Unique spirocyclopiperazinium salt III: Further investigation of monospirocyclopiperazinium (MSPZ) salts as potential analgesics

Article abstract of DOI:10.1016/j.bmcl.2007.09.026

Two novel classes of monospirocyclopiperazinium salts were designed, synthesized, and evaluated for their in vivo analgesic activities. Some interesting structure-activity relationships are revealed: (1) Spirocyclopiperazinium moiety is favorable to improve the analgesic activity; (2) The size and conformation of spirocyclopiperazinium moiety significantly affects the analgesic activity; (3) Phenylethyl group of 3d is a crucial pharmacophore. Among the compounds synthesized, 3d exhibited the most potent activity with low toxicity. Further antinociceptive mechanism studies of 3d showed that these compounds will be a new kind of analgesics.

Full text of DOI:10.1016/j.bmcl.2007.09.026

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 17 (2007) 6245–6249
Unique spirocyclopiperazinium salt III: Further investigation of
monospirocyclopiperazinium (MSPZ) salts as potential analgesics
Qi Sun,a Cai-Qin Yue,a Jia Ye,a Chang-Ling Li,a Tie-Ming Chenga and Run-Tao Lia,b,
*
aSchool of Pharmaceutical Sciences, Peking University, Beijing 100083, PR China
bState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University,
Beijing 100083, PR China
Received 2 January 2007; revised 28 August 2007; accepted 5 September 2007
Available online 8 September 2007
Abstract—Two novel classes of monospirocyclopiperazinium salts were designed, synthesized, and evaluated for their in vivo anal-
gesic activities. Some interesting structure–activity relationships are revealed: (1) Spirocyclopiperazinium moiety is favorable to
improve the analgesic activity; (2) The size and conformation of spirocyclopiperazinium moiety significantly affects the analgesic
activity; (3) Phenylethyl group of 3d is a crucial pharmacophore. Among the compounds synthesized, 3d exhibited the most potent
activity with low toxicity. Further antinociceptive mechanism studies of 3d showed that these compounds will be a new kind of
analgesics.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The discovery of compounds that can be used to treat
N+
NR
N
N+
I
X
both acute and chronic pain without the side effect of
drug dependency would be an important advance in
pain management. Since the epibatidine was reported
to possess strong analgesic properties as nicotinic acetyl-
choline receptor (nAChR) agonist,1 the studies on the
nAChR ligands have drawn great attention.2 Naturally,
N1,N1-dimethyl-N4-phenylpiperazinium iodide (DMPP,
Fig. 1),3 a well-known unique nAChR agonist, attracted
the interest of medicinal chemists. Numerous DMPP
analogues with substituted phenyl and heteroaromatic
groups have been synthesized and subjected to physio-
logical studies.4
DMPP
MSPZ
Me
N+
N+
N
C6H5CH2CH2N
C6H5CH2CH2N
Y
2X
(CH2)6
N+
N+
DSPZ
Figure 1. Structures of DMPP, MSPZ, DSPZ, and 97-9-G4.
-
N
2Br
Me
1 (97-9-G4)
erazinium salts (1, 97-9-G4, Fig. 1) showed excellent
analgesic activity.9
Our group has engaged in the study on the synthesis and
biological activity of quaternary ammonium salts for
many years.5 Recently, we have reported a novel class
of monospirocyclopiperazinium salts (MSPZ, Fig. 1)6
and dispirocyclopiperazinium salts (DSPZ, Fig. 1)7 with
potent analgesic activities. These results have received
much attention due to their peculiar structure related
to the DMPP.8 Furthermore, we also found that dipip-
On the bases of our research results and Gualtieri’s
report of 3-NO2 and 4-MeO substituted aryl DMPP
derivatives with excellent affinity for the nicotinic recep-
tor,4a we designed and synthesized two series of novel
monospirocyclopiperazinium salts (2 and 3, Fig. 2) to
2
R
+
+
1
N
N
R
N
N
Br
Cl
3
1
R
Keywords: Monospirocyclopiperazinium salts; Analgesic; Structure–
activity relationship; Synthesis.
R
3
2
*
Corresponding author. Tel.: +86 10 82801504; fax: +86 10
82716956; e-mail: lirt@bjmu.edu.cn
Figure 2. General structures of compounds 2 and 3.
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.09.026

6246
Q. Sun et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6245–6249
get additional SAR information and improve the
pharmacological properties. All newly synthesized
compounds were evaluated for their in vivo analgesic
activities and some of them exhibited potent analgesic
activities. Here we report the design, synthesis and anal-
gesic activities of the new spirocyclopiperazinium
derivatives.
was suggested that spirocyclopiperazinium structure
might be favorable to improve the analgesic activity.
It was also found from the Table 1 that the property and
position of the substituents on the benzene ring have sig-
nificant influence on the analgesic activities. For exam-
ple, compound 2b (4-MeO) showed the most potent
analgesic activity among the compounds 2a (H), 2b (4-
MeO), and 2d (4-NO2); compound 2c with electron-
withdrawing group (3-NO2, 61%) exhibited more potent
analgesic activity than compound 2d (16%).
The synthesis of compounds 2a–d is outlined in Scheme
1. Reaction of piperazine with different substituted phe-
nyl iodides10 in the presence of CuI and K3PO4 gave the
key intermediate 1-phenyl-piperazines 4 at room temper-
ature. The intermediates 4a–d were treated with
1,4-dibromobutane in refluxing ethanol using NaHCO3
as acid-adsorbent affording the corresponding monospi-
rocyclopiperazinium salts 2a–d. The DMPP derivatives
2e and 2f were prepared from the quaternarization of 5
with methyl bromide and methyl iodine, respectively.
The synthesis of intermediate 5 is similar to compound 4.
Considering the phenylethyl group as significant phar-
macophore in 97-9-G4, compounds 3a–e in Table 2 were
designed and synthesized to explore the effect of cyclic
size and steric effect of quaternary ammonium salt moi-
eties. Compound 3d (65%) showed excellent biological
activity, 3a with five-member ring (À36%), 3b with six-
member ring (5%), 3c with seven-member ring (4%)
and acyclic compound 3e (18%) did not show measur-
able analgesic activity. This result demonstrates that
the appropriate conformation of the compound was
critical for the interaction between ligand and receptor.
The synthesis of compounds 3a–l is illustrated in Scheme
2. Diethanolamine was N-alkylated with various halides
R1X 6, and then chlorinated with SOCl2 in chloroform
to give the key intermediate 8. Reaction of 8 with differ-
ent secondary amines afforded the desired products 3a–l.
With the biological result of 3d in hand, we synthesized
compounds 3f–l by replacing the phenylethyl of 3d with
various substituted groups R1 and maintaining the spi-
rocyclopiperazinium moiety of 3d to get more potential
compounds. For the substitution on the phenyl ring,
both electron-withdrawing group (3g, NO2–, À24%)
and electron-donating group (3h, MeO–, À47%) were
definitely detrimental to the analgesic activity. Compar-
ing the compound 3i (21%) and 3j (À19%) with 3d, it is
clear that the distance of two methylene units between
phenyl and N-atom is suitable for the analgesic activity.
By introducing an allyl group according to previous
work,6 compound 31 exhibited potent activity. How-
ever, other compounds almost completely lost the activ-
ity. These results indicated that phenylethyl group of
3d was a crucial pharmacophore for the analgesic
activity.
All the target compounds were purified by recrystalliza-
tion and characterized using NMR and elemental anal-
ysis.11 Their analgesic activities were assessed by acetic
acid writhing test,5c and the results are summarized in
Tables 1 and 2.
The data in Table 1 indicate that the most potent com-
pound is 2c (3-NO2, 61% analgesic activity at the dose
of 31 lmol/kg) among compounds 2a–f. However, the
DMPP derivative 2f, which was reported to have high
affinity for the nicotinic receptor,4a did not show any
in vivo analgesic activity. Considering the difference of an-
ion between 2c and 2f, we also synthesized bromide salt 2e
to compare with 2c and 2f. Though 2e exhibits better anal-
gesic activity than 2f, it is still weaker than 2c. Therefore, it
b
+
a
N
N
Br
N
NH
N
I
1
1
1
R
R
R
2a-d
4a-d
CH
+
3
c
N
CH3
d
N
N
I
X
CH
3
NO2
NO2
NO2
2e: X = Br
2f: X = I
5
Scheme 1. Synthesis of compounds 2a–f. Reagents and conditions: (a) piperazine, CuI, K3PO4, i-PrOH, rt; (b) Br(CH2)4Br, NaHCO3, ethanol,
reflux; (c) methyl piperazine, CuI, K3PO4, i-PrOH, rt; (d) CH3X, acetone, rt.
2
OH
OH
Cl
Cl
R
+
c
a
b
1
1
1
1
R
N
N
R X
R
N
R
N
Cl
2
3
3
NHR R
R
6
7
8
3a-l
X=Cl or Br
Scheme 2. Synthesis of compounds 3a–l. Reagents and conditions: (a) bis(hydroxyethyl)amine, K2CO3, ethanol, reflux; (b) SOCl2, CHCl3;
(c)NaHCO3, ethanol, reflux.

Q. Sun et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6245–6249
Table 1. The analgesic activities of compounds 2a–f Table 2. The analgesic activities of compounds 3a–l
6247
2
2
R
+
R
1
+
R
N
N
Cl
N
N
X
3
3
R
R
1
R
Compound
R1
R2, R3
Analgesic
activitya,b (%)
Compound
R1
H
R2, R3
X
Analgesic
activitiesa,b (%)
À36*
2a
Br
20*
56**
61**
16*
3a
3b
3c
3d
3e
3f
5*
4*
2b
2c
2d
2e
2f
4-MeO–
3-NO2–
4-NO2–
3-NO2–
3-NO2–
Br
Br
Br
Br
I
65**
18*
O
Me, Me
Me, Me
22*
Me, Me
N
À16*
À2*
À24*
À47*
21*
O
O
O
O
O
O
O
a Drugs were dissolved in isotonic saline solution (NaCl 0.9%) imme-
diately before use. Drug concentrations were prepared in such a way
that the necessary dose could be administered in a volume of 10 ml/kg.
Acetic acid writhing test was used on mice (eight per each group),
and drugs were administered at the dose of 31 lmol/kg intraperito-
neally (ip).
b % Inhibition = 100 À (A/B · 100), 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.
* P > 0.05.
** P < 0.01.
3g
3h
3i
NO2
CH3O
3j
À19*
À43*
49**
3k
3l
On the bases of above results, we have chosen the most
potential compound 3d (65% inhibition in acetic acid
writhing test) to further investigate its pharmacological
efficacy. The results show that the compound 3d pro-
duced antinociception in chemical and thermal models
of nociception in mice without significant side effects
(LD50 = 1.55 mmol/kg, ip), and the antinociceptive ef-
fect was achieved by activating peripheral neuronal nic-
otinic acetylcholine and muscarinic acetylcholine
receptors, but the effect did not relate to opioid receptors
or a-adrenoreceptors.12 Meanwhile, we also completed
the binding test of compound 3d with nAChR(a4b2).
It was found that the IC50 value of compound 3d
(>10 lM) was far higher than that of epibatidine
(0.00106 lM), which suggested that the antinociceptive
effect of 3d might not closely relate with nAChR(a4b2).
There results coincided with our recent results.12 Further
pharmacological study is in progress.
a,b See footnotes in Table 1.
* P > 0.05.
** P < 0.01.
activity relationships were revealed. These results will
provide insight into new kind of analgesics.
Acknowledgments
This research was supported by the fund of National
Science Foundation of China (NSFC 20372006). Biolog-
ical activities were completed by Department of Phar-
macology, Peking University.
In summary, we have designed and synthesized two ser-
ies of novel monospirocyclopiperazinium salts and eval-
uated their in vivo analgesic activity. Some compounds
showed good analgesic activities. Especially, the com-
pound 3d exhibited not only good activity but also
low toxicity. Meanwhile, some important structure–
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.bmcl.
2007.09.026.

6248
Q. Sun et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6245–6249
H2O: C, 48.62; H, 5.95; N, 12.15. Found: C, 48.42; H,
References and notes
5.74; N, 11.99. Compound 2d: white powder, mp:
278–280 ꢁC. 1H NMR (D2O, 300 MHz): 8.00 (d,
J = 9.6 Hz, 2H, ArH), 6.90 (d, 2H, J = 9.6 Hz, ArH),3.67
(br s, 4H, Ph–N–CH2), 3.48–3.57 (m, 8H, N+–CH2), 2.11
(br s, 4H, N+–C–CH2–CH2–C–N+). Anal. Calcd for
C14H20BrN3O2 Æ 0.1H2O: C, 48.88; H, 5.92; N, 12.21.
Found: C, 48.73; H, 6.28; N, 11.94. Compound 2e: white
solid, mp: 234–237 ꢁC. 1H NMR (D2O, 300 MHz): 7.74 (s,
1H, ArH), 7.68–7.70 (d, J = 7.2 Hz, 1H, ArH), 7.38 (t,
J = 8.4 Hz, 1H, ArH), 7.30 (t, J = 8.4 Hz, 1H, ArH), 3.52–
3.53 (m, 8H, N+–CH2–CH2–N), 3.11 (s, 6H, CH3). Anal.
Calcd for C12H18BrN3O2 Æ 0.2H2O: C, 45.07; H, 5.80; N,
13.14. Found: C, 44.98; H, 5.95; N,13.10. Compound 2f:
yellow solid, mp: 210–212 ꢁC. 1H NMR (D2O, 300 MHz):
7.70 (t, J = 2.1 Hz, 1H, ArH), 7.64 (dq, J = 8.1 Hz, 0.9 Hz,
1H, ArH), 7.36 (t, J = 8.4 Hz, 1H, ArH), 7.28 (dq, 1H,
J = 8.7 Hz, 0.9 Hz, ArH), 3.52 (s, 8H, N+–CH2–CH2–N),
3.13 (s, 6H, CH3). Anal. Calcd for C12H18IN3O2: C, 39.68;
H, 5.00; N, 11.57. Found: C, 39.46; H, 5.21; N, 11.42.
Compound 3a: white powder, mp: 220 ꢁC (dec). 1H NMR
(D2O, 300 MHz): 7.11–7.25 (m, 5H, ArH), 3.30–3.51 (m,
8H, N+–CH2), 2.77 (m, 4H, N–CH2), 2.58–2.73 (m, 4H,
Ph–CH2–CH2), 2.03–2.05 (d, 4H, C–CH2–CH2–C). Com-
pound 3b: white slice, mp: 221–225 ꢁC. 1H NMR (D2O,
300 MHz): 7.10–7.23 (m, 5H, ArH), 3.27 (t, J = 6.0 Hz,
8H, N+–CH2), 2.63–2.66 (m, 4H, N–CH2), 2.74 (s, 4H,
Ph–CH2–CH2), 1.67 (t, J = 5.7 Hz, 4H, N+–C–CH2–C),
1.49 (t, J = 6.0 Hz, 2H, N+–C2–CH2–C2–N+). Anal. Calcd
for C17H27ClN2 Æ H2O: C, 65.26; H, 9.34; N, 8.95. Found:
C, 65.60; H, 9.28; N, 8.70. Compound 3c: white powder,
mp: 220 ꢁC (dec). 1H NMR (D2O, 300 MHz): 7.10–7.24
(m, 5H, ArH), 3.31 (t, J = 4.5 Hz, 8H, N+–CH2), 2.76 (br
s, 4H, N–CH2), 2.64–2.67 (m, 4H, Ph–CH2–CH2), 1.73 (br
s, 4H, N+–C–CH2–C), 1.53 (br s, 4H, N+–C–C–CH2).
Anal. Calcd for C18H29ClN2 Æ 0.5H2O: C, 68.01; H, 9.51;
N, 8.81. Found: C, 67.97; H, 9.70; N, 8.73. Compound 3d:
white powder, mp: 220 ꢁC (dec). 1H NMR (D2O,
300 MHz): 7.12–7.26 (m, 5H, ArH), 4.05–4.14 (m,
2H, O–CH), 3.30–3.64 (m, 8H, N+–CH2), 2.79–2.95
(m, 4H, N–CH2), 2.61–2.74 (m, 4H, Ph–CH2–CH2),
1.05 (d, J = 11.7 Hz, 6H, CH3). Anal. Calcd for
C18H29ClN2O Æ 1.1H2O: C, 62.72; H, 9.12; N, 8.13. Found:
C, 62.50; H, 9.12; N, 8.05. Compound 3e: white powder,
mp: 230 ꢁC (dec). 1H NMR (D2O, 300 MHz): 7.12–7.26
(m, 5H, ArH), 3.30 (t, J = 8.1 Hz, 4H, N+–CH2), 3.04 (s,
6H, CH3), 2.79 (br s, 4H, N–CH2), 2.62–2.69 (m, 4H, Ph–
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1
CH2–CH2). Compound 3f: pink powder, mp: 247 ꢁC. H
NMR (D2O, 300 MHz): 8.26 (d, J = 4.8 Hz, 1H, ArH),
7.62 (t, J = 7.8 Hz, 1H, ArH), 7.20 (d, J = 4.8 Hz, 1H,
ArH), 7.13 (t, J = 6.6 Hz, 1H, ArH), 4.05–4.11 (m, 2H, O–
CH), 3.49–3.62 (m, 4H, N+–CH2), 3.34 (t, J = 5.1 Hz, 2H,
Ar–CH2), 2.71–2.93 (m, 10H, N+–CH2, N–CH2), 1.06 (d,
J = 6.0 Hz, 6H, CH3). Anal. Calcd for C17H28ClN3O: C,
62.66; H, 8.66; N, 12.89. Found: C, 62.38; H, 8.63; N,
12.68. Compound 3g: buff solid, mp: 288–294 ꢁC. 1H
NMR (D2O, 300 MHz): 8.01 (d, J = 8.4 Hz, 2H, ArH),
7.30 (d, 2H, J = 8.4 Hz, ArH), 4.05–4.11 (m, 2H, O–CH),
3.59–3.62 (m, 4H, N+–CH2), 3.35 (t, J = 4.8 Hz, 2H, Ar–
CH2), 2.64–2.94 (m, 10H, N+–CH2, N–CH2), 1.07 (d,
J = 6.3 Hz, 6H, CH3). Anal. Calcd for C18H28ClN3O3: C,
58.45; H, 7.63; N, 11.36. Found: C, 58.75; H, 7.67; N,
11.31. Compound 3h: yellow powder, mp: 265–269 ꢁC. 1H
NMR (D2O, 300 MHz): 7.06 (d, J = 8.4 Hz, 2H, ArH),
6.78 (d, 2H, J = 8.4 Hz, ArH), 4.04–4.10 (m, 2H, O–CH),
3.64 (s, 3H, OCH3), 3.57–3.62 (m, 4H, N+–CH2), 3.33 (t,
J = 4.8 Hz, 2H, Ar–CH2), 2.64–2.94 (m, 10H, N+–CH2,
N–CH2), 1.06 (d, J = 6.3 Hz, 6H, CH3). Anal. Calcd for
C19H31ClN2O2 Æ 0.5 H2O: C, 62.71; H, 8.86; N, 7.70.
10. Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett.
2002, 4, 581.
11. Compound 2a: white powder, mp: 208–209 ꢁC. H NMR
1
(D2O, 300 MHz): 7.25 (dd, J = 7.2 Hz, 8.7 Hz, 2H, ArH),
7.00 (d, J = 8.4 Hz, 1H, ArH), 6.92 (t, J = 7.5 Hz, 2H,
ArH), 3.46–3.54 (m, 8H, N+–CH2), 3.39 (t, J = 4.5 Hz,
4H, N–CH2), 2.01 (br s, 4H, N+–C–CH2–CH2–C–N+).
Anal. Calcd for C14H21BrN2 Æ 0.3H2O: C, 55.56; H, 7.19;
N, 9.26. Found: C, 55.55; H, 6.91; N, 9.26. Compound 2b:
1
orange slice, mp: 201–203 ꢁC. H NMR (D2O, 300 MHz):
6.93–6.99 (m, 2H, ArH), 6.84–6.88 (m, 2H, ArH), 3.65 (s,
3H, OCH3), 3.44–3.52 (m, 8H, N+–CH2), 3.28 (br s, 4H,
N–CH2), 2.07 (br s, 4H, N+–C–CH2–CH2–C–N+). Anal.
Calcd for C15H23BrN2O: C, 55.05; H, 7.08; N, 8.56.
Found: C, 55.00; H, 7.07; N, 8.55. Compound 2c: yellow
powder, mp: 246–249 ꢁC. 1H NMR (D2O, 300 MHz): 7.72
(s, 1H, ArH), 7.65 (d, J = 8.1 Hz, 1H, ArH),7.36 (t,
J = 8.1 Hz, 1H, ArH), 7.28 (d, J = 9.0 Hz, 1H, ArH),
3.50–3.54 (m, 12H, N+–CH2, N–CH2), 2.08 (br s, 4H, N+–
C–CH2–CH2–C–N+). Anal. Calcd for C14H20Cl2N3 Æ 0.2-

Q. Sun et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6245–6249
6249
1
Found: C, 62.68; H, 8.98; N, 7.38. Compound 3i: white
powder, mp: 280 ꢁC (dec). 1H NMR (D2O, 300 MHz):
7.18–7.29 (m, 5H, ArH), 4.02–4.06 (m, 2H, O–CH), 3.53–
3.63 (m, 6H, N+–CH2), 3.31 (t, J = 5.1 Hz, 2H, Ar–CH2),
2.86–2.90 (m, 2H, N+–CH2), 2.71–2.76 (m, 4H, N–CH2),
1.04 (d, J = 6.0 Hz, 6H, CH3). Anal. Calcd for
C17H27ClN2O: C, 65.68; H, 8.75; N, 9.01. Found: C,
65.49; H, 8.47; N, 8.95. Compound 3j: white powder, mp:
220 ꢁC (dec). 1H NMR (D2O, 300 MHz): 7.09–7.24 (m,
5H, ArH), 4.04–4.10 (m, 2H, O–CH–CH3), 3.56–3.64 (m,
4H, N+–CH2), 3.33 (t, J = 4.8 Hz, 2H, Ph–CH2), 2.84 (t,
J = 12.0 Hz, 2H, Ph–C–C–CH2), 2.71 (br s, 4H, N–CH2),
2.84 (t, J = 7.5 Hz, 2H, N–CH2), 2.37 (t, J = 7.5 Hz, 2H,
N–CH2), 1.64 (p, J = 7.8 Hz, 2H, Ph–C–CH2), 1.05 (d,
J = 11.7 Hz, 6H, CH3). Anal. Calcd for C19H31ClN2O: C,
67.33; H, 9.22; N, 8.27. Found: C, 67.29; H, 9.12; N, 8.11.
Compound 3k: white powder, mp: 266–268 ꢁC. H NMR
(D2O, 300 MHz): 7.15–7.35 (m, 5H, ArH), 6.51 (d,
J = 15.9 Hz, 1H, Ph–CH@), 6.06–6.16 (m, 1H, Ph–
C@CH), 4.03–4.08 (m, 2H, O–CH) 2.77–3.58 (m, 14H,
N+–CH2, N–CH2), 1.06 (d, J = 6.0 Hz, 6H, CH3). Anal.
Calcd for C19H29ClN2O Æ 0.4H2O: C, 66.32; H, 8.73; N,
8.14. Found: C, 66.57; H, 8.90; N, 7.70. Compound 3l:
white powder, mp: 236 ꢁC (dec). 1H NMR (D2O,
300 MHz): 5.60–5.72 (m, 1H, @CHA), 5.12–5.18 (m, 2H,
@CH2), 4.05–4.10 (m, 2H, O–CH–CH3), 3.58–3.64 (m,
4H, N+–CH2), 3.34 (t, 2H, @CACH2), 2.74–3.01 (m, 8H,
N–CH2, N+–CH2), 1.08 (d, J = 12.0 Hz, 6H, CH3). Anal.
Calcd for C13H25ClN2O: C, 59.87; H, 9.66; N, 10.74.
Found: C, 59.62; H, 9.61; N, 10.60.
12. Yue, C. Q.; Ye, J.; Li, C. L.; Li, R. T.; Sun, Q. Pharmacol.,
Biochem. Behav. 2007, 86, 643.