Synthesis and structural study of new highly lipophilic 1,4-dihydropyridines

Article abstract of DOI:10.1039/b506018d

A new series of 1,4-dihydropyridines (1,4-DHPs) endowed with ester groups bearing long and functionalised alkoxy chains at the C3 and C5 positions of the nitrogen ring have been prepared from the corresponding β-keto esters which were in turn prepared by a lipase catalysed transesterification reaction. The structural study has been carried out by X-ray crystallography and theoretical calculations at the semiempirical (AM1), ab initio (HF/6-31G*) and B3LYP/6-31G* levels and reveals that the long alkyl chains do not have any influence on the required geometry of the 1,4-DHPs for biological activity. However, these chains have a strong impact on the lipophilicity and, therefore, they could be used to gain a better control of the duration of the pharmacological action. The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2005.

Full text of DOI:10.1039/b506018d

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P A P E R
Synthesis and structural study of new highly lipophilic
1,4-dihydropyridinesw
a
a
a
ab
´
Margarita Suarez,* Merly de Armas, Oney Ramırez, Amaury Alvarez, Roberto
nez-Alvarez,* Dolores Molero, Carlos Seoane, Ramon Liz, Hector Novoa de
´
c
d
c
e
Martı
´
´
Armas,f Norbert M. Blaton,f Oswald M. Peetersf and Nazario Martı
´
n*c
a
´
Laboratorio de Sıntesis Organica, Facultad de Quımica, Universidad de la Habana,
10400 La Habana, CubaE-mail: msuarez@fq.uh.cu
´
´
b Instituto Cubano de Investigaciones de los Derivados de la Can˜a de Azu´car (ICIDCA),
P. O. Box 4026 Cuba
c
´
´
´
Departamento de Quımica Organica, Facultad de Ciencias Quımicas, Universidad
Complutense, E-28040 Madrid, SpainE-mail: nazmar@quim.ucm.es.
E-mail: rma@quim.ucm.es; Fax: þ34 913944103; Tel: þ34 913944227
d CAI-RMN, Universidad Complutense, E-28040 Madrid, Spain
e
´
Departamento de Quımica Organica e Inorganica, Facultad de Quımica, Universidad de
Oviedo, E-33006 Oviedo, Spain
f Laboratorium voor Analytische Chemie en Medicinale Fysicochemie, Faculteit Farmaceustische
Wetenschappen K. U. Leuven, E. Van Evenstraat 4, B-3000 Leuven, Belgium
´
´
´
Received (in Montpellier, France) 29th April 2005, Accepted 5th October 2005
First published as an Advance Article on the web 26th October 2005
A new series of 1,4-dihydropyridines (1,4-DHPs) endowed with ester groups bearing long and functionalised
alkoxy chains at the C3 and C5 positions of the nitrogen ring have been prepared from the corresponding
b-keto esters which were in turn prepared by a lipase catalysed transesterification reaction. The structural
study has been carried out by X-ray crystallography and theoretical calculations at the semiempirical (AM1),
ab initio (HF/6-31G*) and B3LYP/6-31G* levels and reveals that the long alkyl chains do not have any
influence on the required geometry of the 1,4-DHPs for biological activity. However, these chains have a
strong impact on the lipophilicity and, therefore, they could be used to gain a better control of the duration
of the pharmacological action.
channel modulators7 as well as the protective effects of dihy-
Introduction
dropyridine Ca-blockers against endothelial cell oxidative in-
jury due to combined nitric oxide and superoxide.8 It has been
determined that 1,4-dihydropyridines containing NO-donor
furoxan moieties at the 3-positioned basic lateral chain present
vasodilating activity.9
In addition, very recent papers have reported different
biological activities of novel 1,4-DHP derivatives that are not
connected with their calcium channel modulator properties,
such as neurotropic,10 antidiabetic,11 antibacterial,12 and anti-
viral activity.13 New dimeric 4-aryl-1,4-dihydropyridine deri-
vatives were developed as a third class of nonpeptide HIV-1
protease inhibitors.14 Very recently, N-alkoxycarbonylmethyl
derivatives of 1,4-dihydropyridine-3,5-dicarboxylate were re-
ported to act as a new carrier system to deliver drugs to the
brain.15
1,4-Dihydropyridine derivatives (1,4-DHPs) form a class of
heterocyclic compounds with interesting pharmacological and
biological properties.1 It is well known that the 1,4-DHP
nucleus serves as the scaffold of important cardiovascular
drugs and it has been well established that the calcium mod-
ulator activity of this family of compounds is determined by
structural requirements.2 The systematic structural modifica-
tion of the 1,4-DHP ring yields different compounds used in
the treatment of hypertension and angina pectoris.3 The most
prominent of these compounds is nifedipine, which was the
first generation calcium channel blocker marketed by Bayer.4
Since then, a wide variety of novel compounds belonging to the
second and third generations of new biologically active sub-
stances from the 1,4-DHP class have been developed in order
to obtain larger bioavailabilities or greater tissue selectivity.5
Felodipine, lercanidipine, and clinidipine are examples of new-
er DHP-calcium antagonists, which are effective antihyperten-
sive compounds (see Chart 1).
The above studies clearly show that the 1,4-DHP nucleus
appears to be a unique structure interacting with a wide variety
of channels and receptors, its derivatives thus being considered
as a class of privileged pharmacophoric structures.7
Up to now, 1,4-DHPs are still the most potent group of
calcium channel modulators and, therefore, the design and
study of this class of compounds remains desirable.6 Recent
papers have reported novel 1,4-DHP derivatives as calcium
In previous works we have described the synthesis and
structural study, by X-ray crystallographic methods and quan-
tum chemical calculations, of several 1,4-DHP derivatives. We
found that, in general, the conformational features reported
for 1,4-DHP calcium modulators are preserved for these
compounds.16 Very recently, we carried out the synthesis of
novel fulleropyrrolidines bearing biologically active 1,4-dihy-
dropyridines covalently connected to the fullerene core.17
w Electronic supplementary information (ESI) available: Calculated
conformational data for selected compounds 4. See DOI: 10.1039/
b506018d
T h i s j o u r n a l i s & T h e R o y a l S o c i e t y o f C h e m i s t r y a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 5
N e w J . C h e m . , 2 0 0 5 , 2 9 , 1 5 6 7 – 1 5 7 6
1567

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molecules. In spite of the extensive synthetic effort carried out
on the preparation of 1,4-DHPs, the synthesis of 1,4-DHPs
bearing ester groups with long and functionalised alkoxy
chains at positions 3 and 5 of the nitrogen containing ring
has been much less studied. All attempts to obtain these
derivatives directly from the 1,4-DHP by using a classical
transesterification reaction were unsuccessful. Therefore, in
order to obtain this type of compound it was necessary to
obtain previously the b-keto esters with the desired alkyl chain.
The b-keto esters used in this work were synthesised by
following the procedure described by Cordova,21 using methyl
acetoacetate (1a) as the acyl donor and different alcohols in the
presence of Candida antarctica lipase B (CALB) immobilised
on a macroporous resin (Scheme 1).
Compounds 1c–f were thus obtained in good yields. Com-
pound 1g was obtained in 88% yield from 1a and 3-hydro-
xypropionitrile following the same procedure. Ethyl
acetoacetate (1b) was commercially available. From the corre-
sponding b-keto esters 1a and 1c, by treatment with 25%
aqueous ammonia solution in ethyl alcohol, we obtained the
corresponding b-aminocrotonates 2a and 2c (see Scheme 1).
The structures of these compounds (1c–g, 2a and 2c) were
confirmed by spectroscopic methods (see Experimental).
The preparation of compounds 4a–r was carried out by
refluxing equimolar amounts of the b-keto ester 1, alkyl 3-
aminocrotonate 2 and the corresponding aromatic aldehyde 3
in absolute ethanol for 3–4 hours under a nitrogen atmosphere
(see Scheme 2).
Chart 1 Representative examples of DHP-calcium antagonists.
Compounds 4 were obtained as crystalline solids in 60–80%
yields. Formation of the 1,4-dihydropyridine ring takes place
through a Hantzsch-like mechanism via conjugate addition of
the enamine intermediate 2 to the Knovenagel product 5
(obtained from the b-keto ester 1 and the corresponding
aromatic aldehyde 3) followed by imino–enamino tautomerism
and subsequent heterocyclisation and loss of a water molecule
(Scheme 3).
An important drawback found for the parent nifedipine and
other analogous calcium antagonists is their unfavourable
kinetic profile, due to their rapid onset of vasodilator/antihy-
pertensive action, thus leading to sympathetic activation and
reflex tachycardia as a collateral effect. Because of its short
duration of action, it has to be administered 3–4 times daily.18
It has been proved that 1,4-DHP-calcium antagonists with a
high degree of lipophilicity display a slow onset of action and
the reflex tachycardia is not seen after administration of these
compounds.19 Accordingly, the lipophilicity of a compound
might well be the major parameter governing its time of action
as a calcium antagonist.20 In addition, log P-values of DHP-
calcium antagonists, as a measurement of the lipophilicity, can
be used as a predictive parameter for the time of onset of the
action.19
In order to gain a better understanding of the effect of the
substitution pattern of the 1,4-DHP for biological activity, in
this paper we describe the synthesis of novel 1,4-DHPs en-
dowed with long and functionalised alkoxy chains, following a
Hantzsch-like procedure. The b-keto esters with different acyl
chains used as building blocks were synthesised as recently
described by Cordova,21 involving a transesterification reac-
tion from the methyl b-keto ester and the corresponding
alcohol in the presence of Candida antarctica lipase B (CALB)
immobilised on a macroporous resin as a catalyst. Since the
determination of the favoured conformation has been used to
account for the pharmacological effect of different compounds
with similar structures,22 and in order to predict the biological
activity of the compounds synthesised herein, we have carried
out a structural study of these compounds, evaluating the
geometry and conformational features by X-ray crystallogra-
phy and theoretical calculations at the semiempirical and
ab initio levels. Theoretical calculations have also been carried
out to predict the log P values for the compounds obtained.
Compounds 4a–r show satisfactory analytical and spectro-
scopic data. The FTIR spectra of compounds 4 present the
amino and carbonyl signals at 3220–3260 cmꢀ1 (NH) and
1690–1700 cmꢀ1 (C O). In addition to these signals, com-
Q
pounds 4c, 4f, 4i, 4l, 4p and 4r show the CRN signal at 2220–
2225 cmꢀ1
.
1
The H NMR spectra at 300 MHz of 1,4-DHP derivatives
4a–r show a very similar pattern. The NH and the H4 protons
appear as a singlet at B9 ppm and in the range of 4.8–5.1 ppm,
respectively. The methyl groups on C2 and C6 appear as
singlets at B2.2 ppm, and cannot be distinguished in some
compounds because of the similarity of the substituents on C3
1
and C5. The H NMR spectra also show signals between 7.0–
8.5 ppm corresponding to the protons of the aromatic ring on
C4, showing the characteristic multiplicity depending on the
position of the nitrogen atom in the pyridyl ring (2-, 3-, 4-) for
compounds 4a–p. In compounds 4q and 4r, endowed with a
p-nitrophenyl ring, the aromatic protons appear at 8.1 and
7.4 ppm as an AA0BB0 system. The alkoxycarbonyl group
Results and discussion
Scheme 1 Enzymatic synthesis of b-keto esters 1c–g and aminocro-
tonates 2a and 2c. Reagents and conditions: i) CALB, ROH, 40 1C, 10
Torr; ii) CALB, 3-hydroxypropionitrile, 40 1C, 10 Torr; iii) conc.
NH4OH, EtOH.
Since the discovery of the pharmacological activity of 1,4-
DHPs as calcium channel modulators all chemical research in
this field has been devoted to the search for biologically active
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Scheme 2 Synthesis of 1,4-DHPs 4a–r.
shows a number of signals which depends of the size of the
chain. In these cases the methylene group of the alkoxycarbo-
nyl chain (–O–CH2–R) on C3 and C5 appears as a multiplet
due to the presence of a stereogenic center on C4.23 The rest of
the aliphatic protons appear as a broad multiplet at B1.2 ppm
and as a triplet at B0.8 ppm. The protons of the a-methylene
group corresponding to the cyanoethyl group in compounds
4c, 4f, 4i, 4l, 4p and 4r appear as a multiplet at B2.8 ppm and
the b-protons as a triplet at B4.1 ppm.
DEPT(135), HMQC and HMBC. The signals corresponding
to the carbon atoms of the 1,4-DPH ring are relatively
insensitive due to the nature of the substituent and appear at
B146 ppm (C2, C6) and at B100 ppm (C3, C5). C4 appears
between 35–40 ppm. The alkoxycarbonyl sp2-carbon (COOR
or COOR1) appears at B166 ppm. The rest of the signals are in
agreement with the nature of aromatic or aliphatic carbon
atoms. All the compounds showed a similar trend in the
chemical shifts of the common moiety of the molecular back-
bone (see Experimental).
In order to gain a better understanding of the novel com-
pounds, we have calculated the structures of compounds 4a–r
using theoretical calculations. In previous works we have
widely used theoretical calculations for determining the struc-
tural and conformational features of 1,4-DHPs and 3,4-dihy-
dropyridone derivatives and we have demonstrated that ab
initio and semiempirical calculations (at the AM1 level) repro-
duce adequately the geometry of this type of compound, taking
into account the X-ray diffraction studies.24–27
The 13C NMR spectra of these compounds (4a–g) exhibit
signals in the carbonyl, aromatic and aliphatic regions. In
order to assign unequivocally the signals corresponding to
the heterocyclic ring, we used 1D and 2D techniques:
All compounds were calculated using a semiempirical AM1
method. In the case of model compounds 4k, 4n and 4o
calculations were performed using ab initio HF/6-31G* and
DFT (B3LYP/6-31G*) methods for the sake of comparison.
Fig. 1 shows the most stable conformation for 4n as a
representative example, together with its numbering scheme.
Table 1 shows geometrical data calculated for compound 4n
(B3LYP/6-31G*) as well as those determined by X-ray
diffraction.z The data for the remaining compounds, and the
most stable conformations for some representative examples
are collected in the ESI.w
In all cases, the distortion from planarity of the atoms
comprising the 1,4-DHP ring can be clearly seen from the
torsion angles calculated about the ring bonds. The greatest
displacement from zero occurs from N1 and C4, indicating that
the largest degree of puckering occurs at these positions, the
distortion being greatest at the C4 position. The magnitudes
and signs of these torsion angles indicate that both C4 and N1
(Table 1) lie above the plane formed by C2, C3, C5 and C6,
which imparts a boat-like conformation to the DHP ring.
Calculations predict that the substituent on C4 is in a pseu-
doaxial position (torsion angles C2–C3–C4–C10 between 961
and 1021) and bisecting the plane containing the 1,4-DHP ring
(torsion angles C3–C4–C10–C20 between 1431 and 931). In
compounds 4a–f, where the 20-pyridyl ring is attached to C4,
the values of the dihedral angle C3–C4–C10–N20 between 781
and 801 show the nitrogen atom of the 20-pyridyl ring being
z CCDC reference number 284120. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b506018d
Scheme 3 Plausible mechanism for the formation of 1,4-DHPs 4a–r.
N e w J . C h e m . , 2 0 0 5 , 2 9 , 1 5 6 7 – 1 5 7 6
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Table 1 Most relevant bond distances (A) valence angles (1) and
dihedral angles (1) for the most stable conformation of compound 4n
obtained at the B3LYP/6-31G* level, as well as by X-ray diffraction
Bond distances
B3LYP/6-31G*
X-Ray
1.388(7)
N1–C2
C2–C3
1.387
1.362
1.529
1.529
1.362
1.387
1.533
1.223
1.223
1.388
1.339
1.332(8)
1.541(7)
1.515(7)
1.349(8)
1.396(8)
1.540(7)
1.217(8)
1.217(8)
1.340(8)
1.330(9)
C3–C4
C4–C5
C5–C6
C6–N1
C4–C10
C7–O8
C9–O10
C20–N30
N30–C40
Bond angles
C2–N1–C6
O10–C9–C5
O8–C7–C3
C3–C4–C5
C20–N30–C40
Torsion angles
N1–C2–C3–C4
C2–C3–C4–C5
C3––C4–C5–C6
C4–C5–C6–N1
C5–C6–N1–C2
123.9
126.4
126.4
110.9
117.1
122.7(5)
128.0(7)
125.8(6)
110.4(4)
117.0(5)
6.3
ꢀ21.9
21.9
6.1(9)
ꢀ24.8(7)
23.9(8)
ꢀ6.3
ꢀ12.7
12.7
ꢀ4.6(9)
ꢀ18.0(9)
17.1(9)
C6–N1–C2–C3
P
|r|
81.8
94.5(8)
127.4(6)
97.9(6)
C3–C4–C10–C20
C2–C3–C4–C10
C2–C3–C7–O8
C6–C5–C9–O10
117.7
103.0
ꢀ2.0
2.0
ꢀ0.9(10)
10.5(11)
The geometries for the molecules 4k, 4n, and 4o were
optimised by means of Hartree–Fock calculations using the
basis set 6-31G*. We also decided to include electronic correla-
tion in the form of a DFT calculation, using the B3LYP/6-
31G* basis set; the results were similar to those obtained using
the HF/6-31G* method. The overall analysis shows that all the
methods employed (AM1, HF/6-31G* and B3LYP/6-31G*)
predict the same geometry features, although the AM1 results
should be analysed carefully and only allow us to characterise
the systems in a qualitative way, high level calculations are
necessary in order to check the validity of the approach.
Therefore, taking as a reference the results from the DFT
calculation (B3LYP/6-31G*) we conclude that HF/6-31G*
shows basically the same results, and the AM1 semiempirical
method stands as a very powerful and fast way to get reliable
results.
Fig. 1 (a) Most stable conformation for compound 4n calculated at
the B3LYP/6-31G* level. (b) Conformation of 4n in the solid state
showing the sp,sp orientation of the carboxylic groups with respect to
the endocyclic double bonds of the 1,4-DHP ring, and the alkyl side
chains are seen to fold upwards, positioned parallel to the flat face of
the 30-pyridyl ring. The carbons of the long alkyl chain are disordered
in the crystal, as shown by the ellipsoids representing the high thermal
motion. Displacement ellipsoids are drawn at the 50% probability level
and H-atoms are represented as spheres of arbitrary size.
synperiplanar to the H4 atom on C4 in the most stable
conformation. On the other hand, in compounds 4g–n the
values of the dihedral angle C3–C4–C10–C20 between 1421 and
1431, clearly show that the nitrogen atom of the 30-pyridyl ring
The N1 atoms show an sp2 hybridisation as can be seen from
calculated values of the bond angles, about 1201, and the same
trend is observed for the N atom in the pyridyl ring.
lies synperiplanar to the DHP ring.
The sum, |r|, of the absolute values of the internal torsion
angles is a measure of its planarity (see Table 1). Compounds
P
The compound 4n was crystallised and its crystal structure
determined by X-ray diffraction.z In the solid state, the 1,4-
DHP ring in 4n adopts a boat conformation with the N1 and
C4 atoms defining the stern and bow positions and deviating
from the least-squares plane by 0.138(5) and 0.181(5) A,
respectively. The puckering parameters30 of the 1,4-DHP ring
(N1–C2–C3–C4–C5–C6) are Q ¼ 0.282(6) A, y ¼ 100.8(12)1,
j ¼ 358.1(13)1. The average ring bond distance is 1.430(3) A.
The 30-pyridyl ring is positioned above the concave site of the
1,4-DHP ring in an axial position, perpendicular to the mean
plane of the 1,4-DHP ring and bisecting it [defined by torsion
angle C5–C4–C10–C20 ¼ 109.9(6)1] owing to the steric hin-
drance of the long alkyl chains in the molecules. The confor-
mation found in the crystal corresponds to that of the
heteroatom (N) of the 30-pyridyl ring being synperiplanar to
the H atom at C4 of the 1,4-DHP moiety due to the presence of
P
4a–r exhibit a
within the range of values found for compounds with biologi-
|r| between 761 and 881, these values are
cal activity.28 In the case where the substituent on C4 is the 2-
pyridyl ring the
P
|r| shows the highest values (831–871),
clearly due to the proximity of the nitrogen atom to the 1,4-
DHP ring increasing the puckering of the ring. In all cases the
C2–C3–C7–O8 and C6–C5–C9–O10 torsion angles are be-
tween 131 and ꢀ111, showing that both carbonyl groups are
sp (synperiplanar) to the respective endocyclic double bonds of
the 1,4-DHP ring; this sp,sp orientation is 0.6 kcal molꢀ1 more
stable than the sp,ap conformation and 1.3 kcal molꢀ1 more
stable than the ‘pure’ antiperiplanar ap,ap conformation. This
sp,ap conformation has also been found in felodipine and other
DHP structures.29
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Table 2 Calculated log P for compounds 4a–r
character of the 1,4-DHPs bearing ester groups with long alkyl
chains which may be of interest for a better control of the
pharmacological action. The results obtained from the X-ray
diffraction study of two representative compounds of the series
correspond well with the geometrical features calculated by the
different parameterisations employed in the DFT and ab initio
theoretical calculations and the semiempirical AM1 approach.
These findings corroborate the use of these theoretical methods
for predicting and reproducing adequately the geometry of this
type of compound.
Compound Ar
R
R1
log P
4a
4b
4c
4d
4e
4f
2-Pyridyl
C8H17
C12H25
CH3
CH3
CH3
4.69
6.47
1.10
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
3-Pyridyl
3-Pyridyl
3-Pyridyl
3-Pyridyl
3-Pyridyl
3-Pyridyl
3-Pyridyl
3-Pyridyl
4-Pyridyl
4-Pyridyl
CH2CH2CN
CH2CH3
C8H17
C8H17 4.98
C8H17 7.20
C8H17 4.58
CH2CH2CN
C8H17
C10H21
4g
4h
4i
CH3
CH3
CH3
4.66
5.56
1.08
CH2CH2CN
CH2CH3
4j
C8H17 4.95
(CH2)2O(CH2CH2)2CH3 CH3 2.73
Experimental
4k
4l
Commercially available starting materials and reagents were
purchased from commercial sources (BDH and Fluka) and
were used without further purification.
CH2CH2CN
C8H17
C8H17 4.55
C8H17 7.19
C8H17 7.88
C8H17 7.20
4m
4n
4o
4p
4q
4r
C10H21
C8H17
CH2CH2CN
Melting points were determined in a capillary tube in an
Electrothermal C14500 apparatus and are uncorrected. The
NMR spectra were recorded on a Bruker DPX300 spectro-
meter (300 MHz-1H and 75.47 MHz-13C). Chemical shifts are
given as d values referred to the solvent and J values are given
in Hz. The IR spectra were measured with a Shimadzu FTIR
8300 instrument as potassium bromide pellets. The 70 eV EI
mass spectra were recorded using an HP 5989A quadrupole
instrument with a source temperature of 200 1C. Microanalyses
were performed in a Perkin Elmer 2400 CHN by the CAI de
Microanalisis of Universidad Complutense de Madrid. The
reactions were monitored by TLC performed on silica-gel
plates (Merck 60F250) and using hexane–ethyl acetate (1 : 1)
as eluent. Semiempirical calculations were carried out using the
AM1 method.33 Ab initio calculations were carried out using
the Hartree–Fock method with the 6-31G* basis set,34 DFT
were performed using a B3LYP/6-31G* basis set.35 All calcu-
lations were carried out using the GAUSSIAN 98 program.36
No geometry constrains were specified during the optimisation
process.
CH3
CH3
CH3
1.12
5.24
1.82
4-NO2C6H4 C8H17
4-NO2C6H4 CH2CH2CN
a hydrogen bond between the N atom of the pyridyl and the N
atom of the 1,4-DHP ring. This hydrogen bond [N1ꢁ ꢁ ꢁN40 ¼
3.006(6) A, N1–H1ꢁ ꢁ ꢁN40 ¼ 1511] holds the molecules to-
gether, forming one-dimensional infinite chains along 001.
The packing diagram of 4n is included in the ESI.w Both
carbonyl groups are sp to the respective endocyclic double
bonds of the 1,4-DHP ring, and the alkyl side chains are seen to
fold upwards, positioned parallel to the flat face of the 30-
pyridyl ring, as found in ab initio calculations in the gas phase.
The carbons in these long alkyl chains appear to be disordered
in the crystal structure, as stated during the refinement by the
high temperature factors.
In this matter, the presence of long carbon chains in the ester
moiety of the 1,4-DHP ring does not modify significantly the
geometry features of the 1,4-DHP pharmacophore, particu-
larly the degree of puckering of the DHP ring (see Table 1).
In order to predict the influence of ester groups, on C3 and
C5, endowed with long and functionalised alkoxy chains on the
lipophilicity of the 1,4-DHP 4a–r, we have calculated the log P
values for all synthesised compounds (see Table 2) as well as
for nifedipine (2.06), lecardipine (7.28), clinidipine (3.92) and
felodipine (3.82). The experimental log P of nifedipine31 and
felodipine32 are 2.20 and 3.86, respectively.
It is interesting to note that although log P values can be
only considered as a guide, they clearly show that long alkyl
chains on C3 and C5 significantly increase the lipophilic
character of the 1,4-DHP. Therefore, they can present a low
onset and long duration of the pharmacological action. In this
way, the conformational features reported for 1,4-DHP cal-
cium modulators are preserved for the compounds presented in
this work, which indicates the potential activity of these
compounds as biologically active systems, in spite of the long
alkyl chains which also can improve the lipophilic character of
the 1,4-DHPs.
The calculations of the log P values were carried out using
the interactive analysis log P predictor available at www.
logp.com which uses an implementation of the Molconn-Z
program from Edusoft.37 Calculations were performed on an
IBM-RS6000 workstation.
Enzymatic synthesis of alkyl acetoacetates (1)
The synthesis was performed as described by Cordova21 with
some modifications. A homogeneous mixture of alcohol (30
mmol) and 3-oxobutyric acid methyl ester (1a) (180 mmol, 20
mL) was treated with 10% (w/w of alcohol) of Candida
antarctica lipase B (CALB) and swirled in a 50 mL flask
connected to a rotavapor at 40 1C and 10 Torr. After 5–7
hours, 10 mL of CH2Cl2 was added and the polymer-supported
lipase removed by filtration. The solvent was removed under
reduced pressure and the excess of b-keto ester was removed by
distillation in the vacuum line. The crude product was purified
by silica gel column chromatography with increasing amounts
of ethyl acetate in hexane.
Conclusions
3-Oxobutyric acid octyl ester (1c). From 1a and octan-1-ol.
1
In summary, we report a new series of 1,4-DHPs endowed with
long and functionalised alkoxy chains at the C3 and C5
positions of the nitrogen ring, that strongly influence the
spectroscopic as well as the lipophilic properties without
modifying the required structural features for biological activ-
ity. The synthesis of the novel 1,4-DHPs bearing long alkyl
chains on the ester groups at the C3 and C5 positions requires
the use of a lipase catalysed transesterification for the prepara-
tion of the intermediate b-keto esters. Finally, theoretical
calculations predict an interesting increase of the lipophilic
6 h. Yield 90%, IR (KBr) n 1744, 1720, 1653, 1238 cmꢀ1; H
NMR (DMSO-d6 200 MHz) d 4.05 (2H, t, J ¼ 6.6 Hz, OCH2),
3.59 (2H, s, CH2), 2.18 (3H, s, CH3), 1.55 (2H, m, CH2), 1.27
(10H, br. s, 5 ꢂ CH2), 0.87 (3H, t, J ¼ 6.6 Hz, CH3); 13C NMR
(DMSO-d , 50 MHz) d 201.4 (C O), 167.3 (C O), 64.2
Q
Q
6
(CH2), 49.4 (CH2), 31.0 (CH2), 29.8 (CH2), 29.3 (CH2), 28.4
(CH2), 27.8 (CH2), 25.1 (CH3), 21.9 (CH2), 13.7 (CH3); MS-EI
m/z(%) 215 ([M þ H]1, 1), 103 (88), 85 (32), 57 (20), 43 (100).
Anal. Calc. C12H22O3 (214.30): C, 67.26; H, 10.35. Found: C,
67.38; H, 10.43%.
N e w J . C h e m . , 2 0 0 5 , 2 9 , 1 5 6 7 – 1 5 7 6
1571

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6.94 (2H, br s, NH2), 4.29 (1H, s, ¼ CH), 3.90 (2H, t, J ¼ 6.6
Hz, CH2), 1.80 (3H, s, CH3), 1.55 (2H, m, CH2), 1.24 (10H, br
s, 5 ꢂ CH2), 0.85 (3H, t, J ¼ 6.6 Hz, CH3); 13C NMR (DMSO-
d , 50 MHz) d 169.2 (C O), 161.1 (C O), 81.4 (CH ), 61.5
(CH2), 31.2 (CH2), 28.7 (CH2), 28.6 (CH2), 28.3 (CH2), 25.6
(CH3), 22.1 (CH2), 21.5 (CH2), 14.0 (CH3); MS-EI m/z(%) 213
(M1, 9), 101 (30), 84 (58), 71 (30), 57 (89), 56 (28), 43 (100).
Anal. Calc. C12H23NO2 (213.32): C, 67.57; H, 10.87; N, 6.57.
Found: C, 67.78; H, 10.65; N, 6.34%.
3-Oxobutyric acid decyl ester (1d). From 1a and decan-1-ol.
1
7 h. Yield 85%, IR (KBr) n 1743, 1718, 1650, 1238 cmꢀ1; H
NMR (DMSO-d6 250 MHz) d 4.13 (2H, t, J ¼ 7.2 Hz, OCH2),
3.44 (2H, s, CH2), 2.27 (3H, s, CH3), 1.62 (2H, m, CH2), 1.26
(14H, br. s, 7 ꢂ CH2), 0.87 (3H, t, J ¼ 7.2 Hz, CH3); 13C NMR
Q
Q
6
2
(DMSO-d , 50 MHz) d 201.5 (C O), 167.1 (C O), 65.6
Q
Q
6
(CH2), 50.1 (CH2), 31.8 (CH2), 30.1 (CH2), 29.5 (CH2), 29.4
(CH2), 29.2 (CH2), 28.4 (CH2), 26.4 (CH2), 25.8 (CH3), 22.6
(CH2), 14.1 (CH3); MS-EI m/z(%) 243 ([M þ H]1, 2), 200 (2),
103 (100), 85 (33), 70 (31), 43 (84). Anal. Calc. C14H26O3
(242.35): C, 69.36; H, 10.81. Found: C, 69.62 H, 10.64%.
Synthesis of 1,4-dihydropyridines (4)
A mixture of the b-keto ester (1) (3 mmol), the corresponding
aromatic aldehyde (3) (3 mmol) and the alkyl 3-aminocroto-
nate (2) in absolute ethanol (30 mL), was heated under reflux
for 3–4 hours under a nitrogen atmosphere. After cooling to
ꢀ5 1C, the precipitate was filtered and recrystallised from
ethanol.
3-Oxobutyric acid dodecyl ester (1e). From 1a and dodecan-
1-ol. 7 h. Yield 96%, IR (KBr) n 1770 (br. s), 1651, 1238 cmꢀ1
;
1H NMR (DMSO-d6 250 MHz) d 4.13 (2H, t, J ¼ 6.7 Hz,
OCH2), 3.44 (2H, s, CH2), 2.26 (3H, s, CH3), 1.62 (2H, m,
CH2), 1.25 (18H, br. s, 9 ꢂ CH2), 0.87 (3H, t, J ¼ 6.7 Hz, CH3);
13C NMR (DMSO-d , 50 MHz) d 201.1 (C O), 167.3 (C O),
Q
Q
6
65.6 (CH2), 50.1 (CH2), 31.9 (CH2), 30.1 (CH2), 29.6 (CH2),
29.5 (CH2), 29.4 (CH2), 29.3 (CH2), 29.2 (CH2), 28.4 (CH2),
25.8 (CH3), 25.1 (CH2), 22.6 (CH2), 14.1 (CH3); MS-EI m/z(%)
271 ([M þ H]1, 6), 201 (35), 103 (93), 85 (42), 69 (32), 43 (100).
Anal. Calc. C16H30O3 (270.41): C, 71.07; H, 11.18. Found: C,
71.22; H, 11.32%.
5-Methyl 3-octyl 2,6-dimethyl-4-(20-pyridyl)-1,4-dihydropyri-
dine-3,5-dicarboxylate (4a). Obtained from 1c, 2a and 3a in
65% yield, mp: 154–155 1C, IR (KBr) n 3260 (NH), 1697
(C O), 1643 and 1625 (C C); 1H NMR (DMSO-d ), d: 8.78
Q
Q
6
(1H, s, NH), 8.38 (1H, d, J ¼ 4.7 Hz, H30), 7.58 (1H, td, J ¼ 7.7
Hz, J ¼ 1.8 Hz, H50), 7.11 (2H, m, H40, H60), 5.01 (1H, s, H4),
3.94 (2H, m, OCH2), 3.53 (3H, s, OCH3), 2.23 (3H, s, CH3–
C2), 2.22 (3H, s, CH3–C6), 1.48 (2H, m, OCH2CH2), 1.24
(10H, br. s, 5 ꢂ CH2), 0.85 (3H, t, J ¼ 6.79 Hz, CH3); 13C
3-Oxobutyric acid 2-butoxyethyl ester (1f). From 1a and 2-
butoxyethanol. 5 h. Yield 96%, IR (KBr) n 1747, 1718, 1247
1
cmꢀ1; H NMR (DMSO-d6 250 MHz) d 4.28 (2H, t, J ¼ 5.8
NMR (DMSO-d ), d: 167.5 (C5–C O), 166.9 (C3–C O),
Q
Q
6
Hz, CH2), 3.62 (2H, m, CH2), 3.45 (4H, m, 2 ꢂ CH2), 2.27 (3H,
s, CH3), 1.56 (2H, m, CH2), 1.32 (2H, m, CH2), 0.90 (3H, t, J ¼
164.9 (C10), 149.1 (C30), 146.1, 146.1 (C2, C6); 135.6 (C50),
121.4, 121.3 (C40, C60), 100.3 (C3) 100.2 (C5), 62.9 (OCH2),
50.6 (OCH3), 41.2 (C4), 31.2 (CH2), 28.6 (2 ꢂ CH2), 28.3
(OCH2CH2), 25.5 (OCH2CH2CH2), 22.1 (CH2), 18.3 (2 ꢂ
CH3), 13.9 (CH2CH3); MS-EI m/z(%) 400 (M1, 1), 322
(100), 271 (4), 210 (41), 178 (8), 165 (6). Anal. Calc.
C23H32N2O4 (400.51): C, 68.97; H, 8.05; N, 6.99. Found: C,
68.72; H, 8.21; N, 6.77%.
8.1 Hz, CH3); 13C NMR (DMSO-d , 50 MHz) d 200.1 (C O),
Q
167.0 (C O), 71.0 (CH ), 68.1 (CH ), 64.2 (CH ), 49.9 (CH ),
6
Q
2
2
2
2
31.5 (CH2), 29.9 (CH3), 19.1 (CH2), 13.7 (CH3); MS-EI m/z(%)
203 ([M þ H]1, 63), 129 (78), 100 (22), 85 (70), 56 (100), 43
(93). Anal. Calc. C10H18O4 (202.75): C, 59.39; H, 8.97. Found:
C, 59.46; H, 8.31%.
3-Dodecyl 5-methyl 2,6-dimethyl-4-(20-pyridyl)-1,4-dihydro-
pyridine-3,5-dicarboxylate (4b). Obtained from 1e, 2a and 3a
in 75% yield, mp: 121–122 1C, IR (KBr) n 3261 (NH), 1697
3-Oxobutyric acid 2-cyanoethyl ester (1g). From 1a and 3-
hydroxypropionitrile. 5 h. Yield 88%, IR (KBr) n 3504, 2230,
1
1751, 1717, 1655, 1630, 1271 cmꢀ1; H NMR (DMSO-d6 200
1
(C O), 1645 and 1627 (C C), cmꢀ1; H NMR (DMSO-d6),
MHz) d 4.24 (2H, t, J ¼ 6.0 Hz, CH2), 3.66 (2H, s, CH2), 2.88
Q
Q
(2H, t, J ¼ 6.0 Hz, CH2), 2.20 (3H, s, CH3); 13C NMR
d: 8.79 (1H, s, NH), 8.38 (1H, d, J ¼ 4.0 Hz, H30), 7.59 (1H, td,
J ¼ 7.6 Hz, J ¼ 1.8 Hz, H50), 7.09 (2H, m, H40, H60), 5.01 (1H,
s, H4), 3.91 (2H, m, OCH2), 3.53 (3H, s, OCH3), 2.23 (3H, s,
CH3–C2), 2.21 (3H, s, CH3–C6), 1.47 (2H, m, OCH2CH2), 1.23
(18H, br. s, 9 ꢂ CH2), 0.85 (3H, t, J ¼ 6.4 Hz, CH3); 13C NMR
(DMSO-d , 50 MHz) d 200.1 (C O), 166.7 (C O), 118.2
Q
Q
6
(CN), 59.3 (CH2), 49.1 (CH2), 29.8 (CH2), 17.2 (CH3); MS-EI
m/z(%) 155 (M1, 2), 85 (18), 43 (100); Anal. Calc. for
C7H9NO3 (155.15): C, 54.19; H, 5.85; N, 9.03. Found: C,
54.36; H, 5.68; N, 9.26%.
(DMSO-d ), d: 167.4 (C5–C O), 166.9 (C3–C O), 164.9
Q
Q
6
(C10), 149.1 (C30), 146.1, 146.0 (C2, C6); 135.5 (C50), 121.4,
121.2 (C40, C60), 100.3 (C3) 100.2 (C5), 62.9 (OCH2), 50.0
(OCH3), 41.1 (C4), 31.3 (CH2), 29.0 (2 ꢂ CH2), 28.9 (CH2),
28.7 (CH2), 28.6 (2 ꢂ CH2), 28.2 (OCH2CH2), 25.5 (CH2), 22.1
(CH2), 18.3 (2 ꢂ CH3), 13.9 (CH2CH3); MS-EI m/z(%) 456
(M1, 1), 378 (100), 271 (4), 210 (41), 178 (5), 165 (6). Anal.
Calc. C27H40N2O4 (456.62): C, 71.02; H, 8.83; N, 6.13. Found:
C, 71.29; H, 8.75; N, 6.22%.
Synthesis of alkyl 3-aminocrotonates (2)
To 0.06 mol of b-keto ester (1a or 1c) were added 0.20 mol of
25% aqueous ammonia and 25 mL of ethyl alcohol with
stirring at room temperature.
3-Aminobut-2-enoic acid methyl ester (2a). After 7 h the white
solid was precipitated, filtered off and rinsed with cold ethyl
alcohol. Crystallisation from ethanol gives 65% yield. IR
;
(KBr) n 3335, 1664, 1624, 1288 cmꢀ1 1H NMR (DMSO-d6
3-(2-Cyanoethyl) 5-methyl 2,6-dimethyl-4-(20-pyridyl)-1,4-di-
hydropyridine-3,5-dicarboxylate (4c). Obtained from 1g, 2a and
3a in 65% yield, mp: 167–169 1C, IR (KBr) n 3260 (NH), 2225
(CN), 1690 (C O), 1628 and 1593 (C C); 1H NMR (DMSO-
300 MHz) d 7.12 (2H, br. s, NH2), 4.53 (1H, s, ¼ CH), 3.81
(3H, s, CH3), 1.78 (3H, s, CH3); 13C NMR (DMSO-d6, 50
Q
Q
MHz) 168.9 (C O), 162.3 (C O), 83.7 (CH ), 58.6 (CH ),
3
Q
Q
d6), d: 8.90 (1H, s, NH), 8.40 (1H, d, J ¼ 4.7 Hz, H30), 7.58 (1H,
td, J ¼ 7.7 Hz, J ¼ 1.8 Hz, H50), 7.18 (1H, d, J ¼ 7.7 Hz, H60),
7.11 (1H, dd, J ¼ 7.7 Hz, J ¼ 4.7 Hz, H40), 5.01 (1H, s, H4),
4.14 (2H, t, J ¼ 6.0 Hz, OCH2), 3.53 (3H, s, OCH3), 2.83 (2H,
2
27.2 (CH3). Anal. Calc. C5H9NO2 (115.13): C, 52.16; H, 7.88;
N, 12.17. Found: C, 52.27; H, 7.94; N, 12.25%.
3-Aminobut-2-enoic acid octyl ester (2c). After 14 h the
solvent was removed under reduced pressure, obtaining the
compound as a yellow liquid, 83% yield. IR (KBr) n 3443,
3335, 1654, 1624, 1288 cmꢀ1; 1H NMR (DMSO-d6 200 MHz) d
m, CH2CN), 2.25 (3H, s, CH3–C2), 2.24 (3H, s, CH3–C6); 13
C
NMR (DMSO-d ), d: 167.4 (C5–C O), 166.5 (C3–C O),
Q
Q
6
164.7 (C10), 149.1 (C30), 147.2, 146.1 (C2, C6), 135.8 (C50),
121.6 (C60), 121.4 (C40), 118.8 (CN), 100.5 (C5), 99.5 (C3), 58.4
1572
N e w J . C h e m . , 2 0 0 5 , 2 9 , 1 5 6 7 – 1 5 7 6

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(OCH2), 50.6 (OCH3), 41.0 (C4), 18.6 (CH3–C2), 18.3 (CH3–
C6), 17.5 (CH2–CN); MS-EI m/z(%) 341 (M1, 2), 263 (100),
210 (26), 178 (5). Anal. Calc. C18H19N3O4 (341.36): C: 63.33;
H: 5.61; N: 12.31. Found: C, 63.62; H, 5.33; N, 12.45%.
7.23 (1H, dd, J ¼ 7.8 Hz, J ¼ 4.7 Hz, H50), 4.89 (1H, s, H4),
3.90 (2H, m, OCH2), 3.54 (3H, s, OCH3), 2.28 (3H, s, CH3–
C2), 2.26 (3H, s, CH3–C6), 1.48 (2H, m, OCH2CH2), 1.21
(10H, br. s, 5 ꢂ CH2), 0.85 (3H, t, J ¼ 6.6 Hz, CH3); 13C NMR
(DMSO-d ), d: 167.1 (C5–C O), 166.6 (C3–C O), 148.5
Q
Q
6
(C20), 147.2 (C40), 143.2 (C10), 146.3, 146.3 (C2, C6), 134.6
(C60), 123.5 (C50), 100.9, 100.8 (C3, C5), 63.2 (OCH2), 50.8
(OCH3), 36.8 (C4), 31.1 (CH2), 28.6 (2 ꢂ CH2), 28.2
(OCH2CH2), 25.5 (CH2), 22.1 (CH2), 18.2 (CH3–C6), 18.1
(CH3–C2), 13.9 (CH2CH3); MS-EI m/z(%) 400 (M1, 3), 322
(100), 271 (4), 210 (41), 178 (7), 165 (6). Anal. Calc.
C23H32N2O4 (400.51): C, 68.97; H, 8.05; N, 6.99. Found: C,
68.81; H, 8.16; N, 6.88%.
5-Ethyl 3-octyl 2,6-dimethyl-4-(20-pyridyl)-1,4-dihydropyri-
dine-3,5-dicarboxylate (4d). Obtained from 1b, 2c and 3a in
68% yield, mp: 133–135 1C, IR (KBr) n 3260 (NH), 1693 (C
Q
O), 1643 and 1626 (C C); 1H NMR (DMSO-d ), d: 8.76 (1H,
Q
6
s, NH), 8.38 (1H, br. d, J ¼ 4.5 Hz, H30), 7.58 (1H, td, J ¼ 7.6
Hz, J ¼ 1.9 Hz, H50), 7.12 (1H, d, H60, overlapping with 7.09),
7.09 (1H, d, H40, overlapping with 7.12), 5.00 (1H, s, H4), 3.90
(4H, m, 2 ꢂ OCH2), 2.23 (3H, s CH3), 2.21 (3H, s CH3), 1.47
(2H, m, OCH2CH2), 1.20 (10H, br. s, 5 ꢂ CH2), 1.12 (3H, t,
J ¼ 7.4 Hz, CH3), 0.84 (3H, t, J ¼ 6.79 Hz, CH3); 13C NMR
(DMSO-d ), d: 166.9 (C3–C O, C5–C O), 165.1 (C10), 149.1
3-Decyl 5-methyl 2,6-dimethyl-4-(30-pyridyl)-1,4-dihydropyri-
dine-3,5-dicarboxylate (4h). Obtained from 1d, 2a and 3b in
Q
Q
6
(C30), 146.2, 145.9 (C2, C6), 135.4 (C50), 121.7 (C60), 121.3
(C40), 100.4, 100.3 (C3, C5), 62.9 (OCH2), 58.9 (OCH2CH3),
41.3 (C4), 31.2 (CH2), 28.6 (2 ꢂ CH2), 28.3 (OCH2CH2), 25.6
68% yield, mp: 159–160 1C, IR (KBr) n 3267 (NH), 1691 (C
Q
O), 1645 and 1587 (C C); 1H NMR (DMSO-d ), d: 8.98 (1H,
Q
6
s, NH), 8.35 (1H, d, J ¼ 1.6 Hz, H20), 8.30 (1H, dd, J ¼ 4.7 Hz,
J ¼ 1.6 Hz, H40), 7.48 (1H, dt, J ¼ 7.9 Hz, J ¼ 1.6 Hz, H60),
7.24 (1H, dd, J ¼ 7.9 Hz, J ¼ 4.7 Hz, H50), 4.85 (1H, s, H4),
3.92 (2H, m, OCH2), 3.54 (3H, s, OCH3), 2.27 (3H, s, CH3–
C2), 2.25 (3H, s, CH3–C6), 1.47 (2H, m, OCH2CH2), 1.22
(14H, br. s, 7 ꢂ CH2), 0.85 (3H, t, J ¼ 6.4 Hz, CH3); 13C NMR
(OCH2CH2CH2), 22.1 (CH2), 18.3 (2
ꢂ
CH3), 14.2
(OCH2CH3), 13.9 (CH2CH3); MS-EI m/z(%) 414 (M1, 1),
336 (100), 308 (3), 224 (20), 211 (5), 179 (5). Anal. Calc.
C24H34N2O4 (414.54): C: 69.54; H: 8.27; N: 6.76. Found: C,
69.68; H, 8.38; N, 6.81%.
(DMSO-d ), d: 167.1 (C5–C O), 166.5 (C3–C O), 148.5
Q
Q
6
(C20), 147.1 (C40), 143.1 (C10), 146.3, 146.2 (C2, C6), 134.6
(C60), 123.5 (C50), 100.9 (C5) 100.8 (C3), 63.1 (OCH2), 50.7
(OCH3), 37.2 (C4), 31.6 (CH2), 29.2 (CH2), 29.2 (CH2), 29.0
(CH2), 28.9 (CH2), 28.3 (OCH2CH2), 25.9 (CH2), 22.5 (CH2),
18.2 (CH3–C2), 18.1 (CH3–C6), 13.9 (CH2CH3); MS-EI
m/z(%) 428 (M1, 2), 350 (100), 287 (10), 243 (8), 210 (43),
178 (5), 165 (6). Anal. Calc. C25H36N2O4 (428.56): C, 70.06;
H, 8.47; N, 6.54. Found: C, 70.18; H, 8.32; N, 6.59%.
3,5-Dioctyl 2,6-dimethyl-4-(20-pyridyl)-1,4-dihydropyridine-
3,5-dicarboxylate (4e). Obtained from 1c, 2c and 3a in 76%
yield, mp: 132–133 1C, IR (KBr) n 3226 (NH), 1693 (C O),
Q
1
1639 and 1626 (C C); H NMR (DMSO-d ), d: 8.77 (1H, s,
Q
6
NH), 8.38 (1H, d, J ¼ 4.0 Hz, H30), 7.55 (1H, td, J ¼ 7.6 Hz,
J ¼ 1.8 Hz, H50), 7.10 (2H, m, H40, H60), 5.02 (1H, s, H4), 3.91
(4H, m, 2 ꢂ OCH2), 2.22 (6H, s, 2 ꢂ CH3), 1.48 (4H, m, 2 ꢂ
OCH2CH2), 1.21 (20H, br. s, 10 ꢂ CH2), 0.85 (6H, t, J ¼ 6.4
Hz, 2 ꢂ CH3); 13C NMR (DMSO-d ), d: 166.9 (C5–C O,
Q
6
C3–C O), 165.1 (C10), 149.1 (C30), 146.1 (C2, C6); 135.3
3-(2-Cyanoethyl) 5-methyl 2,6-dimethyl-4-(30-pyridyl)-1,4-di-
hydropyridine-3,5-dicarboxylate (4i). Obtained from 1g, 2a and
3b in 68% yield, mp: 186–187 1C, IR (KBr) n 3269 (NH), 2220
(CN), 1691 (C O), 1643 and 1600 (C C); 1H NMR (DMSO-
Q
(C50), 121.6, 121.3 (C40, C60), 100.3 (C3, C5), 62.9 (2 ꢂ
OCH2), 41.2 (C4), 31.2 (2 ꢂ CH2), 28.6 (4 ꢂ CH2), 28.3 (2 ꢂ
OCH2CH2), 25.6 (2 ꢂ CH2), 22.1 (2 ꢂ CH2), 18.2 (2 ꢂ CH3),
13.9 (2 ꢂ CH2CH3); MS-EI m/z(%) 498 (M1, 1), 420 (100), 308
(10), 256 (8), 178 (3). Anal. Calc. C30H46N2O4 (498.70): C:
72.25; H: 9.30; N: 5.62. Found: C, 72.42; H, 9.20; N, 5.77%.
Q
Q
d6), d: 9.08 (1H, s, NH), 8.38 (1H, d, J ¼ 1.7 Hz, H20), 8.32 (1H,
dd, J ¼ 4.7 Hz, J ¼ 1.7 Hz, H40), 7.52 (1H, dt, J ¼ 7.7 Hz, J ¼
1.7 Hz, H60), 7.24 (1H, dd, J ¼ 7.7 Hz, J ¼ 4.7 Hz, H50), 4.86
(1H, s, H4), 4.15 (2H, t, J ¼ 5.9 Hz, OCH2), 3.54 (3H, s,
OCH3), 2.84 (2H, m, CH2CN), 2.29 (3H, s, CH3–C2), 2.28 (3H,
3-(2-Cyanoethyl) 5-octyl 2,6-dimethyl-4-(20-pyridyl)-1,4-dihy-
dropyridine-3,5-dicarboxylate (4f). Obtained from 1g, 2c and 3a
in 60% yield, mp: 133–134 1C, IR (KBr) n 3260 (NH), 2225
(CN), 1697 (C O), 1643 and 1625 (C C); 1H NMR (DMSO-
s, CH3–C6); 13C NMR (DMSO-d ), d: 166.9 (C5–C O), 166.1
Q
6
(C3–C O), 148.5 (C20), 147.3 (C40), 146.3, 146.2 (C2, C6),
Q
142.9 (C10), 134.7 (C60), 123.5 (C50), 118.7 (CN), 101.2 (C5),
100.2 (C3), 58.6 (OCH2), 50.8 (OCH3), 36.7 (C4), 18.5 (CH3–
C2), 18.2 (CH3–C2), 17.4 (CH2–CN); MS-EI m/z(%) 341 (M1,
3), 363 (100), 243 (6), 210 (25), 178 (6). Anal. Calc.
C18H19N3O4 (341.36): C: 63.33; H: 5.61; N: 12.31. Found: C,
63.52; H, 5.45; N, 12.49%.
Q
Q
d6), d: 8.99 (1H, s, NH), 8.39 (1H, br. d, J ¼ 4.8 Hz, H30), 7.56
(1H, td, J ¼ 7.8 Hz, J ¼ 1.6 Hz, H50), 7.19 (1H, d, J ¼ 7.8 Hz,
H60), 7.09 (1H, dd, J ¼ 7.8 Hz, J ¼ 4.8 Hz, H40), 5.02 (1H, s,
H4), 4.13 (2H, t, J ¼ 5.8 Hz, OCH2CH2CN), 3.93 (2H, m,
OCH2), 2.83 (2H, m, CH2CN), 2.24 (3H, s, CH3), 2.23 (3H, s,
CH3), 1.48 (2H, m, OCH2CH2), 1.20 (10H, m, 5 ꢂ CH2), 0.85
(3H, t, J ¼ 6.7 Hz, CH3); 13C NMR (DMSO-d6), d: 166.9 (C5–
5-Ethyl 3-octyl 2,6-dimethyl-4-(30-pyridyl)-1,4-dihydropyri-
dine-3,5-dicarboxylate (4j). Obtained from 1b, 2c and 3b in
70% yield, mp: 151–152 1C, IR (KBr) n 3262 (NH), 1701 and
1690 (C O), 1647 (C C); 1H NMR (CDCl ), d: 6.61 (1H, s,
C
O), 166.5 (C3–C O), 164.8 (C10), 149.1 (C30), 147.1, 146.0
Q
Q
(C2, C6), 135.5 (C50), 121.8 (C60), 121.4 (C40), 118.8 (CN),
100.7 (C3), 99.5 (C5), 63.0 (OCH2), 58.4 (OCH2CH2CN), 41.1
(C4), 31.2 (CH2), 28.6 (2 ꢂ CH2), 28.2 (OCH2CH2), 25.5
(CH2), 22.1 (CH2), 18.6 (CH3), 18.3 (CH3), 17.5 (CH2–CN),
13.9 (CH2CH3); EM m/z(%) 439 (M1, 1), 420 (7), 361 (100),
249 (27), 211 (8), 152 (10). Anal. Calc. C25H33N3O4 (439.55): C:
68.31; H: 7.57; N: 9.56. Found: C, 68.52; H, 7.38; N, 9.78%.
Q
Q
3
NH), 8.52 (1H, d, J ¼ 1.6 Hz, H20), 8.36 (1H, dd, J ¼ 4.8 Hz,
J ¼ 1.6 Hz, H40), 7.61 (1H, dt, J ¼ 7.8 Hz, J ¼ 1.6 Hz, H60),
7.15 (1H, dd, J ¼ 7.8 Hz, J ¼ 4.8 Hz, H50), 4.98 (1H, s, H4),
4.05 (4H, m, 2 ꢂ OCH2), 2.34 (3H, s, CH3), 2.32 (3H, s, CH3),
1.88 (2H, m, OCH2CH2), 1.20 (10H, br. s, 5 ꢂ CH2), 1.19 (3H,
t, J ¼ 7.1 Hz, CH3), 0.88 (3H, t, J ¼ 6.7 Hz, CH3); 13C NMR
(CDCl ), d: 167.3, 167.2 (C5–C O, C3–C O), 149.4 (C20),
5-Methyl 3-octyl 2,6-dimethyl-4-(30-pyridyl)-1,4-dihydropyri-
dine-3,5-dicarboxylate (4g). Obtained from 1c, 2a and 3b in
Q
Q
3
147.1 (C40), 143.5 (C10), 145.0, 144.9 (C2, C6), 135.6 (C60),
123.0 (C50), 103.1, 103.1 (C3, C5), 64.0 (OCH2), 59.8 (OCH2),
37.7 (C4), 31.7 (CH2), 29.2 (2 ꢂ CH2), 28.6 (OCH2CH2), 26.0
(CH2), 22.60 (CH2), 19.3 (2 ꢂ CH3), 14.2 (CH2CH3), 14.1
(CH2CH3); MS-EI m/z(%) 414 (M1, 4), 336 (100), 257 (6), 224
65% yield, mp: 158–160 1C, IR (KBr) n 3265 (NH), 1692 (C
Q
O), 1643 and 1587 (C C); 1H NMR (DMSO-d ), d: 8.97 (1H,
Q
6
s, NH), 8.35 (1H, d, J ¼ 1.6 Hz, H20), 8.31 (1H, dd, J ¼ 4.7 Hz,
J ¼ 1.6 Hz, H40), 7.47 (1H, dt, J ¼ 7.8 Hz, J ¼ 1.6 Hz, H60),
N e w J . C h e m . , 2 0 0 5 , 2 9 , 1 5 6 7 – 1 5 7 6
1573

View Article Online
(20), 179 (6). Anal. Calc. C24H34N2O4 (414.54): C, 69.54; H,
8.27; N, 6.76. Found: C, 69.71; H, 8.37; N, 6.52%.
s, H4), 4.02 (4H, m, 2 OCH2), 2.36 (6H, s, 2 ꢂ CH3), 1.58 (4H,
m, 2 ꢂ OCH2CH2), 1.25 (24H, m, 12 ꢂ CH2), 0.88 (3H, t, J ¼
6.4 Hz, CH3), 0.85 (3H, t, J ¼ 6. 9 Hz, CH3); 13C NMR
(CDCl ), d: 167.6 (C5–C O, C3–C O), 147.3 (C20), 144.7,
Q
Q
5-(2-Butoxyethyl) 3-methyl 2,6-dimethyl-4-(30-pyridyl)-1,4-di-
hydropyridine-3,5-dicarboxylate (4k). Obtained from 1f, 2a and
3b in 80% yield, mp: 158–159 1C, IR (KBr) n 3270 (NH), 1703
3
144.6 (C40, C10), 145.5 (C2, C6), 138.1 (C60), 123.8 (C50), 103.2
(C5, C3), 64.5 (2 ꢂ OCH2), 38.0 (C4), 31.9 (CH2), 31.8 (CH2),
29.5 (2 ꢂ CH2), 29.3 (CH2), 29.2 (CH2), 29.2 (2 ꢂ CH2), 28.6 (2
ꢂ OCH2CH2), 26.0 (2 ꢂ CH2), 22.7 (CH2), 22.6 (CH2), 19.5 (2
ꢂ CH3), 14.4 (CH2CH3), 14.3 (CH2CH3); MS-EI m/z(%) 526
(M1, 2), 476 (8), 448 (100), 420 (15), 336 (6), 178 (6). Anal.
Calc. C32H50N2O4 (526.75): C, 72.96; H, 9.57; N, 5.32. Found:
C, 72.82; H, 9.42; N, 5.44%.
1
and 1693 (C O), 1645 and 1635 (C C); H NMR (DMSO-
Q
Q
d6), d: 9.00 (1H, s, NH), 8.38 (1H, d, J ¼ 1.7 Hz, H20), 8.31 (1H,
dd, J ¼ 4.7 Hz, J ¼ 1.7 Hz, H40), 7.50 (1H, dt, J ¼ 7.9 Hz, J ¼
1.7 Hz, H60), 7.23 (1H, dd, J ¼ 7.9 Hz, J ¼ 4.7 Hz, H50), 4.86
(1H, s, H4), 4.06 (2H, m, CH2OCO), 3.52 (3H, s, OCH3), 3.49
(2H, m, CH2O), 3.35 (2H, m, CH2O), 2.27 (3H, s, CH3), 2.26
(3H, s, CH3), 1.45 (2H, m, CH2CH2O), 1.30 (2H, m, CH2CH3),
0.86 (3H, s CH3); 13C NMR (DMSO-d ), d: 167.0 (C3–C O),
3,5-Dioctyl 2,6-dimethyl-4-(40-pyridyl)-1,4-dihydropyridine-
3,5-dicarboxylate (4o). Obtained from 1c, 2c and 3c in 60%
Q
6
166.5 (C5–C O), 148.8 (C20), 147.3 (C40), 143.0 (C10), 147.7
Q
(C2, C6), 134.9 (C60), 123.7 (C50), 101.2 (C3), 101.0 (C5), 70.1
(CH2), 68.3 (CH2), 62.8 (CH2), 50.8 (OCH3), 36.9 (C4), 31.5
(CH2), 19.4 (CH2), 18.5 (CH3), 18.5 (CH3), 14.1 (CH2CH3);
MS-EI m/z(%) 388 (M1, 5), 310 (100), 287 (6), 243 (8), 210
(51), 178 (7). Anal. Calc. C21H28N2O5 (388.46): C, 64.93; H,
7.27; N, 7.21. Found: C, 64.81; H, 7.34; N, 7.32%.
yield, mp: 84–85 1C, IR (KBr) n 3290 (NH), 1703 (C O), 1676
Q
1
and 1645 (C C); H NMR (DMSO-d ), d: 8.99 (1H, s, NH),
Q
6
8.38 (2H, d, J ¼ 5.95 Hz, H30, H50), 7.10 (2H, d, J ¼ 5.9 Hz,
H20, H60), 4.88 (1H, s, H4), 3.94 (4H, m, 2 ꢂ OCH2), 2.27 (6H,
s, 2 ꢂ CH3), 1.49 (4H, m, 2 ꢂ OCH2CH2), 1.21 (20H, m, 10 ꢂ
CH2), 0.85 (6H, t, J ¼ 6.46 Hz, 2 ꢂ CH3); 13C NMR (DMSO-
d ), d: 167.5 (C5–C O, C3–C O), 157.0 (C10), 149.5 (C30,
Q
Q
6
C50), 147.6 (C2, C6), 122.5 (C20, C60), 101.3 (C5, C3), 63.5 (2 ꢂ
OCH2), 38.6 (C4), 31.6 (2 ꢂ CH2), 28.9 (4 ꢂ CH2), 28.6 (2 ꢂ
CH2), 25.4 (2 ꢂ CH2), 22.4 (2 ꢂ CH2), 18.2 (2 ꢂ CH3), 14.1 (2
ꢂ CH2CH3); MS-EI m/z(%) 498 (M1, 1), 420 (100), 308 (11),
229 (6), 178 (3). Anal. Calc. C30H46N2O4 (498.70): C, 72.25; H,
9.30; N, 5.62. Found: C, 72.38; H, 9.45; N, 5.71%.
5-(2-Cyanoethyl) 3-octyl 2,6-dimethyl-4-(30-pyridyl)-1,4-dihy-
dropyridine-3,5-dicarboxylate (4l). Obtained from 1g, 2c and 3b
in 60% yield, mp: 168–169 1C, IR (KBr) n 3271 (NH), 2223
(CN), 1701 (C O), 1636 and 1589 (C C). 1H NMR (DMSO-
Q
Q
d6), d: 9.05 (1H, s, NH), 8.39 (1H, d, J ¼ 1.6 Hz, H20), 8.30 (1H,
dd, J ¼ 4.7 Hz, J ¼ 1.6 Hz, H40), 7.53 (1H, dt, J ¼ 7.8 Hz, J ¼
1.6 Hz, H60), 7.23 (1H, dd, J ¼ 7.8 Hz, J ¼ 4.7 Hz, H50), 4.86
(1H, s, H4), 4.16 (2H, m, OCH2), 4.13 (2H, m, OCH2CH2CN),
2.84 (2H, m, CH2CN), 2.28 (6H, s, 2 ꢂ CH3), 1.48 (2H, m,
OCH2CH2), 1.20 (10H, br. s, 5 ꢂ CH2), 0.85 (3H, t, J ¼ 6. 9
3-(2-Cyanoethyl) 5-methyl 2,6-dimethyl-4-(40-pyridyl)-1,4-di-
hydropyridine-3,5-dicarboxylate (4p). Obtained from 1g, 2a and
3c in 70% yield, mp: 156–157 1C, IR (KBr) n 3262 (NH), 2225
(CN), 1706 and 1683 (C O), 1647 and 1600 (C C); 1H NMR
Hz, CH3); 13C NMR (DMSO-d ), d: 166.5 (C3–C O), 166.1
Q
Q
Q
6
(C5–C O), 148.6 (C20), 147.2 (C40), 143.1 (C10), 147.2, 146.1
(DMSO-d6), d: 9.11 (1H, s, NH), 8.40 (2H, d, J ¼ 5.9 Hz, H30,
H50), 7.14 (2H, d, J ¼ 5.95 Hz, H20, H60), 4.88 (1H, s, H4), 4.16
(2H, t, J ¼ 5.95 Hz, OCH2), 3.55 (3H, s, OCH3), 2.84 (2H, m,
CH2CN), 2.29 (3H, s, CH3), 2.28 (3H, s, CH3); 13C NMR
Q
(C2, C6); 123.4 (C50), 134.8 (C60), 118.6 (CN), 101.4, 100.3
(C3, C5), 63.2 (OCH2), 58.6 (OCH2CH2CN), 36.8 (C4), 31.2
(CH2), 28.6 (2
ꢂ
CH2), 28.2 (OCH2CH2), 25.5
(OCH2CH2CH2), 22.1 (CH2), 18.4 (CH3), 18.1 (CH3), 17.4
(CH2CN), 13.9 (CH2CH3); MS-EI m/z(%) 439 (M1, 3), 420
(10), 361 (100), 326 (8), 282 (10), 249 (27). Anal. Calc.
C25H33N3O4 (439.55): C, 68.31; H, 7.57; N, 9.56. Found: C,
68.43; H, 7.50; N, 9.70%.
(DMSO-d ), d: 167.4 (C5–C O), 166.5 (C3–C O), 155.8
Q Q
6
(C10), 149.8 (C30, C50), 147.1, 146.9 (C2, C6), 122.7 (C20,
C60), 119.9 (CN), 100.9 (C3), 100.5 (C5), 58.9 (OCH2), 51.2
(OCH3), 38.6 (C4), 18.55 (CH3), 18.52 (CH3), 17.7 (CH2–CN);
MS-EI m/z(%) 341 (M1, 2), 263 (100), 224 (52), 210 (33), 192
(10). Anal. Calc. C18H19N3O4 (341.36): C, 63.33; H, 5.61; N,
1231. Found: C, 63.44; H, 5.48; N, 12.43%.
3,5-Dioctyl 2,6-dimethyl-4-(30-pyridyl)-1,4-dihydropyridine-
3,5-dicarboxylate (4m). Obtained from 1c, 2c and 3b in 64%
5-Methyl 3-octyl 2,6-dimethyl-4-(40-nitrophenyl)-1,4-dihydro-
pyridine-3,5-dicarboxylate (4q). Obtained from 1c, 2a and 3d in
yield, mp: 136–137 1C, IR (KBr) n 3226 (NH), 1693 (C O),
Q
1639 and 1636 (C C); 1H NMR (CDCl ), d: 7.97 (1H, s, NH),
Q
3
8.26 (1H, d, J ¼ 1.8 Hz, H20), 8.10 (1H, dd, J ¼ 5.0 Hz, J ¼ 1.8
Hz, H40) 7.43 (1H, dt, J ¼ 7.0 Hz, J ¼ 1.8 Hz, H60), 6.98 (1H,
dd, J ¼ 7.0 Hz, J ¼ 5.0 Hz, H50), 4.75 (1H, s, H4), 3.36 (4H, t,
J ¼ 6.5 Hz, 2 ꢂ OCH2), 2.10 (6H, s, 2 ꢂ CH3), 1.35 (4H, m, 2 ꢂ
OCH2CH2), 1.02 (20H, m, 10 ꢂ CH2), 0.64 (6H, t, J ¼ 6.5 Hz,
2 ꢂ CH3); 13C NMR (CDCl ), d: 166.8 (C5–C O, C3–C O),
70% yield, mp: 127–128 1C, IR (KBr) n 3246 (NH), 1701 (C
Q
O), 1654 and 1602 (C C), 1560 and1344 (NO ); 1H NMR
Q
2
(DMSO-d6), d: 9.03 (1H, s, NH), 8.10 (2H, d, J ¼ 8.7 Hz, H30,
H50), 7.40 (2H, d, J ¼ 8.7 Hz, H20, H60), 4.97 (1H, s, H4), 3.99
(1H, m, OCH2), 3.87 (1H, m, OCH2), 3.54 (3H, s, OCH3), 2.29
(3H, s, CH3–C2), 2.25 (3H, s, CH3–C6), 1.44 (2H, m,
OCH2CH2), 1.08 (10H, br. s, 5 ꢂ CH2), 0.83 (3H, t, J ¼ 7.0
Q
Q
3
147.7 (C20), 145.8 (C2, C6), 145.3 (C40), 143.7 (C10), 135.9
(C60), 122.8 (C50), 101.3 (C5, C3), 63.2 (2 ꢂ OCH2), 37.2 (C4),
31.1 (2 ꢂ CH2), 28.5 (2 ꢂ CH2), 28.5 (2 ꢂ CH2), 28.0 (2 ꢂ
OCH2CH2), 25.4 (2 ꢂ CH2), 21.9 (2 ꢂ CH2), 18.2 (2 ꢂ CH3),
13.5 (2 ꢂ CH2CH3); MS-EI m/z(%) 498 (M1, 2), 420 (100), 385
(10), 308 (12), 229 (6). Anal. Calc. C30H46N2O4 (498.70): C,
72.25; H, 9.30; N, 5.62. Found: C, 72.38; H, 9.18; N, 5.77%.
Hz, CH3); 13C NMR (DMSO-d ), d: 167.0 (C5–C O), 166.5
Q
6
(C3–C O), 155.7 (C40), 146.6, 146.4 (C2, C6), 145.7 (C10),
Q
128.7 (C20, C60), 123.7 (C30, C50), 100.7, 100.6 (C3, C5), 63.6
(OCH2), 51.2 (OCH3), 39.6 (C4), 31.5 (CH2), 28.7 (CH2), 28.6
(CH2), 28.2 (OCH2CH2), 25.5 (CH2), 22.1 (CH2), 18.3 (CH3–
C6), 18.2 (CH3–C2), 13.9 (CH2CH3); MS-EI m/z(%) 444 (M1,
3), 331 (10), 322 (100), 287 (8), 210 (36), 178 (6). Anal. Calc.
C24H32N2O6 (444.52): C, 64.85; H, 7.26; N, 6.30. Found: C,
64.70; H, 7.15; N, 6.37%.
3-Decyl 5-octyl 2,6-dimethyl-4-(30-pyridyl)-1,4-dihydropyri-
dine-3,5-dicarboxylate (4n). Obtained from 1d, 2c and 3b in
70% yield, mp: 133–134 1C, IR (KBr) n 3265 (NH), 1699 and
1687 (C O), 1643 and 1587 (C C); 1H NMR (CDCl3), d:
3-(2-Cyanoethyl) 5-methyl 2,6-dimethyl-4-(40-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylate (4r). Obtained from 1g,
2a and 3d in 72% yield, mp: 150–152 1C, IR (KBr) 3248 (NH),
2225 (CN), 1699, 1681 (C O), 1651, 1602 (C C), 1510, 1344
Q
Q
6.55 (1H, s, NH), 8.51 (1H, d, J ¼ 1.8 Hz, H20), 8.38 (1H, dd,
J ¼ 5.0 Hz, J ¼ 1.8 Hz, H40) 7.83 (1H, dt, J ¼ 7.8 Hz, J ¼ 1.8
Hz, H60), 7.30 (1H, dd, J ¼ 7.8 Hz, J ¼ 5.0 Hz, H50), 5.03 (1H,
Q
Q
1574
N e w J . C h e m . , 2 0 0 5 , 2 9 , 1 5 6 7 – 1 5 7 6

View Article Online
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23, 293–303.
(NO2); 1H NMR (DMSO-d6), d: 9.19 (1H, s, NH), 8.09 (2H, d,
J ¼ 8.7 Hz, H30, H50), 7.44 (2H, d, J ¼ 8.7 Hz, H20, H60), 4.98
(1H, s, H4), 4.14 (2H, t, J ¼ 5.3 Hz, OCH2), 3.53 (3H, s,
OCH3), 2.83 (2H, m, CH2CN), 2.29 (3H, s, CH3–C2), 2.28 (3H,
4
5
6
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Tetrahedron, 2002, 58, 8099–8106; (g) for a recent review see:
R. Lavilla, J. Chem. Soc., Perkin Trans. 1, 2002, 1141–1156; (h)
A. Zarghi, H. Sadeghi, A. Fassihi, M. Faizi and A. Shafiee, Il
Farmaco, 2003, 58, 1077–1081; (i) R. Radhakrishnan Sridhar and
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P. Ramarao, Neuropharmacology, 2002, 42, 467–475; (c) F.
Crespi, E. Vecchiato, C. Lazzarini, M. Andreli and G. Gaviraghi,
J. Cardiovasc. Pharmacol., 2002, 39, 471–477; (d) M. Lohn, U.
Muzzulini, K. Essin, S. Y. Tsang, T. Kirsch, J. Litteral, P.
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F. C. Luft, Y. Huang and M. Gollasch, J. Hypertens., 2002, 20,
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Dehpour and A. Shafiee, Il Farmaco, 2004, 59, 261–269; (f) R.
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3423–3430.
s, CH3–C6); 13C NMR (DMSO-d ), d: 167.0 (C5–C O), 166.2
Q
6
(C3–C O), 155.2 (C40), 147.7 (C10), 146.5, 146.0 (C2, C6),
Q
128.8 (C20, C60), 123.8 (C30, C50), 119.9 (CN), 100.1 (C3, C5),
58.9 (OCH2), 51.2 (OCH3), 39.8 (C4), 18.8 (CH3–C2), 18.6
(CH3–C6), 17.7 (CH2–CN); MS-EI m/z(%) 385 (M1, 3), 263
(100), 210 (27), 178 (6). Anal. Calc. C19H19N3O6 (385.37): C,
59.22; H, 4.92; N, 10.90. Found: C, 59.33; H, 4.81; N, 10.83%.
Crystal structure determination of 4n
Crystal data. C32H50N2O4, M ¼ 526.74, monoclinic, a ¼
22.8754(7), b ¼ 16.1015(12), c ¼ 8.7774(16) A, b ¼ 90.021(7)1,
V ¼ 3233.0(6) A3, T ¼ 293(2) K, space group P21/c (no. 14),
Z ¼ 4, m(Cu-Ka) ¼ 0.542 mmꢀ1, 7434 reflections measured,
5718 unique (Rint ¼ 0.0529) which were used in all calculations.
The final R(F2) and wR(F2) values were 0.0856 and 0.2182
(observed data), respectively. The high R-values of the refine-
ment are due to the disorder of the long alkyl side chains in the
crystal structure.z
7
Acknowledgements
8
9
I. T. Mak, J. Zhang and W. B. Weglicki, Pharmacol. Res., 2002,
45, 27–33.
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Fruttero and A. Gasco, Pharm. Res., 2001, 18, 987–991.
Support of this work by Proyectos Alma Mater (CUBA) and
MCyT of Spain (PQU2002-00855) is gratefully acknowledged.
M. Suarez is grateful to SAB2003-0161 from Secretaria de
Estado de Universidad e Investigacion del Ministerio de
Educacion y Ciencia de Espana. HNdA is indebted to
the Postdoctoral mandate fellowship of the Research Funds
(Onderzoeksfonds), K. U. Leuven, Belgium.
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