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V. Calderone et al. / European Journal of Medicinal Chemistry 41 (2006) 761–767
Table 2
sodilators) and of the reduction of the vasorelaxing effects
1H-NMR in DMSO-d6, ppm from TMS
found in the analogous methoxylated compounds 6b and 6c.
On the contrary, the weak vasorelaxing efficacy of compound
7a (bearing an OH group) is not lowered in the methoxylated
analogue 6a. In other words, the presence of the hydroxy group
in compound 7a does not seem to represent a useful require-
ment, while it is important in compounds 7b and 7c.
It can be suggested that the position ortho of the nitrogen
atom in the pyridine ring could ensure an intramolecular inter-
action with the phenolic hydroxy group, so that this hydroxy
group appears less available for a H-bond interaction with the
receptor site.
The introduction of a thiazole ring in the basic side of the
amide linker seems to be well tolerated, since compound 7d
showed full vasorelaxing effects. The replacement of the hy-
droxy group of 7d with a methoxy substituent (compound
6d) caused a negative impact on the vasorelaxing activity.
Thus, the presence of the nitrogen atom in position ortho of
the thiazole ring of compound 7d does not seem to determine
a deleterious impact, as above observed for compound 7a. This
different behaviour could be probably explained by the basic
properties of the thiazole ring (very lower than those of the
pyridine ring), which could not be sufficient to ensure a signif-
icant interaction with the phenolic hydroxy group.
3a (C11H8ClNO3): (6.72 m, 7.32 d, 7.95 d, 3 H, furyl); (6.93 d, 7.02 d, 7.98 s,
3 H, arom.); 9.1 (NH); 10.5 (OH)
3b (C11H8ClNO2S): (7.21 d, 7.68 d, 7.86 d, 3 H, thienyl); (6.92 d, 7.07 d, 7.99
s, 3H, arom.); 9.5 (NH); 10.1 (OH)
3c (C11H9ClN2O2): (6.18 m, 6.89 d, 7.00 d, 3 H, pyrryl); 6.92 d, 7.03 d, 7.82
s, 3 H, arom.); 9.0 (NH); 10.2 (OH); 11.8 (NH)
3d (C12H9ClN2O2): (7.74 m, 8.17 m, 8.44 d, 8.77 d, 4 H, 2-pyridyl); (6.92 d,
7.09 d, 8.05 s, 3H, arom.); 10.4 (NH); 10.6 (OH)
3e (C12H9ClN2O2): (7.59 m, 8.29 d, 8.76 d, 9.10 s, 4 H, 3-pyridyl); 56.92 d,
7.10 d, 7.77 s, 3 H, arom.); 9.9 broad (NH, OH)
3f (C12H9ClN2O2): (7.84 d, 8.76 d, 4 H, 4-pyridyl); (6.92 d, 7.11 d, 7.75 s, 3
H, arom.); 10.0 broad (NH, OH)
6a (C13H11ClN2O2): 3.96 (s, 3H, OMe); [7.17 d, 7.87 d, 8.20 d, 8.37 d, 4 H,
N-(2-pyridyl)]; (7.27 d, 7.60 d, 7.78 s, 3 H, arom.); 10.5 (NH)
6b (C13H11ClN2O2): 3.88 (s, 3 H, OMe); [7.39 q, 8.16 d, 8.34 d, 8.84 s, 4 H,
N-(3-pyridyl)]; (7.22 d, 7.57 d, 7.64 s, 3 H, arom.); 10.4 (NH)
6c (C13H11ClN2O2): 3.87 (s, 3 H, OMe); [7.68 d, 8.46 d, 4 H, N-(4-pyridyl)];
(7.22 d, 7.55 d, 7.59 s, 3 H, arom.); 10.5 (NH)
6d (C11H9ClN2O2S): 3.92 (s, 3 H, OMe); [7.33 d, 7.56 d, 2 H, N-(2-
thiazolyl)]; (7.25 d, 7.62 d, 7.69 s, 3 H, arom.); 4.12 broad (NH)
6e (C12H15ClN2O3): 3.82 (s, 3 H, OMe); (2.84 m, 3.64 m, 8 H, morpholine);
(7.17 d, 7.46 s, 7.47d, 3 H, arom.); 9.8 broad (NH)
6f (C12H15ClN2O2): 3.85 (s, 3 H, OMe); (2.01 t, 3.56 t, 8 H, pyrrolidine);
(7.22 d, 7.59 d, 7.64 s, 3 H, arom.); 11.7 (NH)
7a (C12H9ClN2O2): [7.18 m, 7.86 t, 8.24 d, 8.36 d, 4 H, N-(2-pyridyl)]; (7.08
d, 7.49 d, 7.97 s, 3 H, arom.); 10.9 (NH); 12.1 (OH)
7b (C12H9ClN2O2.HBr): [8.05 m, 8.68 d, 8.71 d, 9.34 s, 4 H, N-(3-pyridyl)];
(7.10 d, 7.50 d, 7.82 s, 3 H, arom.); 11.0 (NH); 11.5 broad (OH); 13.4 b (H,
hydrobromide)
7c (C12H9ClN2O2.HBr): [7.72 d, 8.48 d, 4 H, N-(4-pyridyl)]; (7.00 d, 7.47 d,
7.81 s, 3 H, arom.); 10.8 (NH); 3.8 broad (OH)
The introduction of morpholine and pyrrolidine heterocycles
in the basic side of the amide spacer (compounds 7e and 7f,
respectively), led to ineffective (7e) or weakly effective (7f)
vasodilators. Again, the weak vasorelaxing effects of 7f were
completely abolished in the methoxy analogue 6f.
7d (C10H7ClN2O2S): [7.27 d, 7.58 d, 2 H, N-(2-thiazolyl)]; (7.01 d, 7.46 d,
7.91 s, 3 H, arom.)]; 12.6 broad (NH, OH)
7e (C11H13ClN2O3): (2.88 m, 3.66 m, 8 H, morpholine); (6.95 d, 7.42 d, 7.84
s, 3 H, arom.); 9.8 broad (NH); 12.2 broad (OH)
7f (C11H13ClN2O2): (1.81 s, 2.94 s, 8 H, pyrrolidine); 6.91 d, 7.37 d, 7.82 s, 3
H, arom.); 9.6 broad (NH); 12.3 broad (OH)
As a preliminary explanation for the fall in vasorelaxing
activity of 7e and 7f, it can be observed that the heterocyclic
moieties of these compounds (morpholine and pyrrolidine) are
devoid of any insaturation and this absence of olephynic bonds
could be the cause of the inadequate function of such substitu-
ents. Indeed, as described in literature [19–21] and in our pre-
vious reports [12,15], an aromatic ring (often substituted with a
electron withdrawing group) is a fundamental element for the
activity, because of its possible involvement in π−π stacking
interaction with a receptorial area.
To date, our studies on these derivatives do not allow us to
recognise whether the influence of the amide linker is due to
the presence of such a specific function or to the ability to
ensure a correct 3D arrangement of the molecule according to
the receptorial site.
Table 3
Experimental results: efficacy (Emax %) and potency values of the tested
compounds
Compounds
Emax %
100
95 11
pIC50
3a
3b
3c
3d
3e
4,82 0.06
4,93 0.05
4,87 0.08
N.C.
4,99 0.17
4,57 0.26
4,77 0.09
N.C.
75
41 16
61
4
2
3f
55 10
67 12
37 14
6a
6b
6c
6d
6e
Future synthetic efforts will be addressed to further modifi-
cation of the amide structure in order to define the pharmaco-
phoric model and the role of the amide linker.
84
2
4,91 0.02
4,51 0.07
N.C.
51 14
Ineffective
Ineffective
52 15
6f
N.C.
5. Experimental protocols
7a
7b
7c
7d
7e
4,51 0.07
4,82 0.03
4,93 0.03
4,80 0.02
N.C.
99
98
97
1
2
3
5.1. Chemistry
Ineffective
45 13
100
Melting points were determined on a Kofler hot-stage and
are uncorrected. IR spectra in nujol mulls were recorded on a
7f
NS1619
N.C.
5.23 0.07
1
Mattson Genesis series FTIR spectrometer. H NMR spectra
N.C. indicates that the parameter of potency could not be calculated because
of the low efficacy (<50%).
were recorded with a Varian Gemini 200 spectrometer in