4-Aminopiperidine derivatives as a new class of potent cognition enhancing drugs

Article abstract of DOI:10.1016/S0960-894X(03)00437-2

Extrusion of one of the nitrogens of the piperazine ring of potent nootropic drugs previously described gave 4-aminopiperidine analogues that maintained high cognition enhancing activity in the mouse passive avoidance test. One of the new compounds (9, active at 0.01 mg/kg ip) may represent a new lead for the development of cognition enhancers useful to treat the cognitive deficit produced by neurodegenerative pathologies like Alzheimer's disease.

Full text of DOI:10.1016/S0960-894X(03)00437-2

Bioorganic & Medicinal Chemistry Letters 13 (2003) 2303–2306
4-Aminopiperidine Derivatives as a New Class of Potent Cognition
Enhancing Drugs
Dina Manetti,a Elisabetta Martini,a Carla Ghelardini,b Silvia Dei,a Nicoletta Galeotti,b
Luca Guandalini,a Maria Novella Romanelli,a Serena Scapecchi,a Elisabetta Teodori,a
Alessandro Bartolinib and Fulvio Gualtieria,*
a
`
Dipartimento di Scienze Farmaceutiche, Universita di Firenze, Via G. Capponi 9, I-50121 Firenze, Italy
`
Dipartimento di Farmacologia Preclinica e Clinica, Universita di Firenze, Viale G. Pieraccini 6, I-50139 Firenze, Italy
b
Received 15 January 2003; revised 31 March 2003; accepted 24 April 2003
Abstract—Extrusion of one of the nitrogens of the piperazine ring of potent nootropic drugs previously described gave 4-amino-
piperidine analogues that maintained high cognition enhancing activity in the mouse passive avoidance test. One of the new com-
pounds (9, active at 0.01 mg/kg ip) may represent a new lead for the development of cognition enhancers useful to treat the
cognitive deficit produced by neurodegenerative pathologies like Alzheimer’s disease.
# 2003 Elsevier Science Ltd. All rights reserved.
Cognitive dysfunction is one of the main symptoms
accompanying ageing, stroke, head injury and neuro-
degenerative diseases like Alzheimer’s disease. Cogni-
tion enhancers,1 often referred to as nootropics, can be
defined as drugs able to facilitate attentional abilities
and acquisition, storage and retrieval of information,
and to attenuate the impairment of cognitive functions
associated with age and age-related pathologies.2 By
definition, this class of drugs improves declining of
cognitive functions but does not change the rate of
progression of neurodegeneration.3
Continuing to explore structure–activity relationships
in the series of piperazine compounds, we have
designed a new series of compounds carrying a
4-aminopiperidine ring. Formally, they can be con-
sidered analogues where one of the nitrogen atoms of
piperazine has been moved out of the six-member cycle
(Chart 2). Besides the side chains that were present in
the leads DM232 and DM235, we have added the iso-
propylsulfonyl group, present in a series of compounds
active as allosteric modulators of AMPA receptor.11,12
As a matter of fact, an ongoing research aimed to
define the mechanism of action of DM232, DM235
and related compounds seems to suggest the involve-
ment of AMPA receptors. (C. Ghelardini, personal
communication).
Recently, we described a new class of compounds with a
1,4-diazabicyclo[4.3.0]nonan-9-one structure4 (Chart 1)
that showed a very potent cognition enhancing activity
on mouse passive avoidance assay. These compounds
were related to the family of piracetam-like
nootropics1,5À7 by the presence of the 2-pyrrolidinone
ring. However, high activity was maintained when the
2-pyrrolidinone ring was opened to give the corre-
sponding piperazine derivatives8 (Chart 1), suggesting
that in this class of compounds the 2-oxopyrrolidine
moiety is not critical for pharmacological action. Both
series of compounds were effective also in other beha-
vioural tests such as social learning and Morris water
maze.8À10
Compounds 5, 6, 11 and 12 have been synthesised as
shown in Scheme 1. 1-Acetyl-4-piperidone and 1-ben-
zoyl-4-piperidone, commercially available, and 1-pro-
pionyl-4-piperidone (17), obtained from 4-piperidone
monohydrate hydrochloride with propionyl chloride,
were transformed in 18–20 by reductive alkylation
with benzylamine, titanium(IV) isopropoxide and
sodium cyanoborohydride.13 The compounds were
then hydrogenated14 to obtain 21–23. Compound 2315
was treated with acetyl or propionyl chloride to
obtain 5 and 6 respectively, while 2116 and 22 were
treated with 4-fluorobenzenesulfonyl chloride to give
1117 and 12.
*Corresponding author. Tel.: +39-05527-57295; fax: +39-0552-
40776; e-mail: fulvio.gualtieri@unifi.it
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00437-2

2304
D. Manetti et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2303–2306
The synthetic pathways used to obtain compounds 7–10
and 13–16 are reported in Scheme 2. Commercially
available 4-amino-1-benzylpiperidine was treated with
the proper acyl chloride or isopropylsulfonyl chloride;
the intermediates 24,18 25,19 2620 and 30 were then
hydrogenated to give 27,21 28,22 2923 and 31. Inter-
mediates 27 and 28 were treated with 4-fluoro-
benzenesulfonyl chloride24 to give 9 and 10 and with
isopropylsulfonyl chloride to give 13 and 14, whereas 29
was treated with acetyl or propionyl chloride to give 7
and 8. Finally, reaction of 31 with acetyl or propionyl
chloride gave 15 and 16 respectively. Chemical and
physical characteristics of compounds 5–16 are reported
in Table 1.
Chart 1.
Cognition enhancing activity was evaluated by the anti-
amnesic test (mouse passive-avoidance test). The test
was performed according to the step-through method
described by Jarvik and Kopp,25 slightly modified by
us.4,26 In short, mice receive a punishment when enter-
ing a dark room in the training session and remember it
in the session of the following day, unless their memory
is impaired by the amnesic drug. The parameter mea-
sured is the entry latency time (expressed in seconds)
occurring between the time the mouse is placed in the
light and the time it enters the dark room. On the first
day there is the training session, while on the second day
the mice are placed again in the light and the new
latency time is measured on animals treated or
untreated with the nootropic drug. A drug is active
when, at a given dose, it restores in the scopolamine-
treated mice the retention time of those treated only
with saline. The highest active doses of the investigated
Chart 2.
Scheme 1. (a) CH3CH2COCl, K2CO3, CHCl2 60 ꢀC: 17, 72%; (b)
benzylamine, (iPrO)4Ti, NaBH3CN, EtOH: 18, 85%, 19, 68%, 20,
26%; (c) HCOONH4, Pd/C 10%, MeOH: 21, 74%, 22, 97%, 23, 75%;
(d) CH3COCl, NaHCO3, CHCl3: 5, 45%, CH3CH2COCl, N(Et)3,
CHCl3: 6, 94%; (e) 4-F-benzenesulfonyl chloride, N(Et)3, CH3CN: 11,
86%, 12, 82%.
Scheme 2. (a) XCOCl, NaHCO3, CHCl3: 24, 79%, 25, 99%, NEt3,
CHCl3: 26, 99%, 15, 55%, 16, 42%; (b) HCOONH4, Pd/C 10%,
MeOH: 27, 98%, 28, 73%, 29, 88%, 31, 50%; (c) isopropylsulfonyl
chloride, N(Et)3, CH3CN: 30, 57%; (d) 4-F-benzenesulfonyl chloride
or isopropylsulfonyl chloride, N(Et)3, CH3CN: 9, 59%, 10, 84%, 13,
43%, 14, 76%; (e) XCOCl, N(Et)3, CHCl3: 7, 47%, 8, 97%.

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)
1. Gualtieri, F.; Manetti, D.; Romanelli, M. N.; Ghelardini,
C. Curr. Pharm. Des. 2002, 8, 125.
1st day
Á
2. Parnetti, L.; Senin, U.; Mecocci, P. Drugs 1997, 53, 752.
3. Hirai, S. Alz. Dis. Ass. Dis. 2000, 14, S11.
4. Manetti, D.; Ghelardini, C.; Bartolini, A.; Bellucci, C.; Dei,
S.; Galeotti, N.; Gualtieri, F.; Romanelli, M. N.; Scapecchi,
S.; Teodori, E. J. Med. Chem. 2000, 43, 1969.
5. Froestl, W.; Maitre, L. Pharmacopsychiatry 1989, 22, 54.
6. Gouliaev, A. H.; Binau Moster, J.; Vedso, M.; Senning, A.
Org. Prep. Proceed. Int. 1995, 27, 273.
7. Gouliaev, A. H.; Senning, A. Brain Res. Rev. 1994, 19, 180.
8. Manetti, D.; Ghelardini, C.; Bartolini, A.; Dei, S.; Galeotti,
N.; Gualtieri, F.; Romanelli, M. N.; Teodori, E. J. Med.
Chem. 2000, 43, 4499.
9. Ghelardini, C.; Galeotti, N.; Gualtieri, F.; Manetti, D.;
Bucherelli, C.; Baldi, E.; Bartolini, A. Drug Dev. Res. 2002, 56,
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.;
Bleisch, T. S.; Cantrell, B.; Simon, R.; Zarrinmayeh, H.;
Baker, S. R.; Gates, M.; Tizzano, J. P.; Bleakman, D. J. Med.
Chem. 2000, 43, 4354.
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.

2306
D. Manetti et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2303–2306
12. Zarrinmayeh, H.; Bleakman, D.; Gates, M.; Yu, H.; Zim-
merman, D. M.; Ornstein, P. L.; McKennon, T.; Arnold,
M. B.; Wheeler, W. J.; Skolnick, P. J. Med. Chem. 2001, 44,
302.
13. Mattson, R. J.; Pham, H. M.; Lenck, D. J.; Cowen, K. A.
J. Org. Chem. 1990, 55, 2552.
24. Stetter, H.; Reinartz, W. Chem. Ber. 1972, 105, 2773.
25. Jarvik, M. E.; Kopp, R. Psycol. Rep. 1967, 21, 221.
26. The apparatus for the passive avoidance test consists of
a two-compartment acrylic box with a lighted compartment
connected to a darkened one by a guillotine door. In the
original method, mice received a punishing electrical shock
as soon as they entered the dark compartment, while in our
modified method, after entry into the dark compartment,
mice receive a non-painful punishment consisting of a fall
(from 40 cm) into a cold water bath (10 ꢀC). For this purpose,
the dark chamber was constructed with a pitfall floor. The
latency times for entering the dark compartment were mea-
sured in the training test (first day) and after 24 h in the reten-
tion test (second day). Mice who did not enter after 60 s latency
were excluded from the experiment. For memory disruption,
mice were ip injected with the amnesic drug scopolamine. All
investigated drugs, dissolved in saline, were given ip 20 min
before the training session, while amnesic drug was injected
immediately after termination of the training session. The
maximum entry latency allowed in the retention session was
120 s. The degree of received punishment memory (fall into cold
water) was expressed as the increase in seconds between train-
ing and retention latencies.
14. ElAim, B.; Anantharanaiah, G. M.; Royer, G. P.; Means,
G. E. J. Org. Chem. 1979, 44, 3442.
15. Bhattacharayya, S.; Neidigh, K. A.; Avery, M. A.; Wil-
liamson, J. S. Syn. Lett. EN 1999, 11, 1781.
16. Suedo, N. Eur. Pat. Appl. EP 625,507, 1994.
17. Yamada, A.; Aoki, S. PCT Int. Appl. WO 0,042,011,
2000.
18. Archibald, J.; Fairbrother, P.; Jackson, J. L. J. Med.
Chem. 1974, 17, 739.
19. Peglion, J. L.; Colpaert, F. Eur. Pat. Appl. EP 457,686,
1991.
20. Harper, N.; Chignell, C. F. J. Med. Chem. 1964, 7, 729.
21. Zenitz, B. L. US 3,124,586,1964; Chem Abst. 1964, 61,
18188.
22. Schnorrenberg, G.; Dollinger, H.; Esser, F.; Brien, H.;
Jung, B.; Speck, G. Gen. Offen. DE 19,519,245, 1996.
23. Archibald, J. L.; Alps, B. J.; Cavalla, J. F.; Jackson, J. L.
J. Med. Chem. 1971, 14, 1054.
27. Irwing, S. Psychopharmacology 1966, 13, 222.