Sinomenine derivatives with embedment of nitrogen-containing heterocycles exhibiting potent TNF-αinhibitory activity

Article abstract of DOI:10.1007/s11426-012-4588-8

Inhibitory effect on tumor necrosis factor-α (TNF-α) production by sinomenine derivatives with embedment of small drug-like nitrogen hetereocyclic moieties has been studied in this work. Several new sinomenine derivatives having chlorophenyl substituent h

Full text of DOI:10.1007/s11426-012-4588-8

SCIENCE CHINA
Chemistry
December 2012 Vol.55 No.12: 2537–2547
doi: 10.1007/s11426-012-4588-8
• ARTICLES •
Sinomenine derivatives with embedment of nitrogen-containing
heterocycles exhibiting potent TNF- inhibitory activity
WANG Meng1, MA LiYan2, LOU YangTong3, BIAN Chao2, ZHOU TingTing1,
ZHOU HaiBin3, LIAO HongZe1, MA Zhao2, YIN DongSheng2, CHEN AiZhong2,
WANG ShaoZhong1, YANG ZhenYu3*, SUN Bing2* & YAO ZhuJun1,3*
1State Key Laboratory of Coordination Chemistry and Nanjing National Laboratory of Microstructures; Institute of Chemical Biology and
Drug Innovation, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China
2Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai
200031, China
3State Key Laboratory of Bioorganic and Natural Products Chemistry; Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
Received January 2, 2012; accepted March 20, 2012; published online May 19, 2012
Inhibitory effect on tumor necrosis factor- (TNF-) production by sinomenine derivatives with embedment of small drug-like
nitrogen hetereocyclic moieties has been studied in this work. Several new sinomenine derivatives having chlorophenyl sub-
stituent have been found to exhibit much more potent TNF-α inhibitory activity than natural sinomenine and other derivatives.
sinomenine, druggability, heterocycle, tumor necrosis factor-, inhibition
ous [35].
For its easy and economic availability, various modifica-
1 Introduction
tions of the naturally existing functionalities of sinomenine
have been conducted in the past several decades [6]. Unfor-
tunately, no achievement has been advanced to the clinical
applications yet (Figure 1). Insufficient druggability of si-
nomenine of plant origin is thought to be a major drawback.
Therefore, developing druggable derivatives should be a
more promising strategy in further efforts. Our recent study
has developed a number of new derivatives by incorporation
of certain druggable fragments into the skeleton of si-
nomenine and examined their inhibitory effect on the
growth of T- and B-cells [7]. The modified compounds
were found to display more potent inhibitory activity than
natural sinomenine in a high hit rate. To exclude possible
complicated environment problems involved in the whole-
cell model, further study of the effects on the key cytokines
associated with the immunomodulating response is neces-
sary. Furthermore, fine tuning and examination of more
Improvement of the druggability of bioactive natural prod-
ucts by proper chemical modifications has influenced mod-
ern drug discovery across the therapeutic spectrum for many
decades [1]. Among numerous naturally occurring com-
pounds, only a small part meet the requirements for further
pharmaceutical development. Many easily available natural
compounds are insufficiently active to be potential drug
candidates. Sinomenine (1, Figure 1), an economically
available alkaloid extracted from the Chinese medicinal
plant Sinomenium acutum [2], is distributed widely as an
ingredient of traditional Chinese medicines for treatment of
rheumatoid arthritis (RA) for centuries. However, si-
nomenine alone only exhibits very weak immunomodulat-
ing activity. Furthermore, the mechanisms associated with
its treatment effects to rheumatoid arthritis are still ambigu-
*Corresponding authors (email: yaoz@nju.edu.cn; bingsun@sibs.ac.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2012
chem.scichina.com www.springerlink.com

2538
Wang M, et al. Sci China Chem December (2012) Vol.55 No.12
N17
D
NMe
H
9
10
11
16
1
8
B 14
H
15
C
6
2
A
O
OMe
13
12
7
3
4
5
O
MeO
OH
MeO
OH
O
sinomenine (1)
NMe
H
NMe
H
R2
OMe
OMe
OR1
O
MeO
OH
O
MeO
R1 = Me, Ac, Bn, PhCO
R2 = Br, HOCH2, SO3
NMe
H
NMe
H
OR3
NNH2
NNH2
OR3
R3 = allyl
MeO
OH
MeO
OH
R3 = allyl
Figure 1 Representative chemical modifications of sinomenine (1).
diverse sinomenine derivatives on the basis of our previous
findings [7] are also helpful to conclude structure-activity
relationships. With these considerations, inhibition of the
production of TNF-α (pro-inflammatory cytokine tumor
necrosis factor-α), which is generally involved in the path-
ogenesis of the disease rheumatoid arthritis (RA) [8], was
employed in this work as the evaluation platform of the
corresponding immunomodulating properties.
Scheme 1 Reagents and conditions: (a) 10% HCl, 80 °C, 86%; (b) 10%
Pd-C, H2O, 79%; (c) PtO2, EtOH, H2, rt, 70%; (d) HOCH2CH2OH, p-TsOH,
PhCH3, reflux, 59%; (e) HCl/ EtOH, reflux, 5a (43%) and 5b (37%).
Table 1 Synthesis of imidazole-fused sinomenine derivatives 7a–7t
2 Results and discussion
In order to avoid the known modifications [6] and identify a
unique modification protocol, we decided to screen a suita-
ble intermediate from scalable transformations as our start-
ing point. We called such a protocol as re-invention. Firstly,
a number of available reactions were examined using natu-
ral sinomenine (1) as the substrate so that we could under-
stand the chemo- and stereoselectivity under protecting-free
conditions (Scheme 1). Hydrogenation of 1 afforded a sin-
gle product 3 (79%) in the presence of 10% Pd/C [9], while
that using catalytic amount of PtO2 gave another single
product 4 (70%) [10]. Treatment of 1 with conc. HCl in
ethanol provided 5a (43%) and 5b (37%), and vicinal diac-
etal 6 was afforded when ethylene glycol was employed as
the solvent [6n]. Simple acid treatment of sinomenine pro-
vided a vicinal diketone compound 2 in 86% yield [7, 9a].
Considering the results of the above reactions and avail-
able further transformations, vicinal diketone 2 was finally
chosen as the starting material for introduction of small het-
erocycles in its C-ring. Two categories of derivatives 7
(fusing with an imidazole-ring to the C-ring, Table 1) and 8
Entry
1
2
3
4
5
6
7
8
R
CH3
Product
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
Yield (%) a)
67
53
80
77
53
75
75
61
71
66
48
78
56
74
p-CH3-C6H4
p-CH3(CH2)6-C6H4
o-Cl-C6H4
m-Cl-C6H4
p-Cl-C6H4
o-F-C6H4
p-Br-C6H4
9
o-CF3-C6H4
p-CH3O-C6H4
p-CH3SO2-C6H4
o-HO-C6H4
2,6-Cl2-C6H3
1-naphtyl
10
11
12
13
14
7m
7n
15
2-pyridinyl
7o
82
16
17
18
3-pyridinyl
2-furanyl
p-ph-C6H4
7p
7q
7r
7s
7t
86
85
61
72
79
19
2-(5-CH3-furanyl)
C6H5
20 b)
a) Isolated yields. b) Derivative 7t was confirmed by the X-ray single
crystallography analysis.

Wang M, et al. Sci China Chem December (2012) Vol.55 No.12
2539
(fusing with a pyrazine-ring to the C-ring, Table 2) were
conveniently prepared from 2 by corresponding one-pot
reactions, respectively.
tory cytokine models, natural sinomenine has been known
to involve in the treatment of rheumatoid arthritis as an in-
gredient of herb medicines. Modern researches also indicate
that TNF- expression in rheumatoid arthritis (RA) patients
is particularly elevated in RA synovial fluid, serum and
synovial fibroblasts. More importantly, these enhanced
TNF- levels correlate well with disease pathology and
severity. Application of anti TNF-α drugs in the clinic has
also proved that blocking TNF-α is an effective way to treat
RA [12].
Three-component reactions of 2 with a variety of alde-
hydes and ammonium acetate in EtOH afforded the corre-
sponding imidazoles 7a–7t in satisfactory yields. Their
structures were determined by NMR methods and further
confirmed by an X-ray single crystallographic structure of
representative derivative 7t. According to this evidence, the
chemistry nature of two newly introduced nitrogen atoms
(positions of NH and N) in derivatives 7 was finally eluci-
dated.
The other category of pyrazines derivatives 8a8r were
prepared by direct dehydrative condensation reactions of
diketone 2 with a variety of symmetrical vicinal diamines in
chloroform under mild conditions. Unfortunately, the reac-
tions with unsymmetrical vicinal diamines afforded a mix-
ture of two regioisomers, which were inseparable by chro-
matographic methods. The structures of few pure single
unsymmetrical isomers separated by several times of careful
chromatographies could not be clearly elucidated by the
NMR methods. For these unambiguous sample problems,
we did not further study them in this work.
With the above sinomenine derivatives in hand, the in
vitro effects on TNF-α production in LPS stimulated mouse
macrophage cells (J774) were then evaluated. TNF- inhib-
itory and stimulating effects of sinomenine (1) and its de-
rivatives 7a7s were assayed in LPS stimulated mouse
macrophage cells (J774) at 10 M concentration. All the
imidazole derivatives 7a7s exhibited TNF-α inhibitory
activity with a higher potency than sinomenine (Figure 2).
Among these, compound 7e (R = m-ClC6H4) bearing a
chlorobenzene moiety provided the highest score with a
47% inhibitory rate, while sinomenine 1 displayed only 7%
inhibitotion and diketone derivative 2 exhibited 26% inhibi-
tion. These imidazoles derived from various aromatic alde-
hydes (phenyl, naphthyl, pyridinyl, furanyl) were generally
found to improve the TNF-α inhibitory activity. This may
indicate that introduction of a lipophilic moiety is helpful.
Furthermore, introduction of one or two halogens into the
phenyl ring is also useful in activity improvement (7d, 7e,
7g, 7h and 7m). Chlorinated derivatives 7d, 7e and 7m are
listed in the four compounds (another one is 7j) exhibiting
over 40% inhibition. Minor change of the halogen position
can also influence the biological effects. Slight activity dif-
ference is found between 7d (R = o-ClC6H4) and 7e (R =
m-ClC6H4), while it is much greater by comparison with
compound 7f (R = p-ClC6H4, less than 20% TNF-α inhibi-
tion). In addition, a smaller substituent at ortho position of
the phenyl ring of R might be helpful for their anti-TNF-α
production activity (7d, R = o-ClC6H4; 7g, R = o-FC6H4; 7l,
R = o-HOC6H4; 7i, R = o-CF3C6H4).
Pyrazine derivatives 8a8r generally exhibit more po-
tent inhibitory effects on the TNF-α production in LPS
stimulated mouse macrophage cells (J774) (Figure 3).
Among these, derivatives 8h (R = o-BrC6H4) displayed
more than 70% inhibitory rate, and 8e (R = o-ClC6H4) and
8k (R = o-FC6H4) showed over 60% inhibitory rates. The
halogen is again found to be helpful in the biological effects.
An ortho halogen substituent in both newly introduced
phenyl rings improves the anti-TNF-α production activity.
Compared to 8c (R = Ph, 50% inhibition of TNF-α produc-
tion), the above three compounds gave higher scores in their
inhibitory activity. Other two substitution positions (meta,
para) seem insignificant in improving the bioactivity (8e vs.
8f and 8g; 8h vs. 8i and 8j; 8k vs. 8l and 8m). A para
substituent in both phenyl rings is again negative to the
Though it is weakly active in the cell or pro-inflamma-
Table 2 Synthesis of pyrazine-fused sinomenine derivatives 8a8r
Entry
1
Diamine/R
Product
Yield (%) a)
79
8a
2
8b
75
3 b)
4
Ph
8c
8d
8e
8f
75
65
59
66
62
64
63
61
66
68
69
75
70
74
71
69
1-naphthyl
o-Cl-C6H4
m-Cl-C6H4
p-Cl-C6H4
o-Br-C6H4
m-Br-C6H4
p-Br-C6H4
o-F-C6H4
5
6
7
8g
8h
8i
8
9
10
11
12
13
14
15
16
17
18
8j
8k
8l
m-F-C6H4
p-F-C6H4
8m
8n
8o
8p
8q
8r
p-CH3-C6H4
p-CF3-C6H4
o-CH3O-C6H4
m-CH3O-C6H4
p-CH3O-C6H4
a) Isolated yields. b) Reported in ref. [11].

2540
Wang M, et al. Sci China Chem December (2012) Vol.55 No.12
Figure 2 TNF- inhibitory and stimulating effects of sinomenine 1 and its derivatives 7a7s in LPS stimulated mouse macrophage cells (J774). Com-
pounds were assayed at 10 M concentration. SB202190 (4-(4-fluor- ophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole), a highly selective, potent
and cell permeable inhibitor of p38 MAP kinase, was used as the positive control [13]. Compound 7t was not determined. IR: inhibitory rate.
Figure 3 TNF- inhibitory and stimulating effects of sinomenine 1 and its derivatives 8a8r in LPS stimulated mouse macrophage cells (J774). Com-
pounds were assayed in 10 M concentration. SB202190 was used as the positive control. IR: inhibitory rate.
biological activity (8g, 8j, 8n, 8o, and 8r), and bigger
aromatic substituent (or ring system) is harmful (8a, 8b, and
8d) either.
introduced phenyl ring(s) can significantly improve the
immunomodulating activity. Further study on other
RA-related immunomodulating cytokines, as well as as-
sessment in animal models, will be reported in due course.
3 Conclusion
4 Experimental section
In summary, embedment of drug-like heterocyclic moieties
has been employed and proven to be an effective modifica-
tion protocol for the readily available but poorly active nat-
ural alkaloid sinomenine. Most of the newly prepared de-
rivatives are found to exhibit improved anti-TNF-α produc-
tion activity than natural sinomenine. Derivative 8h was
identified to significantly inhibit in vitro TNF-α production
in LPS stimulated mouse macrophage cells (J774) with a
73% inhibitory rate. The results also mention that introduc-
tion of a halogen atom at the proper position(s) of the newly
4.1 General
All reactions were conducted using oven-dried glassware.
All melting points were uncorrected. Dichloromethane was
distilled from CaH2, and tetrahydrofuran was distilled from
Na prior to uses. IR spectra were recorded on an FT-IR in-
strument. 1H NMR spectra were recorded at 300, 400 or 500
MHz, and 13C NMR spectra were recorded at 75, 100 or 125
MHz, and assigned in parts per million (δ). Reference peaks
for CDCl3 in H NMR and 13C NMR spectra were set at
1

Wang M, et al. Sci China Chem December (2012) Vol.55 No.12
2541
1.671.59 (2H, m), 1.23-1.20 (8H, m), 0.83 (3H, m); 13C
NMR (CDCl3, 125 MHz): δ 146.0, 144.6, 144.4, 131.2,
126.64, 126.59, 123.8, 118.7, 108.7, 57.1, 56.0, 46.9, 42.7,
42.5, 38.3, 37.3, 32.0, 31.6, 29.2, 28.9, 28.3, 27.5, 23.8,
23.6, 22.5, 14.0; IR (KBr): 3517, 2926, 2852, 1670, 1482,
1438, 1280, 1226, 1064, 1054, 856, 755 cm1; HRMS (ESI,
m/z) Anal. calcd for C26H38N3O2 (M+H+): 424.2959, found:
424.2957.
7.26 and 77.0 ppm, respectively. For CD3OD, the reference
peak of 13C NMR spectra was set at 49.00 ppm, respectively.
Petroleum ether and ethyl acetate were obtained from com-
mercial suppliers and used without distillation.
4.2 Synthesis of imidazoles 7a7t
To a solution of NH4OAc (2.45 g, 31 mmol) in EtOH (30
mL) was successively added diketone 2 (1.0 g, 3.2 mmol)
and the corresponding aldehyde (4.8 mmol) at room tem-
perature. The reaction mixture was stirred at this tempera-
ture and monitored by TLC. The solvent was concentrated
and the residue was then diluted with water and CH2Cl2.
The separated aqueous layer was basified with 10% aqueous
NaHCO3 to pH 8–9 and then extracted with CH2Cl2 for
three times. The combined organic layers were dried over
anhydrous Na2SO4, filtered, concentrated and the residue
was purified by flash chromatography using CH2Cl2 and
CH3OH as the eluents to afford the sinomenine derivative 7
(See Table 1 for the yields).
26
7d: Yellow solid. Mp: 158160 °C; [α]D 144.1 (c 1.7,
1
CHCl3/CH3OH = 10:1); H NMR (CDCl3, 400 MHz): δ
9.96 (1H, brs), 8.16 (1H, d, J = 7.6 Hz), 7.31 (1H, d, J = 8
Hz), 7.22 (1H, t, J = 7.6 Hz), 7.14 (1H, t, J = 7.6 Hz), 6.61
(1H, d, J = 8.4 Hz), 6.59 (1H, d, J = 8.8 Hz), 6.16 (1H, brs),
4.78 (1H, d, J = 16 Hz), 3.73 (3H, s), 3.13 (1H, s), 3.02 (1H,
d, J = 18.8 Hz), 2.92 (1H, dd, J = 6.4, 18.8 Hz), 2.67 (1H,
dd, J = 5.6, 15.2 Hz), 2.462.59 (3H, m), 2.45 (3H, s),
2.302.39 (1H, m), 2.19 (1H, dt, J = 2.4, 12 Hz), 2.00 (1H,
d, J = 12.8 Hz), 1.90 (1H, dt, J = 4.4, 12.8 Hz); 13C NMR
(CDCl3, 75 MHz): δ 144.4, 144.3 ,141.3, 131.2, 130.3,
130.1, 128.9, 128.6, 128.4, 127.1, 124.0, 118.5, 108.5, 57.2,
55.9, 46.9, 42.8, 42.7, 38.4, 37.4, 32.9, 24.9, 23.8; IR (KBr):
3440, 2910, 2842, 1614, 1481, 1437, 1279, 1225, 1104,
1052, 979, 761, 734 cm-1; HRMS (ESI, m/z) Anal. calcd for
C25H27ClN3O2 (M+H+): 436.1786, found: 436.1785.
25
7a: White solid. Mp: 147149 °C; [α]D 113.9 (c 0.18,
1
CHCl3/CH3OH = 10:1); H NMR (CDCl3, 300 MHz): δ
6.62 (1H, d, J = 8.7 Hz), 6.59 (1H, d, J = 9.0 Hz), 4.64 (1H,
d, J = 15.9 Hz), 3.77 (3H, s), 3.05-2.85 (3H, m), 2.542.25
(11H, m), 2.14 (1H, dt, J = 3.0, 12.3 Hz), 1.981.94 (1H, m),
1.84 (1H, dt, J = 4.8, 12.6 Hz); 13C NMR (CDCl3/CD3OD =
10:1, 125 MHz): δ 148.8, 148.5, 146.1, 134.9, 131.5, 131.1,
128.1, 122.3, 112.6, 61.2, 59.7, 50.8, 46.5, 46.3, 42.0, 41.2,
36.4, 28.3, 27.9, 17.2; IR (KBr): 3200, 2914, 2844, 1671,
1481, 1438, 1379, 1279, 1226, 1105, 1063, 1053, 1024, 795,
753, 662 cm1; HRMS (ESI, m/z) Anal. calcd for
C20H26N3O2 (M+H+): 340.2020, found: 340.2028.
26
7e: Yellow solid. Mp: 204206 °C; [α]D 149.3 (c 0.80,
1
CHCl3/CH3OH = 10:1); H NMR (CDCl3, 300 MHz): δ
7.71 (1H, s), 7.58 (1H, d, J = 6 Hz), 7.087.19 (2H, m),
6.506.63 (2H, m), 6.10 (1H, brs), 4.74 (1H, d, J = 15.9 Hz),
3.70 (3H, s), 3.08 (1H, s), 2.98 (1H, d, J = 18 Hz), 2.88 (1H,
dd, J = 5.4, 18.9 Hz), 2.502.67 (2H, m), 2.362.50 (2H, m),
2.44 (3H, s), 2.262.36 (1H, m), 2.092.25 (1H, m),
1.80-2.02 (2H, m); 13C NMR (CDCl3/CDOD3 = 10:1, 75
MHz): δ 144.7, 144.3, 142.8, 134.4, 132.2, 130.2, 129.9,
127.4, 124.4, 123.5, 122.6, 118.4, 108.7, 57.4, 55.8, 46.8,
42.1, 42.0, 37.6, 37.0, 32.4, 24.3, 23.8; IR (KBr): 2916,
2842, 1596, 1481, 1437, 1379, 1279, 1224, 1049, 1021, 979,
790.6, 729, 511 cm1; HRMS (MALDI, m/z) Anal. calcd for
C25H27ClN3O2 (M+ H+): 436.1786, found: 436.1782.
24
7b: White solid. Mp: 213214 °C; [α]D 175.7 (c 0.7,
CHCl3); 1H NMR (CDCl3, 400 MHz): δ 7.63 (2H, d, J = 8.4
Hz), 7.11 (2H, d, J = 8 Hz), 6.61 (1H, d, J = 8 Hz), 6.58
(1H, d, J = 8.4 Hz), 5.96 (1H, brs), 4.73 (1H, d, J = 16 Hz),
3.75 (3H, s), 3.09 (1H, s), 2.99 (1H, d, J = 18.4 Hz), 2.90
(1H, dd, J = 6, 18.4 Hz), 2.63 (1H, dd, J = 5.2, 15.2 Hz),
2.44 2.52 (3H, m), 2.44 (3H, s), 2.312.36 (1H, m), 2.31
(3H, s), 2.19 (1H, dt, J = 4.8, 12 Hz), 1.97 (1H, d, J = 12.8
Hz), 1.89 (1H, dt, J = 4.4, 12.8 Hz); 13C NMR (CDCl3, 100
MHz): δ 144.5, 144.4, 144.3, 137.3, 131.0, 129.2, 127.7,
124.7, 124.1, 118.4, 108.4, 57.1, 55.7, 46.8, 42.6, 42.5,
38.2, 37.2, 32.6, 24.5, 23.8, 21.2; IR (KBr): 3419, 2912,
2841, 1622, 1614, 1481, 1437, 1380, 1279, 1225, 1105,
1053, 1022, 823, 728 cm-1; HRMS (ESI, m/z) Anal. calcd for
C26H30N3O2 (M+H+): 416.2333, found: 416.2337.
7f: Yellow solid. Mp: 181183 °C (dec.); [α]D25 185.0 (c
0.49, CHCl3/CH3OH = 10:1); 1H NMR (CDCl3, 300 MHz):
δ 7.63 (2H, d, J = 9.0 Hz) 7.20 (2H, d, J = 9.0 Hz), 6.63 (1H,
d, J = 8.4 Hz), 6.60 (1H, d, J = 8.4 Hz), 5.91 (1H, brs), 4.71
(1H, d, J = 15.9 Hz), 3.76 (3H, s), 3.063.02 (2H, m),
2.87-2.79 (1H, m), 2.662.48 (4H, m), 2.42 (3H, s),
2.33-2.26 (1H, m), 2.14(1H, dt, J = 3.0, 12.3 Hz), 1.98-1.93
(1H, m), 1.84 (1H, dt, J = 4.8, 12.3 Hz); 13C NMR (CDCl3,
125 MHz): δ 144.4, 144.2, 143.4, 133.1, 131.5, 129.3, 128.7,
125.9, 124.2, 118.6, 108.4, 57.1, 55.9, 46.9, 43.0, 42.8, 38.5,
37.5, 32.9, 24.7, 23.8; IR (KBr): 3508, 2907, 2840, 1621,
1526, 1481, 1437, 1380, 1279, 1225, 1104, 1064, 1053,
1053, 834, 754 cm1; HRMS (ESI, m/z) Anal. calcd for
C25H27N3O2Cl (M+H+): 436.1786, found: 436.1785.
25
7c: White solid. Mp: 144146 °C (dec.); [α]D 126.5 (c
0.52, CHCl3/CH3OH = 10:1); 1H NMR (CDCl3, 300 MHz):
δ 6.64 (1H, d, J = 8.4 Hz), 6.60 (1H, d, J = 8.4 Hz), 4.70
(1H, d, J = 15.9 Hz), 3.79 (3H, s), 3.092.85 (3H; m), 2.66
(2H, t, J = 7.5 Hz), 2.622.51 (2H, m), 2.44 (3H, s),
2.462.36 (2H, m), 2.322.28 (1H, m), 2.17 (1H, dt, J = 2.4,
12.0 Hz), 1.991.95 (1H, m), 1.85 (1H, dt, J = 4.2, 12.6 Hz),
26
7g: Yellow solid. Mp: 158160 °C; [α]D 161.8 (c 2.0,
CHCl3/CH3OH = 10:1); 1H NMR (CDCl3, 400 MHz): δ 9.49

2542
Wang M, et al. Sci China Chem December (2012) Vol.55 No.12
2838, 1624, 1580, 1541, 1481, 1438, 1389, 1280, 1250,
1178, 1063, 1053, 1029, 835, 797, 733 cm1; HRMS (ESI,
m/z) Anal. calcd for C26H30N3O3 (M+H+): 432.2282, found:
432.2281.
(1H, brs), 8.14 (1H, s), 6.997.22 (3H, m), 6.536.63 (2H,
m), 6.13 (1H, brs), 4.75 (1H, d, J = 15.6 Hz), 3.73 (3H, s),
3.11 (1H, s), 3.01 (1H, d, J = 18.4 Hz), 2.90 (1H, dd, J = 6,
18.4 Hz), 2.592.73 (1H, m), 2.472.57 (3H, m), 2.43 (3H,
s), 2.282.37 (1H, m), 2.17 (1H, dt, J = 2.4, 12 Hz), 1.99
(1H, d, J = 12.8 Hz), 1.89 (1H, dt, J = 4.4, 12.8 Hz); 19F
NMR (CDCl3/CD3OD = 10:1, 300 MHz): δ 118.92; 13C
NMR (CDCl3, 75 MHz): δ 159.0 (d, J = 242.9 Hz), 144.4,
144.2, 139.3, 131.4, 128.6 (d, J = 8.8 Hz), 128.0, 124.7,
124.0, 118.5, 118.2 (d, J = 10.5 Hz), 115.6 (d, J = 22.7 Hz),
108.4, 57.1, 55.8, 46.9, 42.9, 42.8, 38.4, 37.4, 32.4, 25.3,
23.8; IR (KBr): 3473, 2909, 2841, 1624, 1609, 1581, 1527,
1481, 1465, 1438, 1279, 1225, 1063, 1052, 1023, 759, 733
cm-1; HRMS (ESI, m/z) Anal. calcd for C25H27N3O2F
(M+H+): 420.2082, found: 420.2081.
26
7k: Yellow solid. Mp: 242 °C (dec.); [α]D 138.5 (c
0.80, CHCl3/CH3OH = 10:1); 1H NMR (CDCl3, 300 MHz):
δ 11.17 (1H, brs), 7.79 (2H, d, J = 8 Hz), 7.63 (2H, d, J =
7.6 Hz), 6.486.66 (2H, m), 6.15 (1H, brs), 4.77 (1H, d, J =
12 Hz), 3.67 (3H, s), 3.07 (1H, s), 2.773.03 (2H, m), 2.96
(3H, s), 2.552.68 (1H, m), 2.402.55 (3H, m), 2.41 (3H,
s), 2.242.35 (1H, m), 2.072.21 (1H, m), 1.94 (1H, d, J =
12.4 Hz), 1.76-1.89 (1H, m); 13C NMR (CDCl3, 75 MHz): δ
144.6, 144.2, 142.2, 138.0, 135.5, 131.0, 127.5, 124.8,
123.9, 118.6, 108.5, 57.1, 55.8, 46.8, 44.2, 42.6, 38.2, 37.3,
23.7, 23.6; IR (KBr): 3419, 2913, 2814, 1593, 1481, 1437,
1279, 1149, 1053, 956, 779, 729, 557 cm1; HRMS (ESI,
m/z) Anal. calcd for C26H30N3O4S (M+H+): 480.1952,
found: 480.1914.
25
7h: White solid. Mp: 216218 °C; [α]D 149.7 (c 1.4,
CHCl3/CH3OH = 10:1); 1H NMR (CDCl3, 400 MHz): δ 7.58
(2H, d, J = 8.4 Hz), 7.34 (2H, d, J = 8.4 Hz), 6.62 (1H, d, J
= 8.4 Hz), 6.59 (1H, d, J = 8.4 Hz), 5.99 (1H, brs), 4.72
(1H, d, J = 15.6 Hz), 3.74 (3H, s), 3.07 (1H, s), 2.98 (1H, d,
J = 18.8 Hz), 2.87 (1H, dd, J = 6.0, 18.8 Hz), 2.432.67
(4H, m), 2.43 (3H, m), 2.262.36 (1H, m), 2.092.23 (1H,
m), 1.95 (1H, d, J = 12.4 Hz), 1.87 (1H, dt, J = 4, 12.4 Hz);
13C NMR (CDCl3, 75 MHz): δ 144.4, 144.2, 143.4, 131.7,
131.2, 129.6, 126.1, 124.0, 121.3, 118.6, 108.3, 57.2, 55.9,
46.9, 42.8, 38.3, 37.4, 32.8, 24.7, 23.7; IR (KBr): 3431,
2911, 2841, 1619, 1481, 1437, 1379, 1279, 1225, 1105,
25
7l: Brown solid. Mp: 208210 °C; [α]D 190.0 (c 0.50,
1
CHCl3/CH3OH = 10:1); H NMR (CDCl3, 400 MHz): δ
9.55 (1H, brs), 7.35 (1H, d, J = 6.8 Hz), 7.13 (1H, t, J = 7.6
Hz), 6.96 (1H, d, J = 8 Hz), 6.77 (1H, t, J = 7.2 Hz),
6.556.65 (2H, m), 4.74 (1H, d, J = 16 Hz), 3.74 (3H, s),
3.10 (1H, s), 3.01 (1H, d, J = 18.8 Hz), 2.90 (1H, dd, J =
5.6, 18.8 Hz), 2.432.67 (4H, m), 2.48 (3H, s), 2.232.35
(1H, m), 2.092.23 (1H, m), 1.98 (1H ,d, J = 12.4 Hz), 1.83
(1H, dt, J = 4, 12 Hz); 13C NMR (CDCl3, 75 MHz): δ 156.8,
144.5, 144.3, 144.2; 131.1, 129.0, 123.9, 123.0, 118.5,
117.2, 113.8, 108.5, 57.1, 55.8, 46.8, 42.6, 38.2, 37.3, 32.5,
24.6, 23.8; IR (KBr): 3405, 2911, 2842, 1625, 1590, 1483,
1456, 1438, 1381, 1279, 1226, 1052, 755 cm1; HRMS
(ESI, m/z) Anal. calcd for C25H28N3O3 (M+H+): 418.2125,
found: 418.2131.
1064, 1023, 831, 727 cm1 HRMS (ESI, m/z) Anal. calcd
;
for C25H27BrN3O2 (M+H+): 480.1281, found: 480.1372.
25
7i: White solid. Mp: 164166 °C (dec.); [α]D 142.4 (c
0.54, CHCl3/CH3OH = 10:1); 1H NMR (CDCl3, 300 MHz):
δ 9.15 (1H, brs), 7.96 (1H, d, J = 7.2 Hz), 7.68 (1H, d, J =
7.8 Hz), 7.53 (1H, t, J = 7.5 Hz), 7.40 (1H, t, J = 7.5 Hz),
6.65 (1H, d, J = 8.1 Hz), 6.61 (1H, d, J = 8.1 Hz), 6.06 (1H,
brs), 4.74 (1H, d, J = 15.3 Hz), 3.78 (3H, s), 3.152.84 (3H,
m), 2.722.51 (4H, m), 2.47 (3H, s), 2.442.36 (1H, m),
2.21 (1H, dt, J = 3.6, 12.0 Hz), 2.031.92 (2H, m); IR (KBr):
3512, 2844, 1606, 1580, 1482, 1493,1315, 1280, 1126,
1054, 755 cm1; HRMS (ESI, m/z) Anal. calcd for
C26H27N3O2F3 (M+H+): 470.2050, found: 470.2048; Anal
calcd. for C26H26F3N3O2: C, 66.51; H, 5.58; N, 8.95; found:
C, 66.34; H, 5.96; N, 8.60.
26
7m: Light yellow solid. Mp: 208210 °C; [α]D 72.4 (c
1
1.5, CHCl3/CH3OH = 10:1); H NMR (CDCl3/CD3OD =
10/1, 400 MHz): δ 7.32 (2H, d, J = 8 Hz), 7.22 (1H, t, J = 8
Hz), 6.65 (1H, d, J = 8 Hz), 6.60 (1H, d, J = 8.4 Hz), 4.75
(1H, d, J = 16 Hz), 3.77 (3H, s), 3.39 (1H, s), 2.873.03
(2H, m), 2.34-2.64 (4H, m), 2.44 (3H, s), 2.112.34 (2H,
m), 2.00 (1H, d, J = 12.8 Hz), 1.73-1.92 (1H, m); 13C NMR
(CDCl3/CD3OD = 10/1, 75 MHz): δ 144.6, 144.4, 138.0,
136.3, 130.7, 130.5, 130.4, 127.8, 123.8, 118.4, 108.7, 57.2,
56.0, 46.7, 42.2, 37.8, 37.1, 32.4, 24.4, 23.8; IR (KBr):
3435, 2911, 1614, 1551, 1482, 1435, 1278, 1224, 1059,
784, 501 cm1; HRMS (MALDI, m/z) Anal. calcd for
C25H26Cl2N3O2 (M+H+) 470.1397, found: 470.1407.
26
7j: Yellow solid. Mp: 186188 °C; [α]D 162.4 (c 2.3,
1
CHCl3/CH3OH = 10:1); H NMR (CDCl3, 400 MHz): δ
8.95 (1H, brs), 7.67 (2H, d, J = 8.4 Hz), 6.73 (2H, d, J = 8.4
Hz), 6.5261 (2H, m), 5.96 (1H, brs), 4.69 (1H, d, J = 16
Hz), 3.72 (3H, s), 3.68 (3H, s), 3.01 (1H, s), 2.95 (1H, d, J =
18.4 Hz), 2.81 (1H, dd, J = 5.6, 18.4 Hz), 2.58 (1H, dd, J =
5.6, 15.6 Hz), 2.382.53 (3H, m), 2.38 (3H, s), 2.212.31
(1H, m), 2.062.18 (1H, m), 1.90 (1H, d, J = 12.4 Hz), 1.81
(1H, dt, J = 4, 12.4 Hz); 13C NMR (CDCl3, 75 MHz): δ
159.1, 144.4, 144.2, 131.4, 130.2, 128.6, 126.2, 124.3,
123.4, 118.4, 113.9, 108.2, 57.1, 55.7, 55.1, 46.9, 42.9,
42.7, 38.4, 37.3, 32.6, 24.6, 23.7; IR (KBr): 3429, 2910,
7n: Yellow solid. Mp: 250 °C (dec.); [α]D26 60.7 (c 0.40,
1
CHCl3/CH3OH = 10:1); H NMR (CDCl3, 400 MHz): δ
8.36 (1H, s), 7.90 (2H, d, J = 8.4 Hz), 7.68 (2H, d, J = 8.4
Hz), 7.35 (2H, t, J = 7.6 Hz), 7.197.31 (2H, m), 6.57 (1H,
d, J = 8 Hz), 6.48 (1H, d, J = 8 Hz), 5.83 (1H, brs), 4.22
(1H, d, J = 16 Hz), 3.71 (3H, s), 2.79 (1H, d, J = 18.4 Hz),
2.462.69 (2H, m), 2.342.44 (1H, m), 2.31 (3H, s),
1.762.13 (5H, m), 1.67 (1H, d, J = 12.4 Hz), 1.431.61

Wang M, et al. Sci China Chem December (2012) Vol.55 No.12
2543
(1H, m); 13C NMR (CDCl3, 75 MHz): δ 144.4, 144.3, 140.7,
131.5, 128.0, 127.9, 126.4, 125.8, 125.1, 124.0, 118.3,
108.5, 57.0, 56.0, 46.7, 42.4, 42.2, 37.7, 36.9, 32.2, 24.1,
23.6; IR (KBr): 3408, 3048, 2912, 2841, 1623, 1481, 1457,
1437, 1278, 1226, 1053, 735 cm1; HRMS (ESI, m/z) Anal.
calcd for C33H32N3O2 (M+H+): 502.2489, found: 502.2501.
7.84 (2H, d, J = 8.0 Hz), 7.52 (2H, d, J = 7.6 Hz), 7.46 (2H,
d, J = 7.6 Hz), 7.37 (2H, t, J = 7.2 Hz), 7.29 (1H, t, J = 7.2
Hz), 6.446.54 (2H, m), 5.99 (1H, brs), 4.74 (1H, d, J = 16
Hz), 3.58 (3H, s), 3.03 (1H, s), 2.94 (1H, d, J = 18.8 Hz),
2.82 (1H, dd, J = 5.2, 18.4 Hz), 2.64 (1H, dd, J = 5.6, 15.6
Hz), 2.402.56 (3H, m), 2.39 (3H, s), 2.242.35 (1H, m),
2.042.18 (1H, m), 1.751.98 (2H, m); 13C NMR (CDCl3,
75 MHz): δ 144.3, 144.2, 144.1, 140.3, 139.7, 131.2, 129.6,
128.6, 127.1, 127.0, 126.7, 125.1, 124.1, 118.4, 108.2, 57.1,
55.6, 46.8, 42.8, 42.7, 38.3, 37.3, 32.8, 24.6, 23.7; IR (KBr):
3497, 2908, 2840, 1622, 1581, 1481, 1437, 1279, 1225,
1104, 1063, 1053, 845, 767, 732, 698 cm1; HRMS
(MALDI, m/z) Anal. calcd for C31H32N3O2 (M+H+):
478.2489, found: 478.2485.
26
7o: Yellow solid. Mp: 172174 °C; [α]D 182.9 (c 2.6,
1
CHCl3/CH3OH = 10:1); H NMR (CDCl3, 400 MHz): δ
10.85 (1H, brs), 8.39 (1H, d, J = 4.4 Hz), 8.01 (1H, d, J =
5.2 Hz), 7.63 (1H, t, J = 8 Hz), 7.027.12 (1H, m),
6.506.60 (2H, m), 6.28 (1H, brs), 4.69 (1H, brs), 3.68 (3H,
s), 3.09 (1H, s), 2.99 (1H, d, J = 18.4 Hz), 2.802.93 (1H,
m), 2.572.76 (1H, m), 2.402.57 (3H, m), 2.41 (3H, s),
2.252.35 (1H, m), 2.082.21 (1H, m), 1.95 (1H, d, J = 12
Hz), 1.85 (1H, dt, J = 3.6, 12.4 Hz); 13C NMR (CDCl3, 75
MHz): δ 148.9, 148.4, 144.4, 144.3, 143.8, 136.8, 131.4,
124.1, 122.0, 119.2, 118.4, 108.4, 57.1, 55.8, 46.8, 42.9,
42.7, 38.4, 37.3, 32.6, 25.8, 23.8; IR (KBr): 3445, 2909,
2841, 1589, 1522, 1480, 1457, 1437, 1402, 1278, 1225,
1148, 1101, 1063, 1052, 730 cm-1; HRMS (MALDI, m/z)
Anal. calcd for C24H27N4O2 (M+H+): 403.2129, found:
403.2129.
26
7s: Yellow solid. Mp: 194196 °C; [α]D 231.0 (c 0.40,
CHCl3); 1H NMR (CDCl3, 400 MHz): δ 6.516.67 (3H, m),
5.97 (1H, d, J = 2.8 Hz), 4.70 (1H, d, J = 15.6 Hz), 3.75
(3H, s), 3.12 (1H, s), 3.00 (1H, d, J = 18.8 Hz), 2.90 (1H,
dd, J = 6, 18.8 Hz), 2.62 (1H, dd, J = 5.6, 14.8 Hz),
2.502.57 (1H, m), 2.392.49 (2H, m), 2.43 (3H, s),
2.292.36 (1H, m), 2.27 (3H, s), 2.18 (1H, dt, J = 2.8, 12
Hz), 1.97 (1H, d, J = 12.4 Hz), 1.88 (1H, dt, J = 4.4, 12.8
Hz); 13C NMR (CDCl3, 75 MHz): δ 151.1, 144.8, 144.4,
144.3, 137.5, 131.1, 124.1, 118.4, 108.4, 107.5, 106.5, 57.1,
55.8, 46.7, 42.6, 42.5, 38.2, 37.3, 32.6, 24.7, 23.8, 13.4; IR
(KBr): 3432, 2916, 2842, 1609, 1580, 1481, 1438, 1279,
1225, 1053, 1022, 788 cm1; HRMS (ESI, m/z) Anal. calcd
for C24H28N3O3 (M+H+): 406.2125, found: 406.2141.
7p: Yellow solid. Mp: 203205 °C (dec.); [α]D2 184.3 (c
1
0.52, CHCl3/CH3OH = 10:1); H NMR (CDCl3/CH3OD =
10:1, 500 MHz): δ 8.91 (1H, s), 8.39 (1H, d, J = 4.8 Hz),
8.14 (1H, m), 7.36(1H, dd, J = 4.8, 7.9 Hz), 6.67(1H, d, J =
8.3 Hz), 6.62 (1H, d, J = 8.3 Hz), 4.90 (1H, J = 15.9 Hz),
3.71 (3H, s), 3.16 (1H, s), 3.083.04 (2H, m), 2.692.65
(1H, m), 2.572.47 (3H, m), 2.46 (3H, s), 2.352.33 (1H,
m), 2.282.23 (1H, m), 2.072.05 (1H, m), 1.88 (1H, dt, J =
5.6, 12.9 Hz); 13C NMR (CDCl3/CD3OD = 10:1, 125 MHz):
δ 146.9, 144.7, 144.6, 144.3, 140.5, 132.2, 130.1, 127.0,
123.6, 123.2, 118.0, 108.5, 56.8, 55.2, 46.3, 41.9, 41.6,
37.4, 36.7, 32.2, 24.0, 23.4; IR (KBr): 3180, 3050, 2900,
1577, 1483, 1439, 1397, 1329, 1281, 1128, 1056, 1022,
851, 813, 755, 709, 653 cm1; HRMS (ESI, m/z) Anal. calcd
for C24H27N4O2 (M+H+): 403.2129, found: 403.2130.
25
7t: White solid. Mp: 205208 °C; [α]D 190.9 (c 0.48,
1
CHCl3/CH3OH = 10:1); H NMR (CDCl3/CD3OD = 10:1,
300 MHz): δ 7.737.70 (2H, m), 7.347.31 (2H, m),
7.277.22 (1H, m), 6.64 (1H, d, J = 8.1 Hz), 6.59 (1H, d, J
= 8.1 Hz), 4.79 (1H, d, J = 15.6 Hz), 3.77 (3H, s), 3.093.08
(1H, m), 2.992.97 (2H, m), 2.642.59 (1H, m), 2.54 2.44
(3H, m), 2.42 (3H, s), 2.33-2.28 (1H, m), 2.20 (1H, dt, J =
3.0, 12.3 Hz), 2.031.99 (1H, m), 1.84 (1H, dt, J = 4.8, 12.9
Hz); 13C NMR (CDCl3/CD3OD=10:1, 125 MHz): δ 144.6,
144.3, 144.2, 130.8, 130.4, 128.4(2C), 127.5, 124.4 (2C),
123.9, 118.3, 108.6, 57.0, 55.7, 46.7, 42.4, 42.2, 37.9, 37.1,
32.5, 24.3, 23.7; IR (KBr): 3508, 2909, 2840, 1623, 1602,
1481, 1458, 1437, 1400, 1278, 1225, 1105, 1063, 1054,
1022, 856, 771, 701, 695 cm1; HRMS (ESI, m/z) Anal.
calcd for C25H28N3O2 (M+H+): 402.2176, found: 402.2179.
25
7q: White solid. Mp: 160162 °C (dec.); [α]D 162.9 (c
0.56, CHCl3/CH3OH = 10:1); 1H NMR (CDCl3, 500 MHz):
δ 7.18 (1H, s), 6.62 (1H, d, J = 3.2 Hz), 6.58 (1H, d, J =
8.9), 6.56 (1H, d, J = 9.0 Hz), 6.27 (1H, d, J = 1.3 Hz),
4.72(1H, d, J = 16.0 Hz), 3.66 (3H, s), 3.08 (1H, s), 2.97
(1H, d, J = 18.6 Hz), 2.88 (1H, dd, J = 6.1, 18.6 Hz),
2.612.53 (2H, m), 2.482.43 (2H, m), 2.43 (3H, s),
2.352.26 (1H, m), 2.202.15 (1H, m), 1.961.93 (1H, m),
1.85 (1H, dt, J = 4.0, 12.5 Hz); 13C NMR (CDCl3, 125
MHz): δ 145.5, 143.4, 143.3, 140.1, 136.2, 130.1, 127.1(2C),
123.0, 117.4, 110.4, 107.5, 104.5, 56.1, 54.8, 45.8, 41.6,
41.5, 37.1, 36.3, 31.6, 23.7, 22.9; IR (KBr): 3503, 2909,
2841, 1604, 1481, 1438, 1279, 1224, 1063, 1053, 1013, 753
cm1; HRMS (ESI, m/z) Anal. calcd for C23H26N3O3
(M+H+): 392.1969, found: 392.1975.
4.3 Synthesis of pyrazines 8a8r
A mixture of diketone 2 and the corresponding diamine 9 in
CHCl3 was stirred at room temperature until completion of
the reaction by TLC monitoring. After removal of the sol-
vent, the residue was purified by flash chromatography us-
ing the mixture of CH2Cl2 and CH3OH as the eluent to af-
ford sinomenine derivative 8 (See Table 2 for the yields).
8a: Yellow solid. Mp: 207209 °C (dec.); []D20 222.9 (c
26
7r: Yellow solid. Mp: 215217 °C; [α]D 175.0 (c 2.6,
1
1
CHCl3/CH3OH = 10:1); H NMR (CDCl3, 400 MHz): δ
0.53, CHCl3); H NMR (CDCl3, 300 MHz):  7.55 (1H, s),

2544
Wang M, et al. Sci China Chem December (2012) Vol.55 No.12
1654, 1484, 1439, 1379, 1280, 1151, 1054, 803, 778 cm1;
HRMS (ESI, m/z) Anal. calcd for C40H36N3O2 (M+H+):
590.2808; found: 590.2802.
7.50 (1H, s), 6.60 (1H, d, J = 8.3 Hz), 6.54 (1H d, J = 8.3
Hz), 5.02 (1H, d, J = 17.0 Hz), 3.62 (3H, s), 3.192.93 (6H,
m), 2.582.55 (2H, m), 2.46 (3H, s), 2.36 (3H, s), 2.31 (3H,
s), 2.22 (1H, dt, J = 3.0, 12.9 Hz), 2.1(1H,d, J = 12.9 Hz)
1.91(1H, dt, J = 4.8, 13.2 Hz); 13C NMR (CDCl3, 75 MHz):
 152.8, 152.4, 145.0, 144.6, 140.4, 140.1, 138.83, 138.77,
131.3, 127.657, 127.2, 123.7, 118.7, 109.0, 77.6, 77.2, 76.8,
56.7, 55.9, 47.0, 44.6, 43.1, 43.0, 38.3, 36.3, 33.6, 23.4,
20.3, 20.2; IR (KBr): 2916, 2802, 1604 1483, 1439, 1335,
1274, 1228, 1153, 1104, 1066, 1054, 1023, 989, 867, 857,
792 cm1; HRMS (EI, m/z): Anal. calcd for C26H30N3O2
(M+): 416.2333, found: 416.2345; Anal. calcd for
C26H29N3O2: C, 75.15; H, 7.03; N, 10.11; found: C, 74.84;
H, 7.29; N, 10.12.
25
8e: Yellow soild. Mp: 142146 °C; [α]D 98.2 (c 0.91,
MeOH); 1H NMR (CDCl3, 300 MHz): δ 7.307.07 (8H, m),
6.70 (2H, dd, J = 8.4, 17.1 Hz ), 5.06 (1H, d, J = 18.0 Hz),
3.82 (3H, s), 3.69 (1H, s), 3.342.89 (6H, m), 2.80 (3H, s),
2.64 (1H, m), 2.41 (1H, m), 2.23 (1H, d, J = 12.6 Hz); 13C
NMR (CDCl3, 75 MHz): δ 150.1, 149.1, 149.0, 148.8,
145.4, 145.4, 144.7, 136.9, 136.8, 133.1, 133.0, 131.05,
130.98, 129.5 (2C), 129.4 (2C), 127.2, 126.1 (2), 121.5,
118.9, 109.7, 58.1, 56.0, 47.2, 41.3, 39.1, 35.4, 35.1, 31.7,
29.5, 23.9; IR (KBr): 3390, 2923, 2851, 1611, 1484, 1438,
1392, 1280, 1155, 1054, 760, 739, 468 cm1; HRMS (ESI,
m/z) Anal. calcd for C32H30Cl2N3O2 (M+H+): 558.1715;
found: 558.1713.
8b: Yellow soild. Mp: 205207 °C (dec.); []D20 203.2 (c
1
0.53, CHCl3); H NMR (CDCl3, 300 MHz): δ 8.04 (1H, s),
8f：Yellow solid. Mp: 121~131 °C; [α]D25 103.5 (c 0.80,
7.94 (1H, s), 6.62 (1H, d, J = 8.4 Hz), 6.58 (1H, d, J = 8.4
Hz), 6.21 (1H, brs), 4.99 (1H, d, J = 17.4 Hz), 3.71 (3H, s),
3.242.88 (6H, m), 2.572.50 (2H, m), 2.47 (3H, s), 2.20
(1H, dt, J = 2.4, 12.3 Hz), 2.09(1H, d, J = 12.3 Hz) 1.91
(1H, dt, J = 4.2, 12.6 Hz); 13C NMR (CDCl3, 125 MHz): δ
155.3, 155.0, 144.7, 144.4, 140.1, 134.0, 132.82, 132.79,
131.0, 129.2, 128.8, 122.9, 118.7, 109.0, 56.4, 55.9, 46.8,
44.6, 43.0, 42.7, 38.1, 36.2, 33.5, 23.1; IR (KBr): 2910,
1603, 1482, 1453, 1441, 1416, 1328, 1279, 1230, 1175,
1153, 1105, 1053, 879, 854, 731, 429 cm1; HRMS (EI,
m/z): Anal. calcd for C24H24N3O2Cl2 (M+): 456.1240, found:
456.1228.
MeOH); 1H NMR (CDCl3, 500 MHz): δ 7.537.25 (4H, m),
7.18-7.09 (4H, m), 6.66 (2H, s), 5.05 (1H, d, J = 17.5 Hz),
3.79 (3H, s), 3.20 (1H, s), 3.1308 (2H, m), 2.992.90
(3H, m), 2.622.50 (3H, m), 2.50 (3H, s), 2.24 (1H, t, J =
12.0 Hz), 2.12 (1H, d, J = 12.5 Hz), 1.94 (1H, m); 13C NMR
(CD3OD, 75 MHz): δ 152.0, 151.0, 149.5, 149.4, 147.2,
146.5, 141.5 (2), 135.15, 135.10, 130.8, 130.64, 130.60,
130.56, 129.9, 129.5 (2), 129.3, 129.2, 123.1, 119.7, 111.1,
58.9, 56.4, 48.0, 42.8, 42.2, 41.8, 37.4, 36.6, 32.8, 24.6; IR
(KBr): 3502, 2905, 2836, 1594, 1568, 1482, 1437, 1380,
1279, 1151, 1053, 785, 691, 462 cm1; HRMS (ESI, m/z)
Anal. calcd for C32H30Cl2N3O2 (M+H+): 558.1715; found:
558.1712.
8c [11]: Yellow solid. [α]D20 = +215.0 (c = 0.53, CHCl3);
1H NMR (CDCl3, 300 MHz): δ 8.017.98 (1H, m),
7.87-7.84 (1H, m), 7.647.57 (2H, m), 6.61 (1H, d, J = 8.4
Hz), 6.57 (1H, d, J = 8.4 Hz), 6.06 (1H, brs), 5.02 (1H, d, J
= 17.4 Hz), 3.71 (3H, s), 3.272.88 (6H, m), 2.612.53 (2H,
m), 2.48 (3H, s), 2.22 (1H, dt, J=2.4, 12.3 Hz), 2.10 (1H, J
= 12.9 ) 1.92 (1H; dt, J = 4.5, 12.9 Hz); 13C NMR
(CDCl3/CD3OD = 10:1, 125 MHz): 153.6, 153.3, 144.7,
144.3, 140.8, 140.5, 130.2, 128.9 (2C), 127.6, 127.5, 122.3,
118.3, 109.1, 56.3, 55.6, 46.6, 43.7, 42.3, 42.0, 41.9, 37.3,
35.8, 32.9, 23.0; IR (KBr): 2932, 1602, 1483, 1400, 1356,
1276, 1228, 1066, 1053, 836, 761 cm1; HRMS (EI, m/z):
Anal. calcd for C24H26N3O2 (M+): 388.2020, found:
388.2012.
25
8g: Yellow solid. Mp: 183186 °C; []D 96.1 (c 0.93,
1
MeOH); H NMR (CD3OD/CDCl3 = 1:1, 300 MHz): δ
7.27-7.20 (8H, m), 6.69 (2H, dd, J = 8.4, 18.6 Hz), 5.11
(1H, d, J = 17.4 Hz), 3.77 (3H, s), 3.56 (1H, s), 3.172.84
(6H, m), 2.56 (3H, s), 2.34 (1H, m), 2.22 (1H, d, J = 12.3
Hz), 2.04 (1H, m); 13C NMR (CD3OD/CDCl3 = 2:1, 75
MHz): δ 151.0, 150.1, 149.34, 149.29, 146.3, 145.7, 137.3,
135.3, 131.7, 131.6, 129.3, 129.0, 122.6, 119.3, 110.4, 58.0,
56.2, 47.6, 42.1, 41.3, 37.1, 36.0, 32.3, 30.2, 24.2; IR (KBr):
3297, 2934, 2517, 1595, 1485, 1443, 1389, 1279, 1158,
1091, 1013, 840, 462 cm1; HRMS (ESI, m/z) Anal. calcd
for C32H30Cl2N3O2 (M+H+): 558.1715; found: 558.1711.
8d：Yellow solid. Mp: 214217 °C (dec.); [α]D25 99.9 (c
25
8h: Yellow solid. Mp: 102106 °C; [α]D 40.4 (c 0.91,
1
MeOH); 1H NMR (CDCl3, 500 MHz): δ 7.537.49 (2H, m),
7.347.22 (2H, m), 7.177.07 (4H, m), 6.66 (2H, dd, J= 8.0,
14.0 Hz ), 4.98 (1H, d, J = 17.5 Hz), 3.81 (3H, s), 3.69 (1H,
s), 3.203.08 (3H, m), 2.972.91 (3H, m), 2.632.58 (2H,
m), 2.50 (3H, s), 2.23 (1H, m), 2.10 (1H, m), 1.94 (1H, m);
13C NMR (CDCl3, 75 MHz): δ 151.2, 150.7, 149.5, 149.3,
144.6, 144.4, 138.9, 138.8, 132.7, 132.7, 131.2, 130.8,
129.5, 129.4, 128.7, 127.6, 126.7, 123.3, 123.1, 118.5,
108.9, 56.5, 56.1, 46.8, 42.8, 42.7, 42.5, 37.8, 36.1, 32.4,
23.2; IR (KBr): 3053, 2907, 2853, 1608, 1482, 1437, 1391,
1279, 1153, 1024, 762, 734, 657 cm1; HRMS (ESI, m/z)
0.28, MeOH); H NMR (CDCl3, 400 MHz): δ 7.697.83
(4H, m), 7.567.65 (2H, m), 7.277.48 (5H, m), 6.957.08
(3H, m), 6.70 (2H, dd, J= 8.2, 23.8), 5.09 (1H, d, J =17.2),
3.86 (3H, s), 3.34 (1H, s), 3.23 (1H, dd, J = 6.6, 18.2),
2.853.15 (4H, m), 2.682.82 (2H, m), 2.56 (3H, s),
2.302.40 (1H, m), 2.022.20 (2H, m); 13C NMR (CDCl3,
100 MHz): δ 150.1, 151.0, 150.2, 149.4, 144.9, 144.6, 135.9,
135.8, 133.6, 133.5, 131.9, 131.6, 128.34 (2), 128.33 (2),
128.13, 128.08, 127.5, 126.1, 126.0, 125.6, 125.5, 124.60,
124.58, 123.1, 118.8, 109.1, 57.1, 56.1, 47.1, 42.4 (d), 41.7,
37.4, 36.0, 32.4, 29.7, 23.4; IR (KBr): 3425, 2926, 2845,

Wang M, et al. Sci China Chem December (2012) Vol.55 No.12
2545
Anal. calcd for C32H30Br2N3O2 (M+H+): 648.0684; found:
648.0686.
1612, 1586, 1485, 1440, 1390, 1280, 1230, 1153, 1054,
789, 701, 458 cm1; HRMS (ESI, m/z) Anal. calcd for
C32H30F2N3O2 (M+H+): 526.2301; found: 526.2301.
25
8i: Yellow solid. Mp: 168172 °C; [α]D 81.9 (c 1.00,
MeOH); 1H NMR (CDCl3, 300 MHz): δ 7.677.59 (2H, m),
7.447.41 (2H, m), 7.167.05 (4H, m), 6.69 (2H, d, J =
3.0Hz ), 5.06 (1H, d, J = 17.7 Hz), 3.81 (3H, s), 3.77 (1H, s),
3.203.08 (3H, m), 2.972.91 (3H, m), 2.632.58 (2H, m),
2.50 (3H, s), 2.23 (1H, m), 2.10 (1H, m), 1.94 (1H, m); 13C
NMR (CDCl3, 75 MHz): δ 149.6, 148.4, 148.21, 148.16,
145.4, 144.6, 140.2 (2), 132.4, 132.3, 131.4, 131.3, 129.5,
129.4, 128.3, 128.1, 126.6, 122.32, 122.27, 121.1, 118.9,
109.5, 58.2, 55.7, 47.2, 41.2, 38.8, 35.2, 34.9, 31.5, 29.6,
23.9; IR (KBr): 3053, 2907, 2853, 1608, 1482, 1437, 1391,
1279, 1153, 1024, 762, 734, 657 cm1; HRMS (ESI, m/z)
Anal. calcd for C32H30Br2N3O2 (M+H+): 648.0684; found:
648.0682.
8m: Yellow solid. Mp: 170176 °C; [α]D25 114.3 (c 0.94,
MeOH); 1H NMR (CDCl3, 300 MHz): δ 7.377.27 (4H, m),
6.996.92 (4H, m), 6.70 (2H, dd, J = 9.0, 3.3 Hz), 6.21 (1H,
brs), 5.04 (1H, d, J = 17.1 Hz), 3.79 (3H, s), 3.69 (1H, s),
3.43 (1H, dd J = 6.6, 19.5 Hz), 3.202.88 (6H, m), 2.83
(3H, s), 2.64 (1H, m), 2.42 (1H, m), 2.23(1H, d, J = 12.9
Hz); 13C NMR (CD3OD/CDCl3 = 5:1, 75 MHz): δ 163.8
(2C) (J = 246.9), 150.6, 149.9, 149.8, 149.5, 147.0, 146.1,
135.3, 132.5, 132.4, 132.3, 128.4, 122.2, 119.6, 116.0,
115.7, 111.0, 59.2, 56.3, 48.0, 42.0, 41.7, 40.8, 36.5, 36.0,
32.2, 24.6; IR (KBr): 3383, 2923, 2850, 1604, 1510, 1484,
1439, 1280, 1225, 1156, 1054, 840, 556 cm1; HRMS (ESI,
m/z) Anal. calcd for C32H30F2N3O2 (M+H+): 526.2301;
found: 526.2300.
25
8j: Yellow solid. Mp: 207212 °C; [α]D 76.2 (c 0.94,
MeOH); 1H NMR (CDCl3, 300 MHz): δ 7.487.38 (4H, m),
7.27-7.19 (4H, m), 6.66 (2H, s), 5.03 (1H, d, J = 17.7 Hz),
3.78 (3H, s), 3.77 (1H, s), 3.203.08 (3H, m), 2.972.91
(3H, m), 2.632.58 (2H, m), 2.50 (3H, s), 2.23 (1H, m),
2.10 (1H, m), 1.94 (1H, m); 13C NMR (CDCl3, 75 MHz): δ
149.6, 149.3, 149.2, 148.8, 144.7, 144.6, 137.6, 137.5,
136.3, 131.1, 129.5, 129.3, 128.7, 128.6, 123.7, 118.4,
108.5, 56.5, 55.7, 46.8, 42.8, 42.5, 38.2, 36.0, 32.5, 23.3,
21.2; IR (KBr): 3383, 2918, 2843, 2521, 1588, 1485, 1442,
1385, 1279, 1159, 1010, 724, 539 cm1; HRMS (ESI, m/z)
Anal. calcd for C32H30Br2N3O2 (M+H+): 648.0684; found:
648.0682.
8n: Yellow solid. Mp: 155158 °C; [α]D25 101.7 (c 0.95,
MeOH); 1H NMR (CDCl3, 300 MHz): δ 7.317.23 (4H, m),
7.07-7.03 (4H, m), 6.64 (2H, s), 5.03 (1H, d, J = 17.7 Hz),
3.78 (3H, s), 3.18 (1H, s), 3.122.87 (5H, m), 2.51 2.49
(2H, m), 2.47 (3H, s), 2.33 (3H, s), 2.31 (3H, s), 2.281.85
(3H, m); 13C NMR (CD3OD/CDCl3 = 1:2, 75 MHz): δ 149.9
(2C), 148.5, 147.5, 145.5 (2), 144.7 (2), 138.0, 135.4, 129.3,
129.1, 128.6 (2), 127.0, 121.3, 118.6, 109.6, 58.0, 55.7,
47.1, 40.9, 40.7, 39.3, 35.4, 34.8, 31.1, 29.4, 23.7, 20.8;IR
(KBr): 2909, 2837, 1610, 1482, 1438, 1392, 1278, 1154,
1066, 822, 788, 553 cm1; HRMS (ESI, m/z) Anal. calcd for
C34H36N3O2 (M+H+): 518.2808; found: 518.2806.
25
8k: Yellow solid. Mp: 188192 °C; [α]D 97.7 (c 0.93,
25
MeOH); 1H NMR (CDCl3, 300 MHz): δ 7.437.32 (2H, m),
7.26-7.23 (2H, m), 7.01 (2H, dd, J = 7.5, 9.9 Hz), 6.80 (2H,
dd, J = 7.2, 9.0 Hz ), 6.68 (2H, d, J = 2.1Hz), 6.12 (1H, brs),
5.09 (1H, d, J = 17.7 Hz), 3.81 (3H, s), 3.212.91 (6H, m),
2.642.59 (2H, m), 2.51 (3H, s), 2.25 (1H, td, J = 12.3, 2.4
Hz), 2.10(1H, d, J = 12.3 Hz) 1.94 (1H, td, J = 12.6, 4.2
Hz); 13C NMR (CDCl3, 75 MHz): δ 159.18 (J = 247.6),
159.13 (J = 247.6), 150.0, 148.8, 146.7, 131.4, 131.2,
130.22, 130.16, 130.1, 127.1, 126.3, 126.2, 123.7, 121.4,
118.7, 115.4, 115.2, 115.0, 109.4, 57.7, 55.6, 47.0, 41.2,
39.1, 35.6, 35.0, 31.6, 29.4, 23.8; IR (KBr): 3504, 2920,
2838, 1616, 1582, 1496, 1483, 1453, 1438, 1279, 1230,
1153, 1054, 758, 458 cm1; HRMS (ESI, m/z) Anal. calcd
for C32H30F2N3O2 (M+H+): 526.2301; found: 526.2295.
8o: Yellow solid. Mp: 144147 °C; [α]D 107.2 (c 0.99,
MeOH); 1H NMR (CDCl3, 300 MHz): δ 7.587.45 (8H, m),
6.69 (2H, d, J = 7.5 Hz), 5.06 (1H, d, J = 16.5 Hz), 3.78
(3H, s), 3.20 (1H, s), 3.142.89 (5H, m), 2.622.49 (2H,
m), 2.47 (3H, s), 2.261.92 (3H, m); 13C NMR (CD3OD/
CDCl3 = 5:1, 75 MHz): δ 152.7, 151.9, 149.45, 149.43,
146.8, 146.2, 143.3, 131.5, 131.4 (2), 131.3 (2), 131.1,
130.7, 127.1, 126.0, 123.8, 123.5, 119.5, 110.7, 57.8, 56.3,
47.7, 43.2, 42.8 (2C), 38.3, 36.9, 33.1, 24.3; IR (KBr):
2910, 2841, 1618, 1484, 1440, 1395, 1325, 1166, 1066,
1017, 847, 622 cm1; HRMS (ESI, m/z) Anal. calcd for
C34H30F6N3O2 (M+H+): 626.2242; found: 626.2238.
8p: Yellow solid. Mp: 123126 °C; [α]D25 168.6 (c 0.91,
MeOH); 1H NMR (CDCl3, 300 MHz): δ 7.337.14 (4H, m),
6.91 (2H, dd, J = 7.2, 15.0 Hz ), 6.686.61 (4H, m), 5.11
(1H, d, J = 17.4 Hz), 3.77 (3H, s), 3.35 (3H, s), 3.31 (3H, s),
3.19-2.90 (6H, m), 2.592.48 (2H, m), 2.46 (3H, s),
2.20-2.09 (2H, m), 1.90 (1H, m); 13C NMR (CD3OD, 75
MHz): δ 157.9 (2C), 151.31, 151.26, 151.2, 150.2, 147.0,
146.5, 132.3, 132.2, 131.2, 131.0 (2C), 129.1, 129.0, 123.9,
120.9 (2C), 119.7, 111.5 (2C), 111.0, 58.1, 56.5, 55.3 (2C),
47.9, 42.7 (3C), 38.4, 36.9, 32.9, 24.5; IR (KBr): 2925,
2833, 1601, 1582, 1497, 1482, 1461, 1436, 1280, 1249,
1153, 1023, 751 cm1; HRMS (ESI, m/z) Anal. calcd for
25
8l: Yellow soild. Mp: 184188 °C; [α]D 110.5 (c 0.98,
MeOH); 1H NMR (CDCl3, 300 MHz): δ 7.286.98 (8H, m),
6.67 (2H, s), 6.11 (1H, brs), 5.05 (1H, d, J = 17.4 Hz), 3.80
(3H, s), 3.232.90 (6H, m), 2.672.62 (2H, m), 2.52 (3H,
s), 2.26 (1H, td, J = 12.9, 2.4 Hz), 2.11(1H, d, J = 10.5 Hz)
1.99 (1H, td, J =12.0, 4.2 Hz); 13C NMR (CDCl3, 75 MHz):
δ 162.6 (2C) (J = 247.0), 149.5, 148.6, 148.5, 145.2, 144.7,
134.6, 131.8, 131.5, 131.4, 131.2, 122.1, 118.7, 115.3,
115.2, 115.0, 114.9, 109.2, 57.5, 55.7, 47.1, 41.6, 40.1,
36.3, 35.3, 31.8, 29.6, 23.7; IR (KBr): 3389, 2930, 2839,

2546
Wang M, et al. Sci China Chem December (2012) Vol.55 No.12
C34H36N3O4 (M+H+): 550.2706; found: 550.2709.
1
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der preventative and treating agent-comprises Stephania
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1944–1947; (g) Shionogi & Co. Ltd. Purification of morphinan de-
8q: Yellow solid. Mp: 125130 °C; [α]D25 146.8 (c 0.93,
MeOH); 1H NMR (CDCl3, 300 MHz): δ 7.177.10 (2H, m),
6.966.82 (4H, m), 6.826.77(2H, m), 6.64 (2H, s) 5.04
(1H, d, J = 17.4 Hz), 3.77 (3H, s), 3.65 (3H, s), 3.63 (3H, s),
3.26 (1H, s), 3.132.88 (5H, m), 2.652.52 (2H, m), 2.53
(3H, s), 2.28 (1H, t, J = 8.7, 21.9 Hz), 2.08 (1H, m), 2.00
(1H, m); 13C NMR (CDCl3, 75 MHz): δ 159.2, 159.1, 149.9,
149.2 (2), 149.0, 144.9, 144.7, 140.20, 140.16, 130.2, 129.0,
128.9, 123.2, 122.1, 121.9, 118.4, 114.8, 114.4, 114.3,
114.0, 108.7, 56.6, 55.6, 54.98, 54.96, 46.8, 42.4, 42.2,
41.6, 37.6, 35.8, 32.2, 23.4; IR (KBr): 2929, 2834, 1600,
1581, 1483, 1437, 1391, 1279, 1230, 1155, 1050, 753 cm1;
HRMS (ESI, m/z) Anal. calcd for C34H36N3O4 (M+H+):
550.2706; found: 550.2709.
2
3
4
5
6
25
8r: Yellow solid. Mp: 137141 °C; [α]D 189.9 (c 0.93,
MeOH); 1H NMR (CDCl3, 300 MHz): δ 7.357.27 (4H, m),
6.816.67 (4H, m), 6.63 (2H, d, J = 2.1 Hz), 5.02 (1H, d,
J = 17.7 Hz), 3.80 (3H, s), 3.79 (3H, s), 3.78 (3H, s), 3.47
(1H, s), 3.14-2.86 (6H, m), 2.66 (3H, s), 2.43 (1H, brs), 2.08
(2H, m), 2.04 (1H, s); 13C NMR (CDCl3, 75 MHz): δ 160.9
(2), 150.62, 150.57, 150.4, 149.4, 146.8, 146.1, 131.9,
131.8, 130.2, 123.4, 119.5, 114.4 (2), 114.3 (2), 110.6,
58.3, 56.3, 55.6 (2), 47.8, 42.5, 42.4, 42.2, 37.7, 35.6, 32.6,
22.4; IR (KBr): 2925, 2837, 1608, 1514, 1483, 1438, 1393,
1280, 1250, 1176, 1027, 835, 754 cm1; HRMS (ESI, m/z)
Anal. calcd for C34H36N3O4 (M+H+): 550.2706; found:
550.2709.
4.4 Cell culture
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The mouse macrophage cell line J774 was used to evaluate
the pro-inflammatory cytokine TNF-under the lipopoly-
saccharide (LPS)-stimulation. Cells were grown in Dulbec-
co’s modified Eagle’s medium (DMEM) containing 10%
fetal bovine serum (FBS), 100 U/mL penicillin, and 100
U/mL streptomycin at 37 °C in a humidified atmosphere of
6% CO2.
Sinomenine and its derivatives were dissolved in dime-
thyl sulfoxide (DMSO) and added at a DMSO concentration
at 0.1%. The same amount of 1% DMSO was added to the
control cultures. Immunoassay of TNF-α cells were plated
in 48-well plates at 105 cells/well and incubated for 12 h.
Then 1 g/mL LPS in the presence or absence of 10 μM of
compounds in DMEM culture medium with 10% FBS was
added to each and well treated for 6 h. The culture superna-
tants were collected and used for assaying the inhibitory
activity on TNF- production by ELISA kit (R&D).
7
This project was financially supported by the National Basic Research
Program of China (973 Program, 2010CB833200), National Natural
Science Foundation of China (90713044, 21032002), SHMCST
(08431903000) and the Fundamental Research Funds for the Central
Universities (1082020502).

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