Synthesis and antihypertensive activity evaluation in spontaneously hypertensive rats of lacidipine analogues

Article abstract of DOI:10.1007/s00044-011-9680-7

Six analogues of lacidipine, (E)-diethyl 4-(2-(3-amino)-3-oxoprop-1-enyl) phenyl-2, 6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylates (compounds 1-6), were synthesized and their antihypertensive effects in spontaneously hypertensive rats were evaluated by

Full text of DOI:10.1007/s00044-011-9680-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:1647–1651
DOI 10.1007/s00044-011-9680-7
ORIGINAL RESEARCH
Synthesis and antihypertensive activity evaluation
in spontaneously hypertensive rats of lacidipine analogues
•
Zeng-jun Guo Kai Zhou Yong-xiao Cao
•
•
•
Yan Li San-qi Zhang
Received: 9 February 2011 / Accepted: 21 May 2011 / Published online: 3 June 2011
Ó Springer Science+Business Media, LLC 2011
Abstract Six analogues of lacidipine, (E)-diethyl 4-(2-
(3-amino)-3-oxoprop-1-enyl)phenyl-2, 6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylates (compounds 1–6), were
synthesized and their antihypertensive effects in spontane-
ously hypertensive rats were evaluated by ig administration.
Amongst the tested compounds, compound 5 exhibited the
highest antihypertensive effect. The lasting time and
potency of compound 5 showed a dose-dependent manner.
The results suggested that N-tert-butyl acrylamide moiety at
20-position of 4-phenyl in the structure of analogues of
lacidipine is necessary to keep antihypertensive effects.
(Sirisha et al., 2010), antitubercular (Kharkar et al., 2002),
antibacterial (Dasgupta et al., 2010), anticoagulant (Kumar
et al., 2011) and antiviral (Hilgeroth and Lilie, 2003)
activities besides antihypertensive activity. 1,4-DHPs are
also known to act as chemosensitizers in MDR tumour
therapy (Edraki et al., 2009; Viale et al., 2011) and BACE-
1 inhibitors (Choi et al., 2010). Therefore, synthesis and
evaluation of novel 1, 4-DHPs derivatives are necessary to
develop new drugs.
Lacidipine, a third generation CCB, exhibits the charac-
teristic of long-acting, high potency as an antihypertension
medication (McCormack and Wagstaff, 2003; Motomura
et al., 1993). A dose of 2–8 mg of lacidipine a day can lower
blood pressure for 24 h (Zanchetti et al., 2007). In addition
to reduce blood pressure, lacidipine also possesses anti-
atherosclerosis (Yetik-Anacak et al., 2010) by protecting
endothelial function (Ferri et al., 1999), inhibiting adhesion
molecules expression (Park et al., 2002), adjusting matrix
metalloproteinases (Bellosta et al., 2001) and beneficial
effect on bone metabolism (Halici et al., 2008).
Keywords Antihypertensive effect ꢀ
1,4-Dihydropyridines ꢀ Lacidipine analogues ꢀ
Spontaneously hypertensive rats (SHR)
Introduction
1,4-Dihydropyridines (1,4-DHPs), a class of calcium
channel blockers (CCB), has been used extensively in
clinic for the treatment of cardiovascular diseases, such as
hypertension (Sabitha et al., 2003; Zolfigol et al., 2006).
Interestingly, 1,4-DHP has emerged as one of the most
important drug scaffold in the field of medicinal chemistry.
1,4-DHP derivatives have been found to exhibit anticancer
The structure–activity relationship of 1,4-DHPs indi-
cates that ester structures at 3- and 5-position are necessary
to keep their antihypertensive activity (Zhou et al., 2005).
There is a tert-butyl acrylate moiety at 20-position of
4-phenyl in the structure of lacidipine. The synthesis and
activity of N-tert-butyl acrylamide moiety at 20-position of
4-phenyl of 1,4-DHP have not been studied yet. The aim of
this study is to synthesize and evaluate new analogues of
lacidipine. Therefore (E)-diethyl 4-(2-(3-substitutedami-
no)-3-oxoprop-1-enyl)phenyl-2, 6-dimethyl-1,4-dihydro-
pyridine-3,5-dicarboxylates (compounds 1–6, Fig. 1) were
synthesized and their antihypertensive effects in sponta-
neously hypertensive rats (SHR) were evaluated. Here, we
report the synthesis and antihypertensive effect of six
lacidipine analogues.
Z. Guo ꢀ K. Zhou ꢀ Y. Li ꢀ S. Zhang (&)
Department of Pharmacy, Xi’an Jiaotong University College of
Medicine, Xi’an, Shaanxi 710061, People’s Republic of China
e-mail: sqzhang@xjtu.edu.cn
Y. Cao
Department of Pharmacology, Xi’an Jiaotong University College
of Medicine, Xi’an, Shaanxi 710061, People’s Republic of China
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Med Chem Res (2012) 21:1647–1651
Fig. 1 The structures of
lacidipine and its analogues
2-(1-Piperidyl)-2-oxoethyl phosphonium chloride: yield
Materials and methods
75.1%, m.p: 159–163°C.
Trichloroacetic acid, tert-butylamine, diethylamine, iso-
butylamine, piperidine and solvent were purchased
from SCRC, China. N-methyl-tert-butylamine and N-methyl-
n-butylamine were purchased from Alfa Aesar. Ethyl
3-aminocrotonate, lacidipine and chloroacetamides were
prepared in our laboratory.
General procedure for synthesis of compounds 1–6
To a mixture containing phthalaldehyde (2.0 g, 14.9 mmol),
phosphonium chloride (14.9 mmol) and dichloromethane
(50 ml) cooled to 0°C was added dropwise a solution of
diisopropylethylamine (3 ml, 17.2 mmol) in dichlorometh-
ane (10 ml) under nitrogen atmosphere. After addition, the
resulting mixture was stirred for 6 h at room temperature,
washed with water (50 ml), diluted hydrochloric acid (1 M,
50 ml92) and brine (50 ml), dried over anhydrous Na2SO4
and concentrated in vacuo to give a brown residue, which
was suspended in isopropanol (60 ml). Ethyl 3-aminocrot-
onate (3.87 g, 30 mmol) and trichloroacetic acid (5.72 g,
35 mmol) were added to above suspension cooled to 0°C.
After addition, the mixture was stirred for 3 h below 3°C and
for 3 h at room temperature, concentrated in vacuo to give a
residue, which was dissolved in ethyl acetate (100 ml). The
organic phase was washed with water (100 ml), saturated
NaHCO3 solution (10092 ml), diluted hydrochloric acid
(1 M, 50 ml) and brine (50 ml92), dried over anhydrous
Na2SO4 and concentrated in vacuo to give a residue, which
was purified by silica gel column chromatography (petro-
leum ether–ethyl acetate/8:1–3:1) to afford the target com-
pound as pale yellow solid. The solid was recrystallized in
ethyl acetate to produce pure compounds 1–6.
All melting points were determined on a Beijing mi-
cromelting-point apparatus and thermometer was uncor-
rected. 1H-NMR spectra were recorded in CDCl3 at
300 MHz with an internal reference tetramethylsilane
(TMS), Bruker NMR spectrometer. All chemical shifts are
reported in parts per million (ppm). Mass spectra were
performed on a Shimadzu GC–MS-QP2010 instrument.
The blood pressure of SHR was measured by a BP-6 ani-
mal non-invasive tail-cuff plethysmography, Chengdu Thai
Union Technology Co., Ltd., China. SHR were purchased
from Beijing Vital River Laboratory Animal Technology
Co., Ltd., China. The experimental protocol was approved
by Ethic’s Committee of Xi’an Jiaotong University.
General procedure for synthesis of phosphonium
chloride
2-N-substituted amino-2-oxoethyl phosphonium chloride
can easily be prepared by refluxing of equal mole of tri-
phenylphosphine and corresponding N-substituted chloro-
acetamide in toluene for 8–12 h.
(E)-diethyl 4-(2-(3-(tert-butylamino)-3-oxoprop-1-
enyl)phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate (1)
2-N-tert-butyl-2-oxoethyl phosphonium chloride: yield
84.5%, m.p: 227–230°C.
2-N-iso-butyl-2-oxoethyl phosphonium chloride: yield
98.0%, m.p: 188–190°C.
Yield 49.1%; m.p 213.0–215.5°C; MS (m/z): 455 (M ? 1),
1
477 (M ? Na); IR, m(cm-1): 3446, 3353, 1691, 1654; H
2-N,N-diethyl-2-oxoethyl phosphonium chloride: yield
78.0%, m.p: 185–187°C.
2-N-methyl-N-n-butyl-2-oxoethyl phosphonium chlo-
NMR (CDCl3), d: 1.16 (t, J = 5.40 Hz, 6H, 29–CH3),
1.43 (s, 9H, 39–CH3), 2.31 (s, 6H, 29–CH3), 4.00–4.04
(m, 4H, 29–OCH2–), 5.33 (s, 1H, CH), 5.57 (s, 1H, –NH–),
5.82 (s, 1H, –NH–CO), 6.13 (d, J = 15.38 Hz, 1H, CH),
7.11 (t, J = 5.51 Hz 1H, Ar–H), 7.22 (t, J = 4.73 Hz, 1H,
ride: yield 78.2%, m.p: 165–168°C.
2-N-methyl-N-tert-butyl-2-oxoethyl phosphonium chlo-
ride: yield 81.5%, m.p: 172–175°C.
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Med Chem Res (2012) 21:1647–1651
1649
Ar–H), 7.37(d, J = 6.34 Hz, 2H, Ar–H), 8.26 (d,
J = 15.49 Hz, 1H, CH).
(CDCl3), d: 1.14 (t, J = 4.51 Hz, 6H, 29–CH3), 1.47 (s,
9H, 39–CH3), 2.30 (s, 6H, 29–CH3), 3.05 (s, 3H, N–CH3),
4.00–4.04 (m, 4H, 29–OCH2–), 5.32 (s, 1H, CH), 5.68 (s,
1H, –NH–), 6.65 (d, J = 15.30 Hz, 1H, CH), 7.12 (t,
J = 5.72 Hz, 1H, Ar–H), 7.26 (t, J = 4.7 Hz, 1H, Ar–H),
7.46 (d, J = 6.6 Hz, 2H, Ar–H), 8.36 (d, J = 15.38 Hz,
1H, CH).
(E)-Diethyl 4-(2-(3-(iso-butylamino)-3-oxoprop-1-
enyl)phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate (2)
Yield 43.3%; m.p 197–200°C; MS (m/z): 455 (M ? 1); IR,
m (cm-1): 3450, 3352, 1695, 1660; 1H NMR (CDCl3)
d:0.97 (d, J = 6.61 Hz, 6H, 29–CH3), 1.16 (t,
J = 5.54 Hz 6H, 29–CH3), 1.85 (m, 1H, CH), 2.32 (s, 6H,
29–CH3), 3.23 (m, 2H, –CH2–), 3.98–4.03 (m, 4H, 29
–OCH2–), 5.34 (s, 1H, CH), 5.82 (s, 2H, 29–NH–), 6.23(d,
1H, CH, J = 15.31 Hz), 7.12–7.43 (m, 4H, Ar–H), 8.33 (d,
1H, CH, J = 15.36 Hz).
(E)-Diethyl 4-(2-(3-(piperidin-1-yl)-3-oxoprop-1-
enyl)phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate (6)
Yield 43.5%; m.p 213.5–216.0°C; MS (m/z): 466 (M), 489
(M ? Na); IR, m (cm-1): 3355, 1698, 1667; 1H NMR
(CDCl3) d:1.14 (t, J = 5.70 Hz, 6H, 29–CH3), 1.60–1.67
[m, 6H, –(CH2)3–)], 2.31 (s, 6H, 29–CH3), 3.63 (m, 4H,
–CH2–N–CH2–), 4.02 (m, 4H, 29–OCH2–), 5.31 (s, 1H,
CH), 5.90 (s, 1H, –NH–), 6.71(d, J = 15.21 Hz, 1H, CH),
7.12-7.43 (m, 4H, Ar–H), 8.34 (d, J = 15.30 Hz, 1H, CH).
(E)-Diethyl 4-(2-(3-(N,N-diethylamino)-3-oxoprop-1-
enyl)phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate (3)
Yield 26.1%; m.p 215–218°C; MS (m/z): 455 (M ? 1), 477
(M ? Na); IR, m (cm-1): 3350, 1697, 1658; 1H NMR
(CDCl3) d:1.16 (t, J = 5.63 Hz, 6H, 29–CH3), 1.26 (t,
J = 5.57 Hz, 6H, 29–CH3), 2.30 (s, 6H, 29–CH3), 3.48
(m, 4H, 29–NCH2–), 3.94–4.01 (m, 4H, 29–OCH2–), 5.33
(s, 1H, CH), 6.06 (s, 1H, –NH–), 6.63(d, J = 15.16 Hz,
1H, CH), 7.15 (t, J = 5.65 Hz, 1H, Ar–H), 7.25 (t,
J = 5.58 Hz, 1H, Ar–H), 7.41(d, J = 7.30 Hz, 2H, Ar–H),
8.41 (d, J = 15.13 Hz, 1H, CH).
Antihypertensive activity
The blood pressure was measured via a non-invasive tail-
cuff plethysmography method. Male SHR weighing
240–280 g was trained for 5 days, loaded in a cage and set
into test box in which the temperature was 37°C. The tail
was passed through the pulse detector and a cuff balloon
and stabilized for 10 to 15 min so that the tail artery was
fully expanded. When the test signal was stable, the blood
pressure was measured and systolic blood pressure was
read. The measurement was repeated two times, and an
average was recorded as the blood pressure of an individual
animal. The values of blood pressure were measured before
and at various hours after ig administration of drugs.
(E)-Diethyl 4-(2-(3-(N-methyl-N-n-butyl)amino-3-oxoprop-
1-enyl) phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate (4)
Yield 36.6%; m.p 181–183°C; MS (m/z): 468 (M); IR, m
1
(cm-1): 3355, 1695, 1663; H NMR (CDCl3) d: 0.96 (t,
J = 5.60 Hz, 3H, –CH3), 1.13 (t, J = 5.68 Hz, 6H, 29
–CH3), 1.25 (m, 2H, –CH2–), 1.36 (m, 2H, –CH2–), 2.30 (s,
6H, 29–CH3), 3.10 (s, 3H, N–CH3), 3.44 (t, J = 6.16 Hz,
2H, N–CH2–), 3.98–4.11 (m, 4H, 29–OCH2–), 5.32 (s, 1H,
CH), 5.77 (s, 1H, –NH–), 6.67(d, J = 15.24 Hz, 1H, CH),
7.13 (t, J = 5.83 Hz, 1H, Ar–H), 7.22 (t, J = 5.04 Hz, 1H,
Ar–H), 7.40 (d, J = 6.63 Hz, 2H, Ar–H), 8.38 (d,
J = 14.31 Hz, 1H, CH).
Result and discussion
Organic synthesis
In the synthesis of compounds 1–6, phosphonium chloride
was converted to the corresponding Wittig reagent in situ
by reaction with DIPEA (Raju et al., 2009). The reaction of
Wittig intermediate with equal mole of phthalaldehyde
gave (E)-N-substituted-3-(2-formylphenyl) acrylamide.
With simple work-up, treatment of the acrylamide with 2
equivalent of ethyl b-aminocrotonate in isopropanol in the
presence of trichloroacetic acid afforded the corresponding
compounds 1–6 in 20.5–49.5% yields (Scheme 1). The
yields were not optimized. The structures of compounds
(E)-Diethyl 4-(2-(3-(N-methyl-N-tert-butyl)amino-3-
oxoprop-1-enyl)phenyl)-2,6-dimethyl-1,4-dihydropyridine-
3,5-dicarboxylate (5)
Yield 20.5%; m.p 164–167°C; MS (m/z): 468 (M), 491
(M ? Na); IR, m (cm-1): 3350, 1697, 1661; 1H NMR
1
1–6 were characterized by H NMR, MS and IR.
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Med Chem Res (2012) 21:1647–1651
Scheme 1 Synthesis of compounds 1–6
Results of antihypertensive activity
effects of compound 2–4 and 6 were weaker than lacidi-
pine. Furthermore, the results demonstrated that antihy-
pertensive effects of compound 1–6 were closely related to
the structure of the N-substituted group in acrylamide
moiety at 20-position of 4-phenyl. The antihypertensive
potency of compounds 1 and 5 was higher than that of
compounds 2–4 and 6 because there is a N-tert-butyl
moiety in both the compounds 1 and 5. So N-tert-butyl is a
favourable group to keep the antihypertensive effect. The
liposolubility (log P in Table 1) of compounds 1–6 does
not connect with their antihypertensive effects. Compound
5 is the most effective drug in the tested compounds.
The antihypertensive effects of compound 5 in SHR in
different dose and lasting time are summarized in Table 2.
Compound 5 was administrated by ig at 0.5, 1.0 and
2.0 mg/kg. The data in Table 2 showed that the antihy-
pertensive effect, as well as lasting time, was dose
dependent. The antihypertensive effect of compound 5 can
last for 4 h at a dose of 1.0 mg/kg and for 20 h at 2.0
mg/kg, respectively.
The antihypertensive activities of compounds 1–6 in SHR
were evaluated by ig administration. The results are sum-
marized in Table 1.
The data indicated that antihypertensive effects of com-
pound 1 and 5 were near to lacidipine and antihypertensive
Table 1 Effects of compound 1–6 on systolic blood pressure (SBP)
in SHR at 1 h (xꢀꢁ s; n ¼ 6
Drugs
Log Pb SBP before
SBP after drugs
drugs (mmHg) administration (mmHg)c
Measured value Reduced value
1
2
3
4
5
6
1.82
2.17
1.85
2.45
2.05
1.91
164
167
166
4
6
5
120 10
152
133 11
129
121 12
140
114 11
155
44 11
15
6
3
33 10
27 11
46 13
22 10
50 12
156 11
163
162 10
3
7
7
Lacidipine 2.50
Solventa
164
156
3
3
7
1
3
Conclusions
a
30% Tween-80, 20% EtOH, 50% distilled water
Predicted by ChemDraw
b
c
Six analogues of lacidipine were synthesized and their
All compounds were administrated by ig 1.0 mg/kg
antihypertensive activities in SHR were evaluated by ig
Table 2 Effects of compound 5 on systolic blood pressure in SHR (xꢀꢁ s; n ¼ 6)
Dose
(mg/kg)
SBP before
drugs (mmHg)
Reduced SBP after drugs administration (mmHg)
1 h
2 h
4 h
6 h
8 h
20 h
0.5
1.0
2–0
0a
162
162
153
156
5
3
3
3
11
46
44
1
5
8
9
3
34
53
5
4
2
20
47
6
3
3
3
45
3
5
3
43
6
3
25
2
4
-1
-1
-2
-3
-2
a
30% Tween-80, 20% EtOH, 50% distilled water
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Med Chem Res (2012) 21:1647–1651
1651
structure–activity relationship of 1,4-dihydropyridines as antitu-
bercular agents. J Med Chem 45:4858–4867
administration. The data demonstrated that antihyperten-
sive effects of compound 1 and 5 are near to lacidipine and
antihypertensive effects of compound 2, 3, 4 and 6 are
weaker than that of lacidipine. The results suggested that
N-tert-butyl acrylamide moiety at 20-position of 4-phenyl
in the structure of analogues of lacidipine is a favourable
group to keep their antihypertensive activity, and the last-
ing time and activity of compound 5 are dose dependent.
Kumar RS, Idhayadhulla A, Jamal Abdul Nasser A, Selvin J (2011)
Synthesis and anticoagulant activity of a new series of 1,4-
dihydropyridine derivatives. Eur J Med Chem 46:804–810
McCormack PL, Wagstaff AJ (2003) Lacidipine: a review of its use in
the management of hypertension. Drugs 63:2327–2356
Motomura S, Wu ZJ, Hashimoto K (1993) Lacidipine, a new long-
acting dihydropyridine calcium antagonist, has high vascular
selectivity against all intracardiac variables. Heart Vessel
8:16–22
Park JK, Fiebeler A, Muller DN, Mervaala EMA, Dechend R, Abou-
Rebyeh F, Luft FC, Haller H (2002) Lacidipine inhibits adhesion
molecule and oxidase expression independent of blood pressure
reduction in angiotensin-induced vascular injury. Hypertension
39:685–689
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facile, one-pot synthesis of lacidipine using in situ generation of
Wittig intermediates. Org Process Res Dev 13:710–715
Sabitha G, Reddy GSKK, Reddy CS, Yadav JS (2003) A novel TMSI-
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Acknowledgments This study was supported financially by a 13115
project, No. 2007ZDKG-78, from Shaanxi Province, PR China.
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