Unique spirocyclopiperazinium salt. Part 2: Synthesis and structure-activity relationship of dispirocyclopiperazinium salts as analgesics

Article abstract of DOI:10.1016/S0960-894X(03)00213-0

Three series of spirocyclopiperazinium derivatives 5a-d, 6a-f and 17a-d were synthesized and evaluated for their in vivo analgesic activities. Compounds 5a, 17a and 17b exhibited excellent analgesic activity. Two important structure-activity relationships were observed from this study: (1) the quaternary ammonium functionality is a critical pharmacophore for analgesic activity; (2) it is important to adjust the lipophilic property of compounds to improve analgesic activity.

Full text of DOI:10.1016/S0960-894X(03)00213-0

Bioorganic & Medicinal Chemistry Letters 13 (2003) 1729–1732
Unique Spirocyclopiperazinium Salt. Part 2: Synthesis and
Structure–Activity Relationship of Dispirocyclopiperazinium Salts
as Analgesics
Xin Wang, Feng-Li Gao, Hong-Bin Piao, Tie-Ming Cheng and Run-Tao Li*
School of Pharmaceutical Sciences, Peking University, Beijing 100083, PR China
Received 10 January 2003; accepted 1 March 2003
Abstract—Three series of spirocyclopiperazinium derivatives 5a–d, 6a–f and 17a–d were synthesized and evaluated for their in vivo
analgesic activities. Compounds 5a, 17a and 17b exhibited excellent analgesic activity. Two important structure–activity relation-
ships were observed from this study: (1) the quaternary ammonium functionality is a critical pharmacophore for analgesic activity;
(2) it is important to adjust the lipophilic property of compounds to improve analgesic activity.
# 2003 Elsevier Science Ltd. All rights reserved.
Introduction
N1,N1-Dimethyl-N4-phenylpiperazinium iodide (DMPP,
1) is a well-known nicotinic agonist1À3 that does not fit
any proposed pharmacophore for nicotinic binding.
This quaternary salt does not cross the blood–brain bar-
rier (BBB) as required for drugs useful to treat neuro-
degenerative diseases, however, it present a Ki=250 nM
as a nicotinic receptor of the rat brain labeled by [3H]-
cytisine (thought to be represented mainly by the a4b2
subtype).4 Therefore, it represents a unique ligand
among the hundreds of nicotinic agonists studied in the
past decades. Recently, more attention has been direc-
ted to the systematic modulation of the chemical struc-
ture5,6 and the pharmacokinetic properties7,8 of DMPP.
In the previous papers, we reported several classes of
piperazinium salts with significant analgesic activity (2–
4),9À12 and their structures are similar to that of DMPP.
As an extension of our research, herein, we report the
synthesis of two series of new dispirocyclopiperazinium
salts 5a–d and 6a–f. According to the analgesic activity
of compounds 5a–d and 6a–f, compound 5a was selec-
ted as lead compound. Compounds 17a–d, a series of 5a
derivatives, were further designed and prepared to
improve the ability across the blood–brain barrier.
*Corresponding author. Tel.: +86-10-6209-1504; fax: +86-10-6234-
6154; e-mail: lirt@mail.bjmu.edu.cn
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00213-0

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X. Wang et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1729–1732
Reaction of 11 with R-X under basic condition pro-
Chemistry
vided the corresponding compounds 12a–d.15 Com-
pounds 12a–d were deprotected and then reacted with
TsCl to afford the key intermediates 14a–d.16,17 The
preparation of 17a–d from 14a–d was also similar to the
preparation of 5a–d.
Compounds 5a–d were synthesized as outlined in
Scheme 1. The reaction of two equivalents of 1-benzoyl
piperazine 713 with one equivalent of the corresponding
a,o-dibromoalkanes in the presence of sodium bicarbo-
nate provided the key intermediates 8a–d. Deprotection
of 8 in 10% hydrochloric acid, followed by neutraliza-
tion with aqueous sodium hydroxide gave the a,o-
di(1-piperazyl)alkanes 9a–d. One equivalent of 9a–d was
reacted with two equivalents of 1,4-dibromobutane to
yield the corresponding spirocyclopiperazinium bro-
mides 5a–d.
Pharmacology
All newly synthesized compounds 5a–d, 6a–f and 17a–d
were tested for their in vivo analgesic and/or sedative
activity utilizing our reported method.11 The results
were summarized in Tables 1–3. In order to further
prove the potency of quaternary ammonium cation for
The synthesis of compounds 6a–f was outlined in
Scheme 2. The key intermediates 10a–f were obtained
by the reaction of piperazine with a,o-diacyl chlorides
at room temperature in good yields. It is crucial to
scrupulously control the pH=4–5 in the reaction sys-
tem. Final compounds 6a–f were synthesized from
intermediates 10a–f utilizing the similar procedure as
described above for the preparation of 5a–d.
The compounds 17a–d was prepared as illustrated in
Scheme 3. The glycerol was treated with phenyl alde-
hyde to give the 1,3-dihydroxyl protected glycerol 11.14
Scheme 1. Synthesis of compounds 5a–d. Reagents and conditions:
(a) C6H5COCl, AcOH; (b) Br(CH2)nBr(1 equiv), KHCO3, EtOH;
(c) 10% HCl; (d) NaOH; (e) Br(CH2)4Br(2equiv), NaHCO 3, EtOH,
reflux.
Scheme 3. Synthesis of compounds 17a–d. Reagents and conditions:
(a) C6H5CHO, H2SO4; (b) CH3(CH2)nCl, NaH; (c) HOAc/H2O;
(d) TsCl; (e) 1-benzoyl piperazine; (f) 10% HCl; (g) NaOH;
(h) Br(CH2)4Br (2equiv), NaHCO 3, EtOH, reflux.
Table 1. The biological activities of compounds 5a–d
Compd
n
Dose
(mg/kg sc)
Sedative
activitya (%)b
Analgesic
activitya (%)c
5a
3
10
5
4.7
0
96.0
45.5
5b
5c
5d
6.4
8
10
272 56.6
298.6
284.6
0
0
aAcetic acid writhing test was used on mice.
b% Inhibition=100À(A/BÂ100), where A=spontaneous locomotion
times in the treated group; and B=spontaneous locomotion times in
the control group.
c% Inhibition=100À(A/BÂ100), where A=incidence of writhing in
the treated group; and B=incidence of writhing in the control group,
occurring from the 5th to 10th min after administration of the noxious
agents.
Scheme 2. Synthesis of compounds 6a–f: (a) HCl, PH=4.5, rt; (b)
ClCO(CH2)nCOCl, 10% ag NaOH, rt; (c) Br(CH2)4Br, NaHCO3,
EtOH, reflux.

X. Wang et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1729–1732
1731
Table 2. The biological activities of compounds 6a–f Table 4. The biological activities of compounds 10d, 18, 19 and 6d
Compd
n
Dose
Sedative
Analgesic
Death dose
(mg/kg sc) activitya (%)b activitya (%)c (mg/kg sc)
6a
6b
6c
6d
6e
6f
1
22
3
4
5
2
0
47.7
0
40
0
00
70.4
0
0
2
267.4
0.28.1
0.020
2
2
0.2
6 7.5 0.022
0
0.2
a,b,c
As defined in Table 1.
Table 3. The biological activities of compounds 17a–d
Compd
n
Dose
(mg/kg sc)
Analgesic
activitya (%)c
17a
1
2
0
90
10
5
20
10
5
2.5
20
20
46
34
100
91
61
49
18
24
Compd
Dose (mg/kg sc)
Analgesic activitya (%)c
17b
5
6d
18
10d
19
0.270.4
10
5
10.9
34.5
60.1
17c
17d
11
17
0.05
a,cAs defined in Table 1.
a,c
As defined in Table 1.
As shown in Table 3, the introduction of suitable lipophilic
group was favorable to improve the analgesic activity.
Thus, compounds 17a and 17b exhibited good analgesic
activity and dose–effect relationship, however, the anal-
gesic activity of compounds 17c and 17d was very weak.
analgesic activity, compound 10d, the hexanedioyl bi(4-
methyl-1-piperazine) dihydrochloride 18 and the hex-
anedioyl bi(4,4-dimethyl-1-piperazine) dibromide 19
were also tested for their analgesic activity (Table 4).
It could be found from Table 4 that the secondary amine
hydrochloride 10d and tertiary amine hydrochloride 18
only exhibited weak analgesic activity; however, the
quaternary ammoniums 19 and 6d showed higher activ-
ity. This result demonstrates that the quaternary
ammonium functionality is a critical pharmacophore
for the analgesics.
Results and Discussion
Most of the compounds tested displayed definite
analgesic or sedative activity. The results reported in
Table 1 clearly show that the distance between two
spirocyclopiperaziniums obviously affected the biologi-
cal activities. The analgesic activity increases as n
decreases, and the sedative activity increases as n
increases. Thus, analgesic activity and sedative activity
of compound 5a (n=3) is 96 and 4.7% separately at the
dose of 10 mg/kg sc. On the contrary, compound 5c
(n=8) exhibited high sedative activity (98.6%) and no
analgesic activity at the dose of 0.2mg/kg sc.
In summary, three series of dispirocyclopiperazinium
salts synthesized in this study showed analgesic and/or
sedative effects, especially, compounds 5a, 17a and 17b
which processed excellent analgesic activity. Two
important structure–activity relationships were observed
from this study: (1) the quaternary ammonium func-
tionality is a critical pharmacophore for the analgesics;
(2) it is important to adjust the lipophilic properties of
compounds for the improvement of analgesic activity.
When two spirocyclopiperazinium cations were linked
with a,o-diacyl in a series of compounds 6, only com-
pound 6d (n=4) was found to show significant analgesic
activity (70.4%, dose 0.2mg/kg), and the others did not
show analgesic activity and various sedative activity
(Table 2). The death doses of derivatives 6a–f were also
tested. It is apparent from the results that the toxicity
was raised with the increase of n.
Acknowledgements
This research was supported by the funds of National
Science Foundation of China (NSFC 29972005). Bio-
logical activities were completed by National Center for
Drug Screening, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences.
Compared with the analgesic activity of compounds 5a–
d and 6a–f, compound 5a is the most potent lead. In
order to improve the ability to across the blood–brain
barrier (BBB), a new class of 5a analogue, 17a–d, in
which a different length of carbon chain was introduced
into compound 5a through an ether bond, was designed
and synthesized. The data of analgesic activity were lis-
ted in Table 3.
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