1.  Hi-Eisai Pharmaceutical, Inc. “Coniel (benidipine) package insert (Philippines)”.MIMS Philippines. CMPMedica. Retrieved 2008-03-31.
2. Hirayama, N. and Shimizu, E.: Acta Cryst., C47, 458 (1991)

Biological Activity

Orally active antihypertensive agent which displays a wide range of activities in vitro and in vivo. Inhibits L-, N- and T-type Ca²⁺ channels. Also inhibits aldosterone-induced mineralocorticoid receptor activation. Exhibits cardioprotective and antiartherosclerotic effects.

Technical Data

M.Wt:

Formula:

Solubility:

Storage:

CAS No:

References

Yao et al (2006) Pharmacological, pharmacokinetic, and clinical properties of benidipine hydrochloride, a novel long-acting calcium channel blocker. J.Pharmacol.Sci. 100 243. PMID: 16565579.

Kosaka et al (2010) The L-, N-, T-type triple calcium channel blocker benidipine acts as an antagonist of mineralocorticoid receptor, a member of nuclear receptor family. Eur.J.Pharmacol. 635 49. PMID: 20307534.

Benidipine hydrochloride, whose chemical name is (±)-(R*)- 1 ,4-dihydro-2,6-dimethyl-4-(meta-nitrophenyl)-3 ,5-pyridinedica rbolate methyl ester [(R*)-l-benzyl-3-piperidine alcohol ester], belongs to dihydropyridine receptor antagonist. It can bind to dihydropyridine receptors at the binding site with high affinity and high specificity, and shows a strong inhibitory effect on Ca channel. Benidipine not only has an inhibitory effect on muscular (L-type) Ca channel, but also has an inhibitory effect on voltage-dependent N- and T-type Ca channels. It is, up to now, the only calcium antagonist that can inhibit all the three Ca channels mentioned above. Furthermore, benidipine has highly affinity with cell membrane, has vascular selectivity and renal protection effect. Therefore, it is an ideal, safe and effective agent for the treatment of hypertension and renal parenchymal hypertension and angina.

There are two chiral atoms in the molecule of benidipine hydrochloride, which locate on site 4 of the dihydropyridine ring and site 3′ of the side chain piperidine ring. Accordingly, benidipine hydrochloride has 4 optical isomers: (S)-(S)-(+)-a, (R)-(R)-(-)-a, (R)-(S)-(+)^ and (S)-(R)-(-)^, and the active ingredients for drug are the mixture of (S)-(S)-(+)-a and (R)-(R)-(-)-0L Therefore, it is necessary to separate a and β isomers during the post- treatment stage of benidipine hydrochloride preparation.

Based on the order of synthesis of dihydropyridine main ring, there mainly are two groups of total 5 synthesis routes of benidipine hydrochloride. Among them, there are two routes which involve synthesis of the main ring first: 1) acylchloridizing the main ring of dihydropyridine and then linking the side chain to synthesize directlybenidipine hydrochloride; 2) After acylchloridizing the main ring of dihydropyridine, 3-piperidinol and then benzyl is added. The routes involve the synthesis of the main ring later includes the following; 1) synthesizing the main ring via β-aminocrotonate; 2) synthesizing the main ring via acetylacetate ester; 3) the One-pot’ method involving 3-nitrobenzaldehyde, β-aminocrotonate and acetylaceate ester.

Several synthetic routes of benidipine hydrochloride and its analogues have been disclosed in EP0063365A1, EP0161877A2, JP57-171968A, EP0106275 A2, etc. Among them, EP0106275 A2 gave a summary of the synthetic pathways ofbenidipine hydrochloride. In all of the above references, it was mentioned to separate the benidipine hydrochloride prepared through column chromatography and spit it into its a and β isomers, thus obtain the therapeutically active (±)-a-benidipine hydrochloride.

In order to obtain a highly purified benidipine hydrochloride meeting pharmaceutical use, it is necessary to perform multiple recrystallization with acetone and/or ethanol. Moreover, the crystallization condition is relatively strict since it should be performed below freezing point or even below -20 ^°C . Furthermore, the crystallization process usually need a relatively long time (more than 24 hours).

JP2007-8819A thus disclosed a method for preparing highly purified benidipine hydrochloride meeting pharmaceutical use by first preparing the monohydrate of benidipine hydrochloride.

Because benidipine hydrochloride has a very low solubility, for dissolving in a solvent quickly, benidipine hydrochloride is often grounded into nanoparticles. CN 1794993 A provided a method to grind benidipine hydrochloride into particles of 1.0^50.0 μπι. The mechanical grinding method is performed by grinding larger particles of crystals into desired smaller size of crystals. This method consumes large amount of energy and time, and results in a widely distribution of the crystal particle size.

PEOPLE found the desired sizes of benidipinehydrochloride nanoparticles could be obtained by ultrasonic crystallization technology. Unlike the method of CN 1794993 A, the method according to the present invention obtains crystals from smaller to larger sizes. The distribution of particle sizes in the method of the present invention is relatively narrower since the solvent crystalizes rapidly and steadily in the solution. Overall, the present invention can save time and energy, and is readily for preparation. Summary of the invention

benidipine preparation are disclosed in EP0106275, after JP 2007008819 discloses the industrial preparation methods, Kyowa Hakko Kogyo Co., Japan Institute of Pharmacology at Arzneimittelforschung magazine published a hydrochloric Benidipine physical and chemical properties and stability studies Japanese Pharmacopoeia 15th edition reproduces the drug. Benidipine given above literature its infrared spectrum (IR) in 3170cm “\ 3066 cm-1, 2950cm-1, 2523cm-1, 1694cm-1, 1666cm-1, 1642cm_ \ l533cm_ \ l491cm_ \ l432cm_ \ l348cm_ \ l299cm_ \ l218cm_ \ lll6cm_ \ l088cm_ \

HPLC

Purity test of benidipine hydrochloride (area normalization method): Chromatography conditions

Detector: ultraviolet absorption detector (detection wavelength: 237nm)

Chromatography column: stainless steel column: 4.6 mm x 10 cm, with octadecylsilyl (ODS) silica as filler.

Column temperature: constant, about 25 ^°C

Mobile phase: mixed solution of 0.05 mol/L potassium dihydrophosphate solution (pH 3.0): methanol : tetrahydrofuran (65:27:8) Flow rate: adjusted to render the retention time of benidipine hydrochloride to be about 20 min.

Chromatogram record time: about 2 times of the peak time of benidipine hydrochloride

CLINICAL TRIALS

http://clinicaltrials.gov/show/NCT00135551