Synthesis and biological evaluation of berberine derivatives as IBS modulator

Article abstract of DOI:10.2174/157018012800389386

Irritable bowel syndrome is the most common functional gastrointestinal disorder characterized by chronic abdominal pain or discomfort in association with a change in bowel habit. 5-HT receptor modulators have been developed as IBS therapeutic agents and proved to be effective in the treatment of the disease. In this letter, 12 berberine derivatives were designed and synthesized as 5-HT receptor modulators. Preliminary biological tests suggested that the new compounds exhibited promising activity for IBS therapy.

Full text of DOI:10.2174/157018012800389386

Letters in Drug Design & Discovery, 2012, 9, 489-493
489
Synthesis and Biological Evaluation of Berberine Derivatives as IBS
Modulator
Xin Deng1, Xinxin Zhao#,1, Jing Han1, Jingjie Wang1, Wenlong Huang1, Hai Qian*,1 and
Liang Ge*,2
1Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China
2School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China
Received December 30, 2011: Revised February 03, 2012: Accepted February 03, 2012
Abstract: Irritable bowel syndrome is the most common functional gastrointestinal disorder characterized by chronic
abdominal pain or discomfort in association with a change in bowel habit. 5-HT receptor modulators have been developed
as IBS therapeutic agents and proved to be effective in the treatment of the disease. In this letter, 12 berberine derivatives
were designed and synthesized as 5-HT receptor modulators. Preliminary biological tests suggested that the new
compounds exhibited promising activity for IBS therapy.
Keywords: 5-hydroxytryptamine, 5-hydroxytryptamine receptor modulators, Berberine, Derivatives, Gastrointestinal disorder,
Irritable bowel syndrome.
INTRODUCTION
life and is deemed to a major cause of work absenteeism
[5,6].
Irritable bowel syndrome (IBS) is the most common
functional gastrointestinal (GI) disorder characterized by
chronic abdominal pain or discomfort in association with a
change in bowel habit [1,2]. According to the Rome II
definition, the prevalence of IBS in North America is 4.7%
to 11.4% and the rates vary from 1% to 8% in other western
Despite the prevalence and impact of IBS in the
community, the aetiological mechanism of IBS remains
unknown [7]. The pathophysiology of IBS is most likely
multifactorial, such as abnormal GI motor function, visceral
hypersensitivity, autonomic dysfunction, mucosal immune
O
O
Cl
Cl
N
N
H
N
O
O
H2N
O
H2N
O
F
1
2
Cl
O
H2N
O
HN
O
O
N
N
O
3
countries [3]. Although only a minority ever seek the health
care for their symptoms, IBS is still one of the most common
disorders in primary care or specialist clinics [4]. In addition,
IBS can severely affect the individual who suffer's quality of
activation, alteration of intestinal flora and psychological
factors [2,8,9]. 5-hydroxytryptamine (5-HT) is an important
neurotransmitter in the GI tract. Recent studies demonstrate
that 5-HT plays a crucial role in the modulation of gut
function, such as motility, sensation, blood flow and
secretion [10,11]. It has also been reported that the plasma 5-
HT levels were abnormal in IBS patients [12].
*Address correspondence to these authors at the Center of Drug Discovery,
China Pharmaceutical University, Nanjing 210009, People’s Republic of
China; Tel: +86-(0)25-83271302; Fax: +86-(0)25-83271297;
E-mail:qianhai24@163.com
Given the important role of 5-HT in IBS, 5-HT receptor
modulators such as cisapride (1), renzapride (2), and ATI-
7505 (3) have been developed as IBS therapeutic agents and
proved to be effective in the treatment of the disease [8].
Tel: +86-(0)25-83271480; Fax: +86-(0)25-83271480;
E-mail: geliang1981@hotmail.com
#Contributed equally to the first author.
1875-628X/12 $58.00+.00
© 2012 Bentham Science Publishers

490 Letters in Drug Design & Discovery, 2012, Vol. 9, No. 5
Deng et al.
These 5-HT receptor modulators have a similar structure and
López-Rodríguez etc. have summarized their pivotal
pharmacophores: 1) an aromatic moiety, 2) a carbonyl
function, and 3) nitrogen heterocyclic ring (Fig. (1)) [13].
with MeOH and concentrated sulfuric acid under room
temperature for 2h. Then solid 7 was dissolved in acetic acid,
acetic anhydride was added to react for 1h. After adding
suitable amount of water, compound 8 was obtained. The
phenolic hydroxyl group of 8 that was substituted by
dimethyl sulphate, ethyl bromide and propyl bromide
respectively yielded compound 9. Halogenating 9 by NCS
and NBS produced compound 10. Hydrolization of 10 with
aqueous NaOH and 95% C2H5OH, then neutralized by
chlorhydric acid separate out 11. Compound 11 reacted with
bromoethanol and bromopropanol catalyzed by EDC and
DMAP in dichlormethane provided 12. Finally, the
quaternary ammonium salt forming reaction was performed
between compound 5 and 12 in nitromethanc under 100℃
[20], the target compounds I 1-12 [21] were obtained after
24h.
(2)
O
(CH2)n
N
X
(1)
(3)
(X = NH, O)
Table 1. Structure of Target Compounds I 1-12
Fig. (1). The pharmacophore model for 5-HT receptor modulators.
(1) aromatic moiety, (2) carbonyl function, (3) nitrogen
heterocyclic ring.
O
O
Although 5-HT receptor modulators contribute to the
therapy for IBS, the serious adverse effects, such as severe
constipation, ischemic colitis, higher cerebrovascular and
cardiac events, result in a number of 5-HT receptors being
withdrawn from the market [14].
O
O
O
N+
Br-
R1
(CH2)n
O
H2N
OR2
Berberine (4) is a natural isoquinoline alkaloid present in
plants of the genus Coptis, Hydrastis and Berberis [15,16]. In
China, berberine has been used for the treatment of
gastroenteritis and diarrhea. Clinical trials have verified that
berberine is an effective drug with lower toxicity [17]. It has
been shown that berberine can greatly relieve the main
symptoms of IBS patients [18]. Furthermore, berberine has
poor intestinal absorption [19] implying that berberine and
its derivatives might be difficult to enter into circulation and
have less side effects.
Compound
n
R1
R2
I 1
I 2
2
3
2
3
2
3
2
3
2
3
2
3
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
-CH3
-CH3
I 3
-CH2CH3
-CH2CH3
I 4
O
I 5
-CH2CH2CH3
-CH2CH2CH3
-CH3
OH-
I 6
N+
O
I 7
O
I 8
-CH3
I 9
-CH2CH3
O
4
I 10
I 11
I 12
-CH2CH3
-CH2CH2CH3
-CH2CH2CH3
MATERIALS AND METHODS
Based on the information above, we have designed and
synthesized a series of berberine derivatives (Table 1) as
novel 5-HT receptor modulators. Among these compounds,
we employed tetrahydroberineper as the nitrogen
heterocyclic ring and the berberine-like structure might
inhibit the absorption in GI tract that attenuates the systemic
side effects.
A rat model of IBS was induced by the method reported
by Zou Baicang et al. and Jun-Ho La et al. Briefly, during a
short anesthesia with ethylether, 4% acetic acid solution
(40ml/L) was injected intrarectally via a polyethylene
catheter inserted 8cm proximal to the anus. 6 days after
acetic acid solution administration, then animals underwent
constraint stimulation for 3 hours. Test agents were
administered intragastrically for 7 days. Animals were
assigned to the following treatment groups, each consisting
of 8 rats: compounds I 1-12 (5mg/kg) and berberine
(5mg/kg). IBS-untreated group (blank group) received 0.3%
Twelve berberine derivatives were prepared as shown in
Scheme 1. Hydrogenation of commercially available
berberine 4 by NaBH4 resulted in tetrahydroberineper 5.
Compound 7 was converted from para-amino salicylic acid 6

Synthesis and Biological Evaluation of Berberine Derivatives as IBS Modulator
Letters in Drug Design & Discovery, 2012, Vol. 9, No. 5 491
O
O
OH-
N+
N
O
O
a)
O
O
O
O
4
5
COOH
COCH3
COCH3
OH
COCH3
OH
OH
OR2
b)
c)
d)
e)
NH2
NH2
NHCOCH3
NHCOCH3
6
7
8
9a-c
COCH3
COOH
COO(CH2)nBr
OR2
OR2
OR2
f)
h)
g)
R1
R1
R1
NHCOCH3
10a-f
NH2
NH2
11a-f
12a-l
O
O
CO(CH2)nBr
OR2
R1
O
N
(CH2)n
O
N+
NH2
+
i)
Br-
O
O
O
O
O
O
R2O
R1
NH2
5
12a-l
I 1-12
Scheme 1. Synthesis of I 1-12: a) NaBH4, 90%C2H5OH, reflux; b) CH3OH, 98%H2SO4; c) (CH3CO)2O, CH3COOH; d) (CH3)2SO4 or
C2H5Br or n-C3H7Br, NaOH, DMF; e) NCS or NBS, DMF; f) 30%NaOH, 95%C2H5OH; g) HCl; h) EDC, DMAP, Br(CH2)nOH; i) CH3NO2
100℃.
Table 2. Results of Water Ratio of IBS Rat Fecesa
Compound
1d (%)
3d (%)
5d (%)
7d (%)
I 1
I 2
79.81±1.41
79.69±1.91
80.50±0.70
79.22±1.12
80.63±0.96
79.97±0.44
81.45±0.21
80.83±1.00
81.29±2.07
80.19±1.11
80.33±0.75
80.21±1.37
80.03±1.62
80.50±1.11
74.43±0.68*
80.28±0.61
78.31±0.90
69.14±0.21**
73.43±2.15*
73.22±1.23*
72.60±2.08*
73.83±1.33*
79.54±0.54
74.31±0.78*
74.73±4.50
76.31±1.31*
73.46±2.75*
80.56±2.87
74.00±0.81*
73.41±0.80*
77.36±0.90
71.31±2.08**
67.17±1.68***
76.79±1.65*
I 3
I 4
63.37±0.59***
72.45±1.16*
70.75±1.00**
71.65±1.74**
69.13±2.35**
72.53±0.40*
71.21±0.90**
70.68±2.14**
73.52±0.73*
71.78±1.95**
79.27±0.75
56.44±0.60***
70.31±1.03**
62.64±0.77***
68.56±1.85**
67.64±0.77***
69.20±1.52**
68.83±0.91**
67.26±1.89***
69.31±0.82**
69.43±0.77**
80.82±1.56
I 5
I 6
I 7
I 8
I 9
I 10
I 11
I 12
berberine
blank
*P < 0.05; **P < 0.01; ***P < 0.001. (Compare to the blank group).
aThe water ratio of rat feces was evaluated at the first, third, fifth and seventh day during administration. The lower value of water ratio means the faster recovery of IBS.

492 Letters in Drug Design & Discovery, 2012, Vol. 9, No. 5
Deng et al.
Table 3. Results of Rectal Distension-Induced Nociception of IBS Ratsa
Compound
1d (ml)
3d (ml)
5d (ml)
7d (ml)
I 1
I 2
0.1167±0.0152
0.1125±0.0125
0.1100±0.0100
0.1109±0.0100
0.1175±0.0035
0.1109±0.0100
0.1100±0.0100
0.1167±0.0057
0.1097±0.0115
0.1167±0.0082
0.1100±0.0063
0.1117±0.0075
0.1167±0.0057
0.1167±0.0057
0.1600±0.0100**
0.1750±0.0191**
0.1333±0.0115
0.1733±0.0115*
0.1900±0.0258*
0.1467±0.0115
0.2000±0.0100**
0.1950±0.0100**
0.1900±0.0141*
0.2367±0.0057***
0.1800±0.0282*
0.2575±0.0170***
0.2200±0.0200**
0.2300±0.0100***
0.2000±0.0200**
0.2067±0.0082**
0.2100±0.0089**
0.2100±0.0063**
0.1933±0.0503*
0.1500±0.0100
I 3
I 4
0.1800±0.0200**
0.1225±0.0035
0.1933±0.0230**
0.1700±0.0141*
0.2050±0.0100***
0.2000±0.0200**
0.1733±0.0115*
0.1933±0.0152**
0.1883±0.0075*
0.1933±0.0152**
0.1900±0.6724*
0.1533±0.0230
I 5
I 6
0.1700±0.0200**
0.1517±0.0076**
0.1500±0.0100**
0.1600±0.0200**
0.1583±0.0075**
0.1550±0.0054**
0.1633±0.0052**
0.1467±0.0115*
0.1167±0.0057
I 7
I 8
I 9
I 10
I 11
I 12
berberine
blank
0.1333±0.0015
*P < 0.05; **P < 0.01; ***P < 0.001. (Compare to the blank group).
aThe thresholds of rectal distension-induced nociception of rats were tested at the first, third, fifth and seventh day during administration. The higher volume value indicates the lower
visceral sensitivity.
[2]
[3]
[4]
Drossman D. A. ; Camilleri M.; Mayer E. A.; Whitehead WE.
AGA technical review on irritable bowel syndrome.
Gastroenterology, 2002, 123(6), 2018-2031.
Rey E.; Talley N. J. Irritable bowel syndrome: Novel views on the
epidemiology and potential risk factors. Dig. Liver Dis., 2009,
41(11), 772-780.
Müller-Lissner S. A.; Bollani S.; Brummer RJ.; Coremansd G.;
Dapoigny M.; Marshall J. K.; Muris J. W. ; Oberndorff-Klein
Wolthuis A.; Pace F.; Rodrigo L.; Stockbrügger R.; Vatn. M. H.
Epidemiological Aspects of Irritable Bowel Syndrome in Europe
and North America. Digestion, 2001, 64(3), 200-204.
Wilson A.; Longstreth G. F.; Knight K.; Wong J.; Wade S.; Chiou
C. F.; Barghout V.; Frech F.; Ofman J. J. Quality of life in
managed care patients with irritable bowel syndrome. Manag. Care
Interface, 2004, 17(2), 24-28.
CMC-Na solution to serve as a control. To evaluate the anti-
IBS activities of berberine derivatives I 1-12, the feces water
ratio and rectal distension-induced nociception of IBS rats
were tested respectively during the period of administration
[22,23]. The results are presented in Tables 2 and 3. As it
can be seen from the data, all of the new compounds
exhibited favorable effect on IBS therapy, such as reduced
the water ratio of feces, relieved rectal distension-induced
nociception. Especially the compounds I 4 and I 6 showed
higher activity than berberin. The results might provide
insight into the further research on these compounds for IBS
therapy.
[5]
[6]
[7]
Spiegel B. M. The burden of IBS: looking at metrics. Curr.
Gastroenterol. Rep., 2009, 11(4), 265-269.
Gaman A.; Bucur M. C.; Kuo B. Therapeutic advances in
functional gastrointestinal disease: irritable bowel syndrome.
Therap. Adv. Gastroenterol., 2009, 2(3), 196-181.
Camilleri M.; Andresen V. Current and novel therapeutic options
for irritable bowel syndrome management. Dig. Liver Dis., 2009,
41(12), 854-862.
Camilleri M. Evolving concepts of the pathogenesis of irritable
bowel syndrome: to treat the brain or the gut? J. Pediatr.
Gastroenterol. Nutr., 2009, 48(suppl 2), S46-S54.
CONCLUSION
In conclusion, twelve berberine derivatives were
designed and synthesized. The biological evaluation tests
suggested that all the novel compounds showed potential for
IBS therapy, and two of which exhibited promising activity
that were capable of further researching.
[8]
[9]
[10]
Manning D. D; Cioffi C. L; Usyatinsky A.; Fitzpatrick K.; Masih
L.; Guo C.; Zhang Z.; Choo S. H.; Sikkander M. I.; Ryan K. N.;
Naginskaya J.; Hassler C.; Dobritsa S.; Wierschke J. D.; Earley W.
G.; Butler A. S.; Brady C. A.; Barnes N. M.; Cohen M. L.; Guzzo
P. R. Novel serotonin type 3 receptor partial agonists for the
potential treatment of irritable bowel syndrome. Bioorg. Med.
Chem. Lett., 2011, 21(1), 58-61.
Camilleri M. Serotonin in the Gastrointestinal Tract. Curr. Opin.
Endocrinol Diabetes Obes., 2009, 16(1), 53-59.
Sikander A.; Rana S. V.; Prasad K. K. Role of serotonin in
gastrointestinal motility and irritable bowel syndrome. Clin. Chim.
Acta., 2009, 403(1-2), 47-55.
CONFLICT OF INTEREST
Declared none.
ACKNOWLEDGEMENTS
[11]
[12]
This study was supported by the National Natural
Science Foundation of China (No. 81172932), the
Fundamental Research Funds for the Central Universities of
China (No.2J10023) and the Project Program of State Key
Laboratory of Natural Medicines, China Pharmaceutical
University (No. JKGZ201103).
[13]
López-Rodrígueza M. L.; Morcillob M. J.; Benhamúa B.; Rosado
M. L. Comparative receptor mapping of serotoninergic 5-HT3 and
5-HT4 binding sites. J. Comput. Aided Mol. Des., 1997, 11(6),
589-599.
[14]
[15]
Chang J. Y.; Talley N. J. Current and emerging therapies in
irritable bowel syndrome: from pathophysiology to treatment.
Trends Pharmacol. Sci., 2010, 31(7), 326-334.
Li B.; Zhu W.; Chen K. Advances in the study of berberine and its
derivatives. Acta Pharm. Sin., 2008, 43(8), 773-787.
REFERENCES AND NOTES
[1]
Camilleri M. Management of the irritable syndrome.
Gastroenterology, 2001, 120(3), 652-668.

Synthesis and Biological Evaluation of Berberine Derivatives as IBS Modulator
Letters in Drug Design & Discovery, 2012, Vol. 9, No. 5 493
[16]
[17]
[18]
[19]
Siow Y. L.; Sarna L.; Karmin O. Redox regulation in health and
disease—Therapeutic potential of berberine. Food Res. Int., 2011,
44(8), 2409-2417.
Imanshahidi M.; Hosseinzadeh H. Pharmacological and
Therapeutic Effects of Berberis vulgaris and its Active Constituent,
Berberine. Phytother. Res., 2008, 22(8), 999-1012.
6.17(s, 2H, OCH2O), 5.41(m, 1H, NCH), 4.98(m, 2H,
OCH2CH2N), 4.09-4.11(d, 6H, 9,10-OCH3), 1.34-3.87(m, 16H),
0.83(t, 3H, OCH2CH2CH3); m/z: [M-Br-H]+ 609.3; IR(KBr,υ):
3415, 2923, 1700, 1602, 1494, 1275, 854.
I 7: yield 24.0%, amber crystal, m.p.200-201℃, 1H NMR(DMSO-
d6, 300MHz, δppm): δ: 7.90(s, 1H, ArH), 7.28-7.55(m, 4H, ArH),
6.83(s, 1H, ArH), 6.31(s, 1H, ArH), 6.03(s, 2H, OCH2O), 5.04(m,
1H, NCH), 4.71(m, 2H, OCH2CH2N), 4.50(m, 2H, OCH2CH2N),
4.05(s, 3H, ArOCH3), 3.79-3.82 (d, 6H, 9, 10-OCH3), 2.50-3.50
(m, 8H); m/z: [M-Br+H]+ 613.0; IR(KBr,υ): 3500, 2960, 1703,
1626, 1497, 1281, 887.
I 8: yield 26.5%, amber crystal, m.p.175-176℃, 1H NMR(DMSO-
d6, 300MHz, δppm): δ: 7.84(s, 1H, ArH), 7.28-7.55(m, 4H, ArH),
6.84(s, 1H, ArH), 6.32(s, 1H, ArH), 6.03(s, 2H, OCH2O), 5.07(m,
1H, NCH), 4.62(m, 2H, OCH2CH2N), 4.48(m, 2H, OCH2CH2N),
4.05(s, 3H, ArOCH3), 3.79-3.84 (d, 6H, 9, 10-OCH3), 2.50-3.50
(m, 10H); m/z: [M-Br+H]+ 627.2; IR(KBr,υ): 3416, 2918, 1705,
1631, 1494, 1246.
I 9: yield 31.5%, amber crystal, m.p.165-166℃, 1H NMR(DMSO-
d6, 300MHz, δppm): 8.22(d, 1H, ArH), 8.01(d, 1H, ArH), 7.81(s,
1H, ArH), 7.35(s, 1H, ArH), 7.09(s, 1H, ArH), 6.45(s, 1H, ArH),
6.30(s, 2H, OCH2O), 5.37(m, 1H, NCH), 4.95(m, 2H,
OCH2CH2N), 4.07-4.10(d, 6H, 9,10-OCH3), 2.00-3.90(m, 12H),
0.87(t, 3H, OCH2CH3); m/z: [M-Br+H]+ 627.1; IR(KBr,υ): 3410,
2901, 1700, 1621, 1497, 1280, 872.
Wang Y. B.; Tang X. S.; Xu Z. X. Observation on Therapeutic
Effect of Berberine Hydrochloride in Treatment of Irritable Bowel
Syndrome. J. Cap. Univ. Med. Sci. 2002, 23(2), 151-152.
Chen W.; Miao Y. Q.; Fan D. J.; Yang S. S.; Lin X.; Meng L. K.;
Tang X. Bioavailability Study of Berberine and the Enhancing
Effects of TPGS on Intestinal Absorption in Rats. AAPS
PharmSciTech., 2011, 12(2), 705-711.
Wang R. F.; Xu G. Y.; Hua W. Y. Synthesis and Antiarrhythmic
Activity of Tetrahydroberineper Quaternary Ammonium
Compounds. Chinese J. Med. Chem., 1996, 6(4), 557-595.
Chemical data of compound I 1: yield 29.1%, marron crystal,
m.p.200-201℃, 1H NMR (DMSO-d6, 300MHz, δppm): 7.50(s,
1H, ArH), 6.83-7.11(m, 4H, ArH), 6.27(s, 1H, ArH), 6.03(s, 2H,
OCH2O), 5.03(m, 1H, NCH), 4.69(m, 2H, OCH2CH2N), 4.46(m,
2H, OCH2CH2N), 4.08(s, 3H, ArOCH3), 3.79-3.82 (d, 6H, 9,10-
OCH3), 2.50-3.50 (m, 8H); MS(ESI) m/z: [M-Br-H]+ 569.1;
IR(KBr,υ): 3470, 3028, 1725, 1599, 1497, 1280, 873.
I 2: yield 27.5%, amber crystal, m.p.172-173℃, 1H NMR(DMSO-
d6, 300MHz, δppm): δ: 7.51(s, 1H, ArH), 6.84-7.18(m, 4H, ArH),
6.28(s, 1H, ArH), 6.03(s, 2H, OCH2O), 5.06(m, 1H, NCH),
4.61(m, 2H, OCH2CH2N), 4.47(m, 2H, OCH2CH2N), 4.07(s, 3H,
ArOCH3), 3.81-3.83 (d, 6H, 9, 10-OCH3), 2.17-3.50 (m, 10H);
m/z: [M-Br-H]+ 581.2; IR(KBr,υ): 3453, 2975, 1723, 1600, 1456,
1182, 854.
I 3: yield 28.3%, amber crystal, m.p.204-205℃, 1H NMR(DMSO-
d6, 300MHz, δppm): 7.92(d, 1H, ArH), 7.82(d, 1H, ArH), 7.53(s,
1H, ArH), 7.34(s, 1H, ArH), 7.10(s, 1H, ArH), 6.76(s, 1H, ArH),
6.44(s, 2H, OCH2O), 5.38(m, 1H, NCH), 4.82(m, 2H,
OCH2CH2N), 4.09-4.10(d, 6H, 9,10-OCH3),2.28-3.86(m, 12H),
0.89(t, 3H, OCH2CH2CH3); m/z: [M-Br-H]+ 581.1; IR(KBr,υ):
3300, 2942, 1715, 1607, 1507, 1261, 888.
I 4: yield 31.1%, amber crystal, m.p.166-167℃, 1H NMR(DMSO-
d6, 300MHz, δppm): 8.10(d, 1H, ArH), 7.90(d, 1H, ArH), 7.71(s,
1H, ArH), 7.39(s, 1H, ArH), 7.12(s, 1H, ArH), 6.44(s, 1H, ArH),
6.24(s, 2H, OCH2O), 5.39(m, 1H, NCH), 4.84(m, 2H,
OCH2CH2N), 4.08-4.09(d, 6H, 9,10-OCH3),1.54-3.96(m, 14H),
0.86(t, 3H, OCH2CH2CH3); m/z: [M-Br-H]+ 595.2; IR(KBr,υ):
3344, 2937, 1711, 1600, 1504, 1275, 855.
I 5: yield 27.3%, amber crystal, m.p.197-198℃, 1H NMR(DMSO-
d6, 300MHz, δppm): 8.21(d, 1H, ArH), 8.00(d, 1H, ArH), 7.80(s,
1H, ArH), 7.50(s, 1H, ArH), 7.10(s, 1H, ArH), 6.46(s, 1H, ArH),
6.18(s, 2H, OCH2O), 5.45(m, 1H, NCH), 4.96(m, 2H,
OCH2CH2N), 4.07-4.09(d, 6H, 9,10-OCH3),2.00-3.90(m, 14H),
0.82(t, 3H, OCH2CH2CH3); m/z: [M-Br-H]+ 595.1; IR(KBr,υ):
3340, 2961, 1710, 1605, 1497, 1281, 873.
[20]
[21]
I
10: yield 27.9%, amber crystal, m.p.181-182℃, 1H
NMR(DMSO-d6, 300MHz, δppm): 8.21(d, 1H, ArH), 8.00(d, 1H,
ArH), 7.81(s, 1H, ArH), 7.34(s, 1H, ArH), 7.10(s, 1H, ArH),
6.45(s, 1H, ArH), 6.29(s, 2H, OCH2O), 5.35(m, 1H, NCH),
4.97(m, 2H, OCH2CH2N), 4.06-4.12(d, 6H, 9,10-OCH3), 1.46-
3.90(m, 14H), 0.83(t, 3H, OCH2CH3); m/z: [M-Br+H]+ 641.2;
IR(KBr,υ): 3571, 2926, 1711, 1594, 1503, 1273, 855.
I
11: yield 21.8%, amber crystal, m.p.195-196℃, 1H
NMR(DMSO-d6, 300MHz, δppm): 8.22(d, 1H, ArH), 8.02(d, 1H,
ArH), 7.81(s, 1H, ArH), 7.35(s, 1H, ArH), 7.11(s, 1H, ArH),
6.45(s, 1H, ArH), 6.27(s, 2H, OCH2O), 5.40(m, 1H, NCH),
4.96(m, 2H, OCH2CH2N), 4.00-4.07(d, 6H, 9,10-OCH3), 1.34-
3.90(m, 14H), 0.84(t, 3H, OCH2CH3); m/z: [M-Br-H]+ 639.0;
IR(KBr,υ): 3517, 2942, 1705, 1607, 1497, 1281, 887.
I
12: yield 22.6%, amber crystal, m.p.177-178℃, 1H
NMR(DMSO-d6, 300MHz, δppm): 8.13(d, 1H, ArH), 7.91(d, 1H,
ArH), 7.71(s, 1H, ArH), 7.41(s, 1H, ArH), 7.13(s, 1H, ArH),
6.64(s, 1H, ArH), 6.15(s, 2H, OCH2O), 5.41(m, 1H, NCH),
5.01(m, 2H, OCH2CH2N), 4.09-4.10(d, 6H, 9,10-OCH3), 1.37-
3.86(m, 16H), 0.87(t, 3H, OCH2CH3); m/z: [M-Br+H]+ 653.0;
IR(KBr,υ): 3504, 2943, 1710, 1600, 1505, 1275, 871.
[22]
[23]
Zou B.; Dong L.; Cao M.; Wang Y.; Wang S. Expression and role
of 5-hydroxytryptamine in the brain and intestine in rats with
irritable bowel syndrome. J. Xi'an Jiaotong Uni. (Medical
Sciences), 2008, 29(1), 42-46.
La J. K.; Kim T. W.; Sung T. S.; Kang J. W.; Kim H. J.; Yang I. S.
Visceral hypersensitivity and altered colonic motility after
subsidence of inflammation in a rat model of colitis. World J. of
Gastroenterol., 2003, 9(12), 2791-2795.
I 6: yield 21.5%, amber crystal, m.p.165-166℃, 1H NMR(DMSO-
d6, 300MHz, δppm): 8.22(d, 1H, ArH), 7.92(d, 1H, ArH), 7.81(s,
1H, ArH), 7.51(s, 1H, ArH), 7.11(s, 1H, ArH), 6.76(s, 1H, ArH),