Unique spirocyclopiperazinium salt I: Synthesis and structure-activity relationship of spirocyclopiperazinium salts as analgesics

Article abstract of DOI:10.1016/S0960-894X(03)00177-X

Based on the structure of compound 3, two series of spirocyclopiperazinium derivatives 7a-n and 10a-h were synthesized and evaluated for their in vivo analgesic and sedative activities. Compounds 7f and 10c were discovered to exhibit excellent analgesic activity. Structure-activity relationships revealed that anion of the quaternary salt affected the analgesic and sedative activity significantly; the allyl group is a most effective group among the compounds 7a-n; the electron-released substitute on the aromatic ring is favorable to increase the analgesic activity.

Full text of DOI:10.1016/S0960-894X(03)00177-X

Bioorganic & Medicinal Chemistry Letters 13 (2003) 1535–1537
Unique Spirocyclopiperazinium Salt I: Synthesis and
Structure–Activity Relationship of Spirocyclopiperazinium
Salts as Analgesics
Feng-Li Gao, Xin Wang, Hong-Mei Zhang, Tie-Ming Cheng and Run-Tao Li*
School of Pharmaceutical Sciences, Peking University, Beijing 100083, PR China
Received 10 January 2003; accepted 17 February 2003
Abstract—Based on the structure of compound 3, two series of spirocyclopiperazinium derivatives 7a–n and 10a–h were synthesized
and evaluated for their in vivo analgesic and sedative activities. Compounds 7f and 10c were discovered to exhibit excellent
analgesic activity. Structure–activity relationships revealed that anion of the quaternary salt affected the analgesic and sedative
activity significantly; the allyl group is a most effective group among the compounds 7a–n; the electron-released substitute on the
aromatic ring is favorable to increase the analgesic activity.
# 2003Elsevier Science Ltd. All rights reserved.
Introduction
During our study on the synthesis and biological activ-
ity of quaternary piperazinium salts,16,17 compound 3,
whose structure is similar to the DMPP, was found to
show significant analgesic activity. In an effort to
explore the structure–activity relationships of this kind
of compounds and look for the more potential analgesic
compounds with low toxicity, a series of spiro-
cyclopiperazinium derivatives 7a–n and 10a–h were
prepared. Herein, we report their synthesis and in vivo
analgesic and sedative activity.
The discovery of high efficient analgesics without the
side effects of drug dependency is highly desirable in
pain management. In this respect, it has been suggested
that selective neuronal nicotinic acetylcholine receptor
(nAChR) agonists may be useful. Nicotine itself has
long been known to have antinociceptive properties, but
a variety of side effects make it a poor therapeutic
choice.1À4 The discovery of epibatidine5À7 (1), a potent
analgesic and nAChR modulator, brought about a
renewed interest for compounds acting through
nAChRs. N1, N1-dimethyl-N4-phenylpiperazinium iodide
(DMPP, 2) is a well-known nicotinic agonist8À10 that
does not fit any proposed pharmacophore for nicotinic
binding. This quaternary salt does not cross the blood–
brain barrier (BBB) as required for the drugs useful to
treat neurodegenerative diseases; however, it presents 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).11 Therefore, it represents a
unique ligand among the hundreds of nicotinic agonists
studied in the past decades. Recently, more attention
has been directed to the systematic modulation of the
chemical structure and the pharmacokinetic properties
of DMPP.12À15
Chemistry
The synthetic route of compounds 7a–n was outlined in
Scheme 1. The piperazine was reacted with benzoyl
chloride in the presence of sodium acetate to give the
intermediate 1-benzoyl piperazine 4.18 Reaction of 4
with various alkyl halides provided the corresponding
1-benzoyl-4-alkylpiperazine 5. Compound 5 was depro-
tected by 10% hydrochloric acid, and then neutralized
*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 # 2003Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00177-X

1536
F.-L. Gao et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1535–1537
Table 1. The biological activities of compounds 7a–n
Compd
Dose
(mg/kg sc)
Analgesic activitya
(%)c
Sedative activitya
(%)b
3
20
20
20
20
20
20
20
10
20
20
20
20
20
20
20
20
64
0
0
0
10
9
100
45
36
20
0
27
42
19
32
24
57
0
0
0
0
4
0
0
25
10
33
59
51
12
12
10
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
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 1. Synthesis of compounds 7a–n. Reagents and conditions:
(a) C6H5COCl, AcOH; (b) RX, NaHCO3, EtOH; (c) 10% HCl, reflux;
(d) NaOH; (e) Cl(CH2)4Cl(7a) or Br (CH2)4Br(7b–n), NaHCO3,
EtOH, reflux.
with NaOH aqueous solution gave the 1-alkyl piperazine
6. The intermediate 6 was reacted with 1,4-dihalo-
robutane in the presence of sodium bicarbonate to yield
target compounds 7a–n.
by neutralization,to afford the key intermediate 9.
The compounds 10a–h were prepared from the Man-
nich reactions of 9 with formaldehyde and various
acetophenones.
As shown in Scheme 2, the reaction of benzoyl piper-
azine 4 with 1,4-dibromobutane gave 8-benzoyl-5,8-
diaza-spiro[4.5] decane 8. Deprotection of 8, followed
Pharmacology
The in vivo analgesic and sedative activities of com-
pounds 7a–n and 10a–h, summarized in Tables 1 and 2
respectively, were evaluated according to our reported
method.19
Results and Discussion
Based on the Verma’s report20 that the anion of qua-
ternary ammonium influenced the neuromuscular block
activity obviously, we firstly wanted to explore whether it
Table 2. The biological activities of compounds 10a–h
Compd
Dose
(mg/kg sc)
Analgesic activitya
(%)c
Sedative activitya
(%)b
10a
10b
10c
20
20
20
10
20
20
20
20
20
25
14
100
77
25
12
15
59
11
13
85
—
14
3
0
0
35
10d
10e
10f
10g
10h
Scheme 2. Synthesis of compounds 10a–h. Reagents and conditions:
(a) Br(CH2)4Br, NaHCO3, EtOH; (b) 10% HCl, reflux; (c) HCHO,
MeCOAr, MeOH, reflux.
12
a,b,c
See footnotes in Table 1.

F.-L. Gao et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1535–1537
1537
was also important for the analgesic activity. Therefore,
Acknowledgements
compound 7a (X=Cl) was synthesized to compare with
compound 3 (X=Br). Comparing the biological results
of compounds 3 and 7a, the former showed better
analgesic activity (64%) and sedative activity (57%) at
the dose of 20 mg/kg, however, the compound 7a did
not show any activity at the same dose. Thus, it was
revealed that the anion of quaternary ammonium also
influenced the analgesic activity distinctively.
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.
References and Notes
With the above result in mind, we selected compound 3
as the lead compound and synthesized its derivatives
7b–n and 10a–h to further study on the structure–activ-
ity relationship.
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As seen from the Table 1, compound 7f (R=allyl,
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(100%) than 3-OH substituted compound 10b (14%);
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(12%) exhibited lower analgesic activity than 3-NO2
substituted compound 10g (59%).
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In summary, two series of three analogues 7a–n and
10a–h were synthesized and evaluated for their in vivo
analgesic and sedative activity. Compounds 7f and 10c
were showed excellent analgesic activity. Some useful
structure–activity relationships were revealed.