Bonet and coworkers
560
Results and Discussion
and norchlorcyclizine (1: R’ =
=
= H). These
drugs are more effective than their corresponding dechlori-
nated analogs in lowering serum cholesterol level in
Chemistry
cholesterolemic mice
found about hypocholesterolemic activity in cinnarizine, its
monochlorinated analog clocinizine (1: R’ = 4-Cl,
= cinnamyl) slightly reduces serum cholesterol concen-
tration, also in normocholesterolemic
.
Moreover, whilst no reports are
As is outlined in Scheme 1, the first step to all products
were the corresponding monosubstituted piperazines 3,
which were prepared by a known procedure’), reacting the
appropriate benzhydryl chloride 2 with an excess of pip
erazine.
= H,
Clocinizine’s activity seems to be weaker than the ob-
served for the
4 were prepared
compounds reported in the
through a
reaction between 2-thienylacetylene,
present paper, but no direct comparison is possible because
the different model employed and, thus, further experiments
are required to elucidate whether the second chlorine atom
contributes to an enhancement of the activity.
formaldehyde and the adequate 3 in the presence of
drous cupric sulfate, 2-thienylacetylene was obtained by
coupling 2-iodothiophene and trimethylsilylacetylene ac-
cording
The 2-thienylpropenylpiperazines 6 were prepared by re-
duction of the corresponding alkynyl compounds 4 using
Experimental Part
lithium aluminium hydride*). The resulting products show
E
configuration.
The
piperazine (5) was prepared reacting 3b with
Melting points: in open capillaries, Biichi-Tottoli apparatus,
Chromatography: silica gel (Merck 60.
mesh), 5 cm
spectra:
diameter columns.
pressure. Flow rate
propynyl bromide in the presence of anhydrous sodium car-
bonate and using potassium iodide as catalyst.
Most of the final products (except 5) showed quick de-
composition signs at room temp., for this reason all of them
were stored and pharmacologically tested as their
Perkin-Elmer 638 spectrophotometer.- ‘H-NMR spectra: Perkin-Elmer
24 spectrometer, TMS as internal standard.- Elemental analyses: lnstitut de
de Catalunya. C.S.I.C. Barcelona (Spain).
acid salts.
physical and pharmacological data of these
A mixture of
(3. g. 29.2
I
salts are summarized in Table 1.
erazine
(7.37 g. 29.2
anhydrous
paraformaldehyde (1.19 g, 39.5 mmol
(0.34 g). and dry peroxide-free THF
Pharmacology
was stirred and heated under reflux for 5 h 45 min. After cooling, the result-
ing mixture was diluted with (400 filtered, and extracted with
The acid extract was treated with
and extracted with (4 x
HCI 2.5
(2 x 250
ro render
The assays were carried out in groups of six mice made
hypercholesterolemic by being fed a high cholesterol-cholic
acid diet for seven days. The test compound was adminis-
tered orally in the sixth and seventh days a half dose each
time. After fasting overnight, serum cholesterol and heparin
precipitating lipoproteins (HPL, corresponding to LDL and
VLDL fractions) concentrations were measured. Reduction
in these concentrations, in relation to hypercholesterolemic
control animals, by more than 15 and 20%. respectively,
enough 5 M
The org. layer was dried
and the solvent evaporated to give a
g of silica gel, using
brown oil (10.55 g). Chromatography on
gave the title product as a clear oil (9.88 g.
which
was convetted in the corresponding dimaleate. A sample of the free base re-
covered from an analytical sample of the dimaleate showed the following
data:
(neat):
3020; 2930;
‘H-NMR
4.2
1595: 1490:
= 2.25 (m,
6.9-7.5 (m.
1005: 845; 755;
3.5 (s,
745; 700
2H.
IH,
H. arom.).
indicates significant activity
confidence test).
Values obtained for each of the tested compounds are dis-
1
played in Table 1. The ratio of the
between treated and control animals
rates
calculated
In a similar way as in the previous case, 4b (6.77 g, 87%) was prepared
from the observed data, are also shown in this table. A value
for this ratio below 0.92 suggests a possible increase in
serum HDL fraction.
from 3b (5.63 g, 17.5 mmol).
(1.89 g. 17.5 mmol),
(0.52 g). and THF
paraformaldehyde (0.76
(90
25.2 mmol
4b was obtained as a low melting point solid: mp.
47°C
1005; 805; 700 cm”.-
3.45
Except
the tested compounds were able, in more or
(neat): 2930;
1485;
less extent, to reduce both cholesterol and HPL serum le-
vels. Two of them (5 and 6b) were more potent than a
commercial drug as bezafibrate and showed also better
NMR
= 2.5
4.1 (s.
6.8-7.1 (m. 11
arom.).
(5)
Dichlorosubstituted compounds were more active than
chlorine lacking ones (4b vs. 4a and 6b vs. 6a). A similar
observation has been reported for the monochlorinated com-
In a flask fitted with a
bromide (4.92 g. 25.2
separator were. poured
(6.00 g, 18.7 mmol),
anhydrous (8.32 g), several crystals
This mixture was stirred and heated under
pounds chlorcyclizine (1:
=
= H, = methyl)
of
and toluene (175
The
are reduced by
to the corresponding property] compounds in good yields and under mild conditions. This is a
recent finding of our laboratory and experiments to elucidate the scope and features of this reaction are in progress. The results will be published soon.
Arch. Pharm.
(1991)
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