D. Manetti et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2303–2306
Table 1. Chemical and physical characteristics of compounds 5–16
2305
The data reported show that the new series of com-
pounds maintains potent cognition enhancing activity,
being effective at doses between 0.01 and 10 mg/kg ip,
while a typical nootropic drug like piracetam, under the
same conditions in experiments performed in parallel
with our compounds, is active at a dose of 30 mg/kg ip.8
In particular, compound 9 is active at a dose of 0.01 mg/
kg ip, which is in the same range of that of DM 235, the
most potent among the parent compounds.8 Therefore,
it may be concluded that transforming the piperazine
moiety into a 4-aminopiperidine one does not alter the
pharmacological behaviour of the original compounds.
In the new series, the two nitrogen atoms are not
equivalent and two regio-isomers are possible for each
couple of substituents. Overall, the regio-isomers show
similar potencies as cognition enhancers. In this respect,
the isomers bearing the aromatic substituents on the
piperidine nitrogen seem to be slightly more potent
(compare 9/11, 10/12, 13/15) than their counterparts,
even if the reverse is true for the couple 5/7 and the
couples 6/8 and 14/16 show the same potency. Finally,
the introduction of the isopropylsulfonic group did not
produce remarkable results, even if compound 13 was
found active at the dose of 1 mg/kg ip.
N
R1
R2
Mp (ꢀC)a
Analysisb
5
6
7
8
COCH3
COC2H5
A
A
136–137
70–71
C14H18N2O2
C15H20N2O2
C14H18N2O2
A
COCH3
COC2H5
B
133–135
107–108
187–188
162–163
131–132
135–136
90–91
85–86
78–79
79–80
A
COCH3
COC2H5
B
C15H20N2O2
9
C13H17FN2O3S
C14H19FN2O3S
C13H17FN2O3S
C14H19FN2O3S
C10H20N2O3S
C11H22N2O3S
C10H20N2O3S
C11H22N2O3S
10
11c
12
13
14
15
16
B
COCH3
COC2H5
C
B
COCH3
COC2H5
C
C
COCH3
COC2H5
C
aAll compounds crystallized from petrol ether.
bThe analytical results are withinÆ0.4% of the theoretical values. 1H
and 13C NMR and IR spectra are consistent with the proposed structure.
cThis compound is among the ones claimed in a recent patent (see ref 17).
In conclusion, we have identified a new class of potent
cognition enhancing drugs, among which compound 9
deserves further study and can be a useful new lead to
develop drugs with cognition enhancing properties.
compounds did not altered animals’ gross behaviour
and were devoid of any behavioural side effect, as
demonstrated by the Irwing test.27 The results obtained
with the new molecules are reported in Table 2, com-
pared with those of the parent compounds 1–4.
Acknowledgements
This research was financed with the funds of Italian
Ministry of Instruction University and Research
(MIUR).
Table 2. Nootropic effect of compounds 1–4 and 5–16 on mouse
passive avoidance test, using scopolamine (S) as amnesing drug
References and Notes
Druga (number Minimal effective
Entry latency (s)
2nd day
of animals)
dose mg/kg (ip)
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1st day
Á
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N.; Gualtieri, F.; Romanelli, M. N.; Teodori, E. J. Med.
Chem. 2000, 43, 4499.
9. Ghelardini, C.; Galeotti, N.; Gualtieri, F.; Manetti, D.;
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23.
10. Ghelardini, C.; Galeotti, N.; Gualtieri, F.; Romanelli,
M. N.; Bucherelli, C.; Baldi, E.; Bartolini, A. N.S. Arch.
Pharmacol. 2002, 365, 419.
11. Ornstein, P. L.; Zimmerman, D. M.; Arnold, M. B.;
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Saline (13)
Scopolamine (6)
1b
—
1.5
10
0.01–0.001
0.01
0.01
10
0.1
1
0.1
0.01
0.1
0.1
10
1
10
10
10
15.0Æ5.9 95.6Æ8.8
80.6
16.6Æ4.7 44.5Æ8.3*27.9
2 (DM235)b,c
3b
4b
5 (18)
6 (7)
7 (11)
8 (7)
9 (9)
10 (10)
11 (8)
12 (16)
13 (21)
14 (19)
15 (18)
16 (16)
12.8Æ4.5 113.5Æ10.2** 100.7
18.0Æ4.7 121.0Æ11.3** 103.0
16.5Æ3.7 99.8Æ9.9**
83.3
19.7Æ5.3 122.8Æ10.4** 103.1
14.5Æ3.8 90.6Æ12.5*** 76.1
17.6Æ3.9 103.4Æ9.5**
23.5Æ5.3 126.8Æ13.8**
15.6Æ4.7 108.2Æ8.4**
14.3Æ2.8 89.7Æ8.5***
14.2Æ3.5 102.8Æ10.5**
15.1Æ3.7 99.3Æ11.3**
14.5Æ3.2 96.9Æ10.6**
85.8
92.6
103.0
75.4
88.6
84.2
82.4
*P<0.01 with respect to mice treated with saline. **P<0.01;
***P<0.05 with respect to mice treated with scopolamine.
aAll compounds dissolved in saline.
bSee ref 9.
cSee ref 10.