture was stirred for about 15 minutes, then cooled to -5°C.
3. A solution of 2.65 kg of sodium hydroxide flakes in 5 liters of water (pre-prepared at 25°C) was added to the reaction mixture at -3°C and kept at -3°C for 2.5 hours. The reaction process was monitored by thin layer chromatography.
4. After completion of the reaction, the mixture was warmed up to 25°C and stirring was continued for 30 minutes. The organic layer was separated and the solvent was removed by atmospheric pressure distillation at 52°C. The residue was kept at 52°C for 15 minutes.
5. 35 liters of n-heptane were added and 4 liters of n-heptane were distilled under 500 mmHg vacuum and at 63 °C. The mixture was then cooled to 0°C and held at 35°C for 1.5 hours.
6. The insoluble material was removed by vacuum filtration and the filter cake was washed with 7.5 liters of n-heptane. The filtrate was transferred to another reactor and the solvent was removed by complete distillation under vacuum at 610 mmHg and 68°C.
7. Cooled to 33 °C, 11.5 liters of isopropanol was added and subsequently cooled to -7 °C.
8. At -7 °C, a solution of 4.25 kg ethyl 3-aminocrotonate in 12.5 liters of isopropanol was slowly added, followed by 2.8 liters of trifluoroacetic acid and 1 liter of isopropanol, and the reaction was kept at -7 °C for 2 hours and 45 minutes. The reaction process was monitored by thin layer chromatography.
9. A solution of 2.6 kg of sodium bicarbonate in 50 liters of water was added to the reaction mixture at 0 °C, followed by 25 liters of ethyl acetate. Increase the temperature to 25°C and stir for 20 minutes. Separate the aqueous layer and extract with 12.5 liters of ethyl acetate. The organic layers were combined and the solvent was removed by atmospheric pressure distillation at 81 °C.
10. Add 5 liters of isopropanol to the residue and distill completely to remove the solvent. This operation is repeated once. Finally, the residue was dissolved in 63 liters of isopropanol and heated to 85°C to obtain a clarified solution.
11. Cool to 2 °C, keep for 1.5 h. Separate the solid by filtration and wash with 2.5 liters of isopropanol. The wet product was dried at 50°C for 30 minutes.
12. The dried substance was added to 23 liters of isopropanol, heated to 65°C and held for 30 minutes, cooled to 2°C and held for 1 hour, filtered and washed with 1.5 liters of isopropanol.
13. The wet solid was dried at 60 °C and 630 mmHg under vacuum for 5 h to give 2.04 kg of ethyl (E)-diethyl 4-(2-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate in 40.9% yield. The content of triphenylphosphine oxide was less than 0.0011 area%.
Drug interactions
Potentially hazardous interactions with other drugs
Aminophylline and theophylline: possibly increased
aminophylline and theophylline concentration.
Anaesthetics: enhanced hypotensive effect.
Antibacterials: metabolism possibly inhibited by
clarithromycin, erythromycin and telithromycin.
Antidepressants: enhanced hypotensive effect with
MAOIs.
Antiepileptics: effect possibly reduced by
carbamazepine, barbiturates, phenytoin and
primidone.
Antifungals: metabolism possibly inhibited by
itraconazole and ketoconazole; negative inotropic
effect possibly increased with itraconazole.
Antihypertensives: enhanced hypotensive effect,
increased risk of first dose hypotensive effect of postsynaptic alpha-blockers.
Antivirals: concentration possibly increased by
ritonavir.
Ciclosporin: 10 kidney transplant patients on
ciclosporin, prednisone and azathioprine were given
4 mg lacidipine daily. A very small increase in the
trough serum levels (+6%) and AUC (+14%) of the
ciclosporin occurred.
Grapefruit juice: concentration increased - avoid
concomitant use
Metabolism
Lacidipine undergoes extensive first-pass metabolism
in the liver. The drug is eliminated primarily by hepatic
metabolism (involving cytochrome P450 CYP3A4).
The principal metabolites possess little, if any,
pharmacodynamic activity.
Approximately 70% of the administered dose is
eliminated as metabolites in the faeces and the remainder
as metabolites in the urine.
References
[1] Patent: US2007/43088, 2007, A1. Location in patent: Page/Page column 6
