Synthesis, antiplatelet and vasorelaxing activities of xanthone derivatives

Article abstract of DOI:10.1002/ardp.200800002

A series of ω-aminoalkoxylxanthones was synthesized and tested in vitro for their ability to inhibit platelet aggregation and cause vasorelaxing action. Compounds 4, 5, 12, 17, and 18 showed significant antiplatelet effects on thrombin-, arachidonic acid (AA)-, collagen-, and platelet activating factor (PAF)-induced washed rabbit platelet aggregation and exhibited inhibition of primary and secondary aggregation induced by adenosine-5′-diphosphate (ADP) in human platelet-rich-plasma (PRP). Compounds 4, 17, and 18 revealed vasorelaxing activities in rat thoracic aorta. We concluded that these compounds may be developed as new antithrombotic agents.

Full text of DOI:10.1002/ardp.200800002

Arch. Pharm. Chem. Life Sci. 2009, 342, 19–26
K.-W. Lin et al.
19
Full Paper
Synthesis, Antiplatelet and Vasorelaxing Activities of Xanthone
Derivatives
Kai-Wei Lin1, Song-Chwan Fang2, Chi-Feng Hung3, Bor-Jinn Shieh4, Shyh-Chyun Yang1,
Che-Ming Teng5, and Chun-Nan Lin1, 6
1 School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
2 Department of Food Nutrition, Chung Hwa University of Medical Technology, Tainan Hsien, Taiwan
3 School of Medicine, Fu-Jen Catholic University, Taipei County, Taiwan
4 Graduate Institute of Chemistry, Chung Yuan Christian University, Chung Li, Taiwan
5 Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan
6 Institute of Life Science, National Taitung University, Taitung, Taiwan
A series of x-aminoalkoxylxanthones was synthesized and tested in vitro for their ability to
inhibit platelet aggregation and cause vasorelaxing action. Compounds 4, 5, 12, 17, and 18
showed significant antiplatelet effects on thrombin-, arachidonic acid (AA)-, collagen-, and plate-
let activating factor (PAF)-induced washed rabbit platelet aggregation and exhibited inhibition
of primary and secondary aggregation induced by adenosine-5'-diphosphate (ADP) in human pla-
telet-rich-plasma (PRP). Compounds 4, 17, and 18 revealed vasorelaxing activities in rat thoracic
aorta. We concluded that these compounds may be developed as new antithrombotic agents.
Keywords: Antiplatelet effect / Vasorelaxing activity / Xanthones derivaties /
Received: January 3, 2008; accepted: April 25, 2008
DOI 10.1002/ardp.200800002
Introduction
Chemistry
Compounds 1–18 were synthesized (Scheme 1) by the
method described in the previous reports [4, 7, 8]. Briefly,
compounds 1–18 were obtained by the reaction of potas-
sium salts of 3-hydroxyxanthone with 1,x-dibromoal-
kane in tert-butanol and then aminated with appropriate
amines to give the final product. The synthetic com-
pounds were characterized by spectroscopic methods
and the spectroscopic data were compared with the data
reported in the literature [4, 7, 8].
Xanthonoids isolated from Gentianaceous plants have
been shown to be potent inhibitors of platelet aggrega-
tion and vasoconstriction [1, 2]. Synthetic xanthone
derivatives have shown antiplatelet effect, inhibiting
effects on cyclooxygenase, vasorelaxing effect and
reduced blood pressure, heart rate, and attenuated iso-
prenaline-induced tachycardia in rats [3–6]. For the study
of structure-activity relationship of various xanthone
derivatives, characterizing their mode of action and their
design as antithrombotic or antihypertensive agents, we
synthesized further x-aminoalkoxylxanthones.
Biological results and discussion
The antiplatelet effects of 1–18 were studied in the aggre-
gation of washed rabbit platelets induced by thrombin,
AA, collagen, and PAF. As shown in Table 1, compounds
3–6 and 12–18 (each at 300 lM) showed potent antiplate-
let effects on the aggregation induced by the four ago-
nists used in Table 1. Compound 2 (300 lM) showed
potent antiplatelet effects on aggregation induced by AA,
Correspondence: Chun-Nan Lin, School of Pharmacy, Kaohsiung Medi-
cal University, Kaohsiung 807, Taiwan.
E-mail: lincna@cc.kmu.edu.tw
Fax: +886 7 556 2365
Abbreviations: arachidonic acid (AA); platelet activating factor (PAF)
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

20
K.-W. Lin et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 19–26
Reagents and conditions: (a) aqueous 20% KOH, tert-BuOH, 1,x-dibromoalkane, reflux; (b) THF or tert-BuOH, various
amines, aqueous NaOH, stirring, 708C.
Scheme 1. Synthesis of the compounds 1–18.
Table 1. Effect of xanthone derivatives on the platelet aggrega-
tion induced by thrombin, AA, collagen, and PAF.
Compound
Platelet aggregation (%)
Thrombin
AA
Collagen
PAF
DMSO (control) 94.8 l 1.0
92.1 l 3.1
92.1 l 0.8
93.8 l 1.6
1
2
3
4
5
96.7 l 3.0
91.3 l 3.0
27.3 l 8.0c)
0.0 l 0.0c)
46.8 l 17.3a) 22.9 l 15.0c) 72.1 l 3.4c)
20.4 l 7.4c)
15.3 l 7.7c)
0.0 l 0.0c)
0.0 l 0.0c)
0.0 l 0.0c)
0.0 l 0.0c)
0.0 l 0.0c)
0.0 l 0.0c)
7.9 l 6.8c)
85.7 l 1.9
83.6 l 3.7
81.5 l 1.8b)
9.2 l 5.5c)
0.0 l 0.0c)
0.0 l 0.0c)
0.0 l 0.0c)
12.7 l 7.2c)
0.0 l 0.0c)
0.0 l 0.0c)
11.7 l 5.9c)
85.4 l 3.9
29.0 l 4.2c)
22.7 l 4.1c)
0.0 l 0.0c)
0.0 l 0.0c)
0.0 l 0.0c)
37.7 l 8.3c)
89.6 l 1.8
89.9 l 1.7
87.3 l 2.0
10.4 l 6.1c)
1.9 l 1.6c)
22.7 l 4.1c)
0.0 l 0.0c)
0.0 l 0.0c)
0.0 l 0.0c)
0.0 l 0.0c)
2.0 l 1.8c)
90.5 l 1.2
6.8 l 5.9c) 18.7 l 7.9c)
6
7
8
9
10
11
12
13
14
15
16
17
18
10.0 l 5.0c)
89.8 l 2.6
95.9 l 0.6
94.6 l 0.6
84.7 l 0.9
85.7 l 3.0a)
34.2 l 8.5c)
27.3 l 8.0c)
13.6 l 5.9c)
28.2 l 5.8c)
9.5 l 4.8c)
0.0 l 0.0c)
13.7 l 8.5c)
0.0 l 0.0c)
31.1 l 15.8b)
84.4 l 6.0
87.8 l 2.4
88.2 l 1.4
68.0 l 6.9c)
0.0 l 0.0c)
15.3 l 7.7c)
0.0 l 0.0c)
0.0 l 0.0c)
0.0 l 0.0c)
0.0 l 0.0c)
4.6 l 4.0c)
0.0 l 0.0c)
Figure 1. Concentration-dependent inhibitory effect of 4, 5, 12,
17, 18, and aspirin on platelet aggregation induced by AA.
Washed rabbit platelets were incubated with various concentra-
tions of 4, 5, 12, 17, 18, and aspirin or dimethylsulfoxide (0.5%)
at 378C for 3 min, then AA (100 mM) was added to trigger the
aggregation. Percent inhibitions are presented as mean-
s l S.E.M. (n = 3–6).
Acetyl salicylic 91.9 l 2.5
acid
Platelets were preincubated with 1–18 (each at 300 lM), aspirin
(50 lM), or DMSO (0.5%, control) at 378C for 3 min, then throm-
bin (0.1 units/mL), AA (10 lM), collagen (10 lg/mL), or PAF (2 ng/
mL) was added. Percentages of aggregation are presented as
means l S.E.M. (n = 3–7).
As shown in Figs. 1 and 2, the antiplatelet effects of 4,
5, 12, 17, and 18 on the aggregation induced by AA and 4,
12, and 18 on the aggregation induced by PAF were con-
centration-dependent. In comparison with the data previ-
ously reported for 3-[3-(cyclopropylamino)propoxy]xan-
thone 19, norathyriol 20, and norathyriol tetraacetate 21
(Scheme 1) [1, 8], compounds 4, 5, 12, 17, and 18 had less
potent antiplatelet effects than 19 and 21, when AA was
used as the aggregation agonist. This indicated that the
increasing carbon number of oxyalkyl side chain or sub-
stitution with various amino groups in the oxyalkyla-
a)
P a 0.05.
P a 0.01.
b)
c)
P a 0.001 as compared with the respective control value.
collagen, and PAF. Among them, compounds 4, 5, 12, 17,
and 18 were the most potent inhibitors with minimal
effective concentrations around 50 lM and maximal
effective concentrations at 300 lM.
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2009, 342, 19–26
Antiplatelet and Vasorelaxing Xanthones
21
Figure 4. Effect of 5 on the aggregation of human PrP induced
by ADP.
Human PrP was pre-incubated with dimethylsulfoxide (0.5%,
control) or various concentrations of 5 for 3 min and then ADP
(20 lM) was added to trigger aggregation.
Table 2. Effect of xanthone derivatives on high K+-, Ca2+-
induced, and noradrenaline-induced contraction of rat thoracic
aorta.a)
Figure 2. Concentration-dependent inhibitory effect of 4, 12, and
18 on platelet aggregation induced by PAF.
Washed rabbit platelets were incubated with various concentra-
tions of 4, 12, and 18 or dimethylsulfoxide (0.5%) at 378C for
3 min and then PAF (2 ng/mL) was added to trigger the aggrega-
tion. Percent inhibitions are presented as means l S.E.M. (n =
3–6).
Compound
(lM)
K+ (80 mM) +
Ca2+ (1.9 mM)
Noradrenaline
(3 lM) Phasic (3 lM) Tonic
Control
1 (120)
2 (120)
3 (10)
4 (120)
5
100 l 7.2
85.9 l 3.7
52.9 l 8.6b)
104.0 l 2.8
33.5 l 6.0d)
ND
100 l 6.7
87.1 l 2.7
52.7 l 5.1d)
72.1 l 2.0b)
8.7 l 0.3c)
100 l 2.3
100.5 l 5.1
68.5 l 1.3c)
84.3 l 7.6
10.2 l 1.3c)
ND
ND
6 (60)
7 (60)
8 (40)
9 (40)
10 (40)
11 (60)
12
56.8 l 3.7c)
105.9 l 4.2
79.4 l 4.7
71.4 l 2.6
64.9 l 1.2b)
35.0 l 4.2d)
ND
86.1 l 1.0
108.3 l 5.9
98.0 l 6.9
87.0 l 1.7
69.1 l 0.6b)
57.1 l 6.7b)
ND
95.5 l 3.2
100.0 l 0.0
110.2 l 5.4
84.6 l 4.3b)
82.7 l 3.2d)
33.3 l 3.0
ND
13 (60)
14 (60)
15 (60)
16 (60)
17 (60)
18 (60)
80.4 l 1.5
28.4 l 1.7c)
66.2 l 7.6b)
16.0 l 0.9c)
15.9 l 2.4c)
14.4 l 2.0c)
88.1 l 3.4
89.2 l 2.9
94.2 l 7.7
75.6 l 1.6b)
90.0 l 1.2
63.8 l 5.4b)
88.9 l 7.9
67.5 l 7.3b)
88.8 l 8.0
55.7 l 3.0c)
85.8 l 3.0b)
39.0 l 11.0d)
Figure 3. Concentration-dependent inhibitory effect of 4, 5, 12,
17, and 18 on platelet aggregation induced by ADP in human
PrP.
Human PrP was incubated with various concentrations of 4, 5,
12, 17, and 18 or dimethylsulfoxide (0.5%) for 3 min and then
ADP (20 lM) was added to trigger aggregation. Data are pre-
sented as means l S.E.M. (n = 3–6).
a)
Rat aorta was preincubated with xanthone derivatives or
DMSO (0.1%, control) at 378C for 15 min, then high K+
(80 mM) and Ca2+ (1.9 mM), or noradrenaline (3 lM) was
added. Percentages of the contraction were calculated and
presented as means l S.E.M (n = 3), ND = not determined.
P a 0.05.
b)
b)
c)
mino side chain of 19 did not enhance the antiplatelet
effects when AA is used as the aggregation agonist.
The antiplatelet effects of selective compounds 4, 5, 12,
P a 0.01.
P a 0.001 as compared with the respective control value.
17, and 18 were also studied on the aggregation of ence in the ADP-receptor interaction [9, 10, 11]. Com-
human PrP induced by ADP. As shown in Fig. 3, all these pounds 4, 12, and 18 significantly inhibited platelet
compounds (each at 100 lM) showed a potent antiplate- aggregation induced by PAF, which did not cause throm-
let effect on ADP-induced aggregation. In human PrP, boxane formation. This inhibition could be due to the
these compounds prevented secondary aggregation and calcium antagonizing effect or inhibitor of intracellular
suppressed the primary aggregation at higher concentra- calcium mobilization [12]. Further experiments are
tions induced by ADP (for example 5 in Fig. 4). We con- needed to elucidate their mechanism of action.
clude that their mechanism of action are chiefly due to
the inhibition of thromboxane formation and interfer- in smooth muscle is mediated by an increase in Ca2+
It has been reported that high K+-induced constrictions
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

22
K.-W. Lin et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 19–26
Table 3. Physical data of xanthone derivatives.
Compound
R
n
Yield (%)
Mp. (8C)
Recrystallization sol-
vent
1
2
3
4
5
6
7
N(CH3)2
N(CH3)2
N(CH3)2
N(CH3)2
N(CH3)2
N(C2H5)2
N(CH3)C2H4OH
2
3
4
5
6
4
4
71
74
75
68
62
51
65
218–220
219–221
212–216
205–208
160–163
172–173
213–214
CHCl3-MeOH
CHCl3-MeOH
CHCl3-MeOH
CHCl3-MeOH
CHCl3-MeOH
CHCl3-MeOH
CHCl3-MeOH
8
9
4
4
4
61
64
62
211–214
188–190
229–232
CHCl3-MeOH
CHCl3-MeOH
CHCl3-MeOH
10
11
12
4
4
54
56
168–171
183–185
CHCl3-MeOH
CHCl3-MeOH
13
14
15
16
17
18
NHC2H5
NHC4H9
NHC2H4OH
NHCH(CH3)C2H5
NHCH(CH3)C2H5
NHCH(CH3)C2H5
4
4
4
3
4
5
72
68
64
66
69
62
208–212
152–154
86–89
217–218
172–175
118–121
CHCl3-MeOH
CHCl3-MeOH
CHCl3-MeOH
CHCl3-MeOH
MeOH
MeOH
influx through voltage-dependent Ca2+ channels. Com-
pounds 4, 14 and 16–18 depressed markedly the constric-
tions induced by Ca2+ (1.9 mM) in high-K+ (80 mM)
medium. These compounds may be blocker of voltage-
dependent Ca2+ channels [2]. The maintenance of tonic
constriction in response to noradrenaline results primar-
ily from Ca2+ influx through receptor activated Ca2+ chan-
nels with little requirement for Ca2+ influx through volt-
This work was supported by a research grant from the National Science
Council of Republic of China (NSC 95-2320-B-037-037).
The authors have declared no conflict of interest.
Experimental
Melting points (uncorrected) were determined with a Yanaco
Micro-Melting Point apparatus (Yanaco Seisakusho Co. Ltd,
Japan). IR spectra were determined with a Perkin-Elmer system
2000 FTIR spectrophotometer (Perkin Elmer, Norwalk, CT, USA).
1H- (400 MHz) and 13C- (100 MHz) NMR spectra were recorded on
a Varian Unity-400 spectrometer (Varian Inc., Palo Alto, CA, USA)
and MS spectra were obtained on a JMS-HX-100 mass spectrome-
ter (JEOL, Ltd. Japan). Elemental analyses were performed by
Vario EL III (Elementar Analysensysteme GmbH, Hanau, Ger-
many). Chromatography was performed using a flash-column
technique on silica gel 60 supplied by E. Merck (Darmstadt, Ger-
many).
age dependent Ca2+ channels. Compound
4 also
depressed markedly the constrictions induced by nora-
drenaline (3 lM) (Table 2). It revealed that 4 may be also a
blocker of receptor-activated Ca2+ channels [2]. Further
experiments are needed to elucidate their mechanism of
action. Compounds 4, 16, and 17 possess antiplatelet and
vasorelaxing activity. This study further verifies that
compounds 4, 5, 12, 17, and 18 showed significant inhibi-
tory effects on platelet aggregation. These compounds
revealed antiplatelet effects on washed rabbit platelets
and in human PrP, and vasorelaxing activities in rat
thoracic aorta. These dual activities revealed that these
compounds can serve as a new antithrombotic agent.
Chemistry
General procedure for the synthesis of compounds 1–5
To a solution of KOH (1.28 g, 22.6 mmol) in H2O (1.0 mL) were
added t-BuOH (30 mL), I (3.72 g, 17.6 mmol) and 1, 2-dibromo-
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2009, 342, 19–26
Antiplatelet and Vasorelaxing Xanthones
23
ethane or 1, 3-dibromopropane or 1, 4-dibromobutane or 1, 5-
dibromopentane or 1, 6-dibromohexane (each 45.2 mmol), and
the mixture was stirred for 3 h under reflux. The reaction mix-
ture was evaporated and the organic material was extracted
with ether. Extracts were washed with H2O, dried, and evapo-
rated in vacuo. The residue was purified by a silica-gel column to
yield II (82–85%). A solution of II (0.76 g, 2.2 mmol) and 50%
aqueous (CH3)2NH (20 mL) in THF (20 mL) was stirred at room
temperature for 6 h. The organic material was extracted with
ether and the extracts were washed with brine, dried, and evapo-
rated in vacuo. The residue dissolved in ether was added etha-
nolic HCl or HBr (20%, 0.5 mL) to afford various crystals, which
were recrystallized from appropriate solvent (Table 1) to obtain
2.85 (s, 6H, Me62), 3.06 (m, 2H, NCH2), 4.09 (t, 2H, J = 6.3 Hz,
OCH2), 6.85 (d, 1H, J = 2.1 Hz, H-4), 6.91 (dd, 1H, J = 9.0, 2.1 Hz, H-
2), 7.37–7.45 (m, 2H, H-6 and H-7), 8.22 (d, 1H, J = 9.0 Hz, H-1),
8.31 (dd, 1H, J = 8.0, 1.8 Hz, H-8). 13C-NMR (CDCl3) d (ppm): 23.2
(CH2), 24.1 (CH2), 28.3 (CH2), 42.8 (N(CH3)2), 57.7 (NCH2), 67.8
(OCH2), 100.6 (C-4), 113.2 (C-2), 115.7 (C-9a), 117.6 (C-5), 121.8 (C-
8a), 123.8 (C-7), 126.5 (C-8), 128.1 (C-1), 134.3 (C-6), 156.1(C-10a),
157.9 (C-4a), 164.2 (C-3), 176.2 (10). EIMS (70 eV) m/z (% rel. int.):
325 [M]+ (1), 183 (3), 155 (4), 139 (6), 114 (37), 58 (100). Anal. Calcd.
for C20H23NO3 N HCl N H2O: C, 63.20; H, 6.90; N, 3.70. Found: C,
63.07; H, 6.89; N, 3.51.
3-(6-(Dimethylamino)hexoxy)xanthone hydrochloride 5
1
(0.50 g, 1.57 mmol), 2 (0.54 g, 1.63 mmol), 3 (0.57 g,
Physical data: see Table 3. IR (KBr) 1640, 1620 cm– 1 1H-NMR
.
1.65 mmol), 4 (0.54 g, 1.50 mmol), and 5 (0.51 g, 1.36 mmol).
(CDCl3) d (ppm): 1.54 (m, 4H, CH262), 1.88 (m, 4H, CH262), 2.78
(s, 6H, Me62), 2.97 (m, 2H, NCH2), 4.08 (t, 1H, J = 6.3 Hz, OCH2),
6.86 (1H, J = 2.4 Hz, H-4), 6.89 (dd, 1H, J = 8.7, 2.4 Hz, H-2), 7.36–
7.45 (m, 2H, H-6 and H-7), 7.69 (m, 1H, H-5), 8.23 (d, 1H, J = 8.7 Hz,
H-1), 8.32 (dd, 1H, J = 8.1, 1.5 Hz, H-8). 13C-NMR (CDCl3) d (ppm):
24.4 (CH2), 25.5 (CH2), 26.4 (CH2), 28.7 (CH2), 42.9 (N(CH3)2), 58.0
(NCH2), 68.2 (OCH2), 100.6 (C-4), 113.5 (C-2), 115.7 (C-9a), 117.7 (C-
5), 121.9 (C-8a), 123.9 (C-7), 126.6 (C-8), 128.2 (C-1), 134.3 (C-6),
156.2 (C-10a), 158.0 (C-4a), 164.4 (C-3), 176.3 (CO). EIMS (70 eV) m/z
(% rel. int.): 339 [M]+ (3), 183 (1), 139 (4), 128 (8), 58 (100). Anal.
Calcd. for C21H25NO3 N HBr N H2O: C, 57.50; H, 6.40; N, 3.20. Found:
C, 58.86; H, 6.85; N, 3.40.
3-(2-(Dimethylamino)ethoxy)xanthone hydrochloride 1
Physical data: see Table 3. IR (KBr) 1645, 1618 cm– 1 1H-NMR
.
(CDCl3-CD3OD) d (ppm): 2.93 (s, 6H, Me62), 3.56 (t, 2H, J = 4.4 Hz,
NCH2), 4.54 (t, 2H, J = 4.4 Hz, OCH2), 6.92 (dd, 1H, J = 8.3, 2.4 Hz, H-
2), 6.94 (d, 1H, J = 2.4 Hz, H-4), 7.32–7.42 (m, 2H, H-6 and H-7),
7.66 (m, 1H, H-5), 8.17 (d, 1 H, J = 8.3 Hz, H-1), 8.22 (dd, 1H, J = 8.1,
1.6 Hz, H-8). 13C-NMR (CDCl3-CD3OD) d (ppm): 43.6 (Me62), 56.3
(NCH2), 63.1 (OCH2), 101.3 (C-4), 113.1 (C-2), 116.4 (C-9a), 117.6 (C-
5), 121.6 (C-8a), 124.1 (C-7), 126.4 (C-8), 128.5 (C-1), 134.7 (C-6),
156.1 (C-10a), 157.8 (C-4a), 162.4 (C-3), 176.5 (CO). EIMS (70 eV) m/z
(% rel. int.): 283 [M]+ (0.9), 195 (4), 155 (4), 139 (25), 58 (100). Anal.
Calcd. for C17H17NO3 . HCl . H2O: C, 60.40; H, 6.00; N, 4.10. Found:
C, 60.51; H, 5.96; N, 4.00.
General procedure for the synthesis of 6–12
To a solution of II (0.85 g, 2.47 mmol) in THF (20 mL) was added
diethylamine or N-methylethanolamine or pyrrolidine or piperi-
dine or N-methylpiperazine or morpholine or 4-hydroxy piperi-
dine (each 3.80 mmol) and NaOH (0.1 g, 2.5 mmol) in H2O
(1.0 mL). The reaction mixture was stirred at 708C for 8 h. The
organic material was extracted with ether and the extracts were
washed with brine, dried, and evaporated in vacuo. To the resi-
due dissolved in ether was added ethanolic HCl or HBr (20%,
0.5 mL) to afford various products which were recrystallized
from appropriate solvent (see Table 1) to yield 6 (0.47 g,
1.26 mmol), 7 (0.61 g, 1.61 mmol), 8 (0.56 g, 1.51 mmol), 9
(0.61 g, 1.58 mmol), 10 (0.62 g, 1.53 mmol), 11 (0.52 g,
1.33 mmol), and 12 (0.56 g, 1.38 mmol).
3-(3-(Dimethylamino)propoxy)xanthone hydrochloride 2
Physical data: see Table 3. IR (KBr) 1645, 1620 cm– 1 1H-NMR
.
(CDCl3-CD3OD) d (ppm): 2.33 (m, 2H, CH2), 2.98 (s, 6H, Me62),
3.41 (t, 2H, J = 6.1 Hz, NCH2), 4.26 (t, 2H, J = 5.8 Hz, OCH2), 7.01
(dd, 1H, J = 8.6, 2.4 Hz, H-2), 7.04 (d, 1H, J = 2.4 Hz, H-4), 7.42–7.55
(m, 2H, H-6 and H-7), 7.77 (m, 1H, H-5), 8.13 (d, 1H, J = 8.6 Hz, H-1),
8.22 (dd, 1H, J = 8.0, 1.6 Hz, H-8). 13C-NMR (CDCl3-CD3OD) d (ppm):
24.1 (CH2), 42.7 (Me62), 56.3 (NCH2), 65.1 (OCH2), 100.7 (C-4),
113.3 (C-2), 115.7 (C-9a), 117.6 (C-5), 121.4 (C-8a), 123.9 (C-7), 126.2
(C-8), 128.0 (C-1), 134.5 (C-6), 156.0 (C-10a), 157.9 (C-4a), 163.6 (C-
3), 176.6 (CO). EIMS (70 eV) m/z (% rel. int.): 297 [M]+ (4) 183 (7),
139 (13), 127 (12), 58 (100). Anal. Calcd. for C18H19NO3 . HCl . H2O:
C, 61.40; H, 6.30; N, 4.00. Found: C, 61.38; H, 6.28; N, 3.75.
3-(4-(Diethylamino)butoxy)xanthone hydrochloride 6
Physical data: see Table 3. IR (KBr) 1640, 1620 cm– 1 1H-NMR
.
3-(4-(Dimethylamino)butoxy)xanthone hydrochloride 3
(CDCl3) d (ppm): 1.42 (m, 6H, Me62), 1.95–2.05 (m, 4H, CH262),
2.96–3.22 (m, 6H, N(CH2) 63), 4.12 (t, 1H, J = 5.7 Hz, OCH2), 6.83
(brs, 1H, H-4), 6.87 (dd, 1H, J = 9.0 Hz) H-2, 7.34, 7.42 (m, each 1H,
H-6 and H-7), 7.67 (m, 1H, H-5), 8.19 (d, 1H, J = 9.0 Hz, H-1), 8.27 (d,
1H, J = 7.8 Hz, H-8). 13C-NMR (CDCl3) d (ppm): 8.6 (Me), 11.1 (Me),
20.6 (CH2), 26.3 (CH2), 42.2 (NCH2), 46.5 (NCH2), 51.1(NCH2), 67.4
(OCH2), 100.7 (C-4), 113.3 (C-2), 115.9 (C-9a), 117.7 (C-5), 121.8 (C-
8a), 123.9 (C-7), 126.5 (C-8), 128.2 (C-1), 134.3 (C-6), 156.1 (C-10a),
157.9 (C-10a), 163.9 (C-3), 176.1 (CO). EIMS (70 eV) m/z (% rel. int.):
339 [M]+ (1), 324 (2), 225 (3), 183 (3), 139 (8), 86 (100). Anal. Calcd.
for C21H25NO3 N HBr N H2O: C, 57.50; H, 6.40; N, 3.20. Found: C,
57.57; H, 6.51; N, 3.55.
Physical data: see Table 3. IR (KBr) 1640, 1620 cm– 1 1H-NMR
.
(CDCl3-CD3OD) d (ppm): 1.88–2.00 (m, 4H, CH262), 3.08 (m, 2H,
NCH2), 4.06 (t, 2H, J = 5.6 Hz, OCH2), 6.79 (d, 1H, J = 2.4 Hz, H-4),
6.84 (dd, 1H, J = 8.7, 2.4 Hz, H-2), 7.29-7.40 (m, 2H, H-6 and H-7),
7.63 (m, 1H, H-5), 8.11 (d, 1H, J = 8.7 Hz, H-1), 8.19 (dd, 1H, J = 7.9,
1.8 Hz, H-8), 13C-NMR (CDCl3-CD3OD) d (ppm): 21.8 (CH2), 26.5
(CH2), 43.1 (N(CH3)2), 57.9 (NCH2), 67.9 (OCH2), 101.2 (C-4), 114.0
(C-2), 116.1 (C-9a), 118.2 (C-5), 122.1 (C-8a), 124.7 (C-7), 126.9 (C-8),
128.6 (C-1), 135.0 (C-6), 155.6 (C-10a), 158.5 (C-4a), 164.6 (C-3),
177.1 (CO). EIMS (70 eV) m/z (% rel. int.): 311 [M]+ (4), 236 (3),183
(3), 139 (9), 83 (26), 69 (38), 58 (100). Anal. Calcd. for C19H21NO3 .
HCl: C, 65.60; H, 6.40; N, 4.00. Found: C, 65.55; H, 6.38; N, 3.95.
3-(4-(N-Methyl-N(2-hydroxyethyl)amino)butoxy)xanthone
3-(5-(Dimethylamino)pentoxy)xanthone hydrochloride 4
hydrochloride 7
1
Physical data: see Table 3. IR (KBr) 1640, 1620 cm– 1
.
1H-NMR
Physical data: see Table 3. IR (KBr) 3300, 1645, 1620 cm– 1. H-
(CDCl3) d (ppm): 1.63 (m, 2H, CH2), 1.89–2.01 (m, 4H, CH262),
NMR (CDCl3-CD3OD) d (ppm): 1.85–2.00 (m, 4H, CH262), 2.84 (s,
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

24
K.-W. Lin et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 19–26
3H, NMe), 3.17 (m, 4H, N(CH262)), 3.89 (t, 2H, J = 5.1 Hz, CH2OH),
4.07 (t, 2H, J = 5.7 Hz, OCH2), 6.81 (d, 1H, J = 2.1 Hz, H-4), 6.85 (dd,
1H, J =8.7, 2.1 Hz, H-2), 7.30–7.38 (m, 2H, H-6 and H-7), 7.63 (m,
1H, H-5), 8.11 (d, 1H, J = 8.7 Hz, H-1), 8.19 (d, 1H, J = 8.1 Hz, H-8).
13C-NMR (CDCl3-CD3OD) d (ppm): 20.8 (CH2), 25.9 (CH2), 40.5
(NCH3), 55.7 (NCH2), 56.3 (NCH2), 57.8 (CH2OH), 67.4 (OCH2), 100.6
(C-4), 115.5 (C-9a), 117.3 (C-5), 121.5 (C-8a), 123.9 (C-7), 126.3 (C-8),
128.0 (C-1), 134.5 (C-6), 156.1 (C-10a), 158.0 (C-4a), 164.1 (C-3),
176.7 (CO). ESIMS m/z 342 [M+1]+. HRESIMS: Calcd. for C20H24NO4:
342.1705. Found: 342.1704.
N(CH263)), 3.92 (m, 4H, OCH262), 4.05 (t, 2H, J = 5.9 Hz, OCH2),
6.81 (d, 1H, J = 2.0 Hz, H-4), 6.84 (dd, 1H, J = 8.7, 2.4 Hz, H-2),
7.26–7.40 (m, 2H, H-6 and H-7), 7.63 (m, 1H, H-5), 8.11 (d, 1H, J =
8.7 Hz, H-1), 8.20 (dd, 1H, J = 8.1, 1.7 Hz, H-8), 13C-NMR (CDCl3-
CD3OD) d (ppm): 20.4 (CH2), 26.2 (CH2), 51.9 (N(CH2)2), 57.4 (NCH2),
63.6 (O(CH2)2), 67.4 (OCH2), 100.7 (C-4), 113.4 (C-2), 115.8 (C-9a),
117.7 (C-5), 121.8 (C-8a), 123.9 (C-7), 126.5 (C-8), 128.3 (C-1), 134.4
(C-6), 156.1 (C-10a), 158.0 (C-4a), 164.0 (C-1), 176.4 (CO). EIMS
(70 eV) m/z (% rel. int.): 353[M]+ (2), 322 (2), 195 (2), 183 (2), 139 (7),
100 (100). Anal. Calcd. for C21H23NO4 N HCl N H2O: C, 61.80; H,
6.40; N, 3.40. Found: C, 61.50; H, 6.58; N, 3.51.
3-(4-Pyrrolidinobutoxy)xanthone hydrochloride 8
Physical data: see Table 3. IR (KBr) 1645, 1620 cm– 1 1H-NMR
.
3-(4-(4-Hydroxypiperidino)butoxy)xanthoen
(CDCl3) d (ppm): 1.98 (m, 2H, CH2), 2.17 (m, 6H, CH263), 3.13–
3.60 (m, 6H, N(CH263)), 4.13 (t, 2H, J = 6.0 Hz, OCH2), 6.85 (d, 1H,
J = 2.1 Hz, H-4), 6.91 (dd, 1H, J = 9.0, 2.4 Hz, H-2), 7.38–7.46 (m,
2H, H-6 and H-7), 7.69 (m, 1H, H-5), 8.23 (d, 1H, J = 9.0 Hz, H-1),
8.32 (dd, 1H, J = 8.1, 1.5 Hz, H-8). 13C-NMR (CDCl3) d (ppm): 22.8
(CH2), 23.3 (CH262), 26.3 (CH2), 53.6 (N(CH2)2), 55.1 (NCH2), 67.5
(OCH2), 100.7 (C-4), 113.4 (C-2), 115.9 (C-9a), 117.7 (C-5), 121.9 (C-
8a), 123.9 (C-7), 126.6 (C-8), 128.3 (C-1), 134.3 (C-6), 156.2 (C-10a),
158.0 (C-4a), 163.9 (C-3), 176.2 (CO). EIMS (70 eV) m/z (% rel. int.):
337 [M]+ (12). Anal. Calcd. for C21H23NO3 N HCl: C, 67.50; H, 6.50; N,
3.70. Found: C, 67.42; H, 6.18; N, 3.40.
hydrochloride 12
1
Physical data: see Table 3. IR (KBr) 3400, 1650, 1620 cm– 1. H-
NMR (CDCl3-CD3OD) d (ppm): 1.90–2.33 (m, 8H, CH264), 3.11–
3.27 (4 m, H, N(CH262), 3.53 (m, 2H, NCH2), 4.15 (m, 2H, OCH2),
6.90 (brs, 1H, H-4), 6.94 (d, 1H, J = 8.7 Hz, H-2), 7.38-7.48 (m, 2H, H-
6 and H-7), 7.74 (m, 1H, H-5), 8.21 (d, 1H, J = 8.7 Hz, H-1), 8.29 (dd,
1H, J = 8.1, 1.5 Hz, H-8). 13C-NMR (CDCl3-CD3OD) d (ppm): 20.7
(CH2), 26.2 (CH2), 29.4 (CH262), 47.5 (N(CH262)), 56.9 (NCH2),
60.0 (CHOH), 67.5 (OCH2), 100.7 (C-4), 113.6 (C-2), 115.6 (C-9a),
117.7 (C-5), 121.6 (C-8a), 124.0 (C-7), 126.4 (C-8), 128.1 (C-1), 134.6
(C-6), 156.1 (C-10a), 158.0 (C-4a), 164.2 (C-3), 176.7 (CO). EIMS
(70 eV) m/z (% rel. int.): 367 [M]+ (2), 212 (7), 195 (2), 114 (100).
Anal. Calcd. for C22H25NO4 N HCl N H2O: C, 62.60; H, 6.70; N, 3.30.
Found: C, 62.30; H, 6.75; N, 3.16.
3-(4-Piperidinobutoxy)xanthone hydrochloride 9
Physical data: see Table 3. IR (KBr) 1640, 1615 cm– 1 1H-NMR
.
(CDCl3-CD3OD) d (ppm): 1.87–2.04 (m, 10H, CH265), 2.63–350
(m, 4H, N(CH2)2), 4.80 (t, 2H, J = 6.0 Hz, OCH2), 6.83 (d, 1H, J =
2.4 Hz, H-4), 6.86 (dd, 1H, J = 8.7, 2.4 Hz, H-2), 7.32–7.41 (m, 2H,
H-6 and H-7), 7.64 (m, 1H, H-5), 8.14 (d, 1H, J = 9.0 Hz, H-1), 8.22
(dd, 1H, J = 7.8, 1.5 Hz, H-8). 13C-NMR (CDCl3-CD3OD) d (ppm): 20.6
(CH2), 21.8 (CH2), 22.5(CH262), 26.1 (CH2), 53.1(N(CH2)2), 56.7
(NCH2), 67.1 (OCH2), 100.6 (C-4), 113.5 (C-2), 115.6 (C-9a), 117.6 (C-
5), 121.5 (C-8a), 123.9 (C-7), 126.3 (C-8), 128.0 (C-1), 134.5 (C-6),
156.1 (C-10a), 158.0 (C-4a), 164.1 (C-3), 176.6 (CO). EIMS (70 eV) m/z
(% rel. int.): 351 [M]+ (2), 195 (1), 183 (1), 139 (4), 98 (100). Anal.
Calcd. for C22H25NO3 N HCl N 2H2O: C, 62.30; H, 7.10; N, 3.30.
Found: C, 62.34; H, 7.51; N, 3.65.
General procedure for the synthesis of 13–18
To a solution of compound II (1.0 g, 2.38 mmol) in t-BuOH
(25 mL) was added ethylamine or n-butylamine or ethanolamine
or sec-butylamine (4.0 mmol) and NaOH (0.2 g, 5.0 mmol) in H2O
(1.0 mL). The reaction mixture was stirred at 708C for 5 h. The
organic material was extracted with ether and the extracts were
washed with brine, dried, and evaporated in vacuo. The residue
was purified by column chromatography. The eluate dissolved
in ether was added ethanolic HCl or HBr (20%, 0.5 mL) to give
various products which recrystallized from appropriate solvent
(see Table 1) to afford 13 (0.55 g, 1.62 mmol), 14 (0.53 g,
1.71 mmol), 15 (0.50 g, 1.52 mmol), 16 (0.51 g, 1.57 mmol), 17
(0.56 g, 1.64 mmol), and 18 (0.52 g, 1.48 mmol).
3-(4-(4-Methylpiperazino)butoxy)xanthone hydrochloride
10
Physical data: see Table 3. IR (KBr) 1645, 1625 cm– 1
.
1H-NMR
3-(4-(Ethylamino)butoxy)xanthone 13
(CDCl3-CD3OD) d (ppm): 1.87–2.02 (m, 4H, CH262), 2.86 (3H,
NMe), 3.21 (m, 2H, NCH2), 3.59–3.76 (m, 8H, N(CH264), 4.05 (t,
2H, J = 6.0 Hz, OCH2), 6.81 (1H, J = 2.4 Hz, H-4), 6.85 (dd, 1H, J =
8.7, 2.4 Hz, H-2), 7.30–7.38 (m, 2H, H-6 and H-7), 7.62 (m, 1H, H-
5), 8.11 (d, 1H, J = 8.7 Hz, H-1), 8.18 (dd, 1H, J = 8.1, 1.8 Hz, H-8).
13C-NMR (CDCl3-CD3OD) d (ppm): 20.5 (CH2), 25.8 (CH262), 42.5
(NCH3), 48.0 (N(CH2)2), 49.6 (N(CH2)2), 56.5 (NCH2), 56.5 (NCH2),
67.1 (OCH2), 100.6 (C-4), 113.4 (C-2), 115.5 (C-9a), 117.6 (C-5), 121.4
(C-8a), 123.9 (C-7), 126.2 (C-8), 128.0 (C-1), 134.5 (C-6), 156.0 (C-
10a), 157.9 (C-4a), 164.0 (C-3), 176.7 (CO). EIMS (70 eV) m/z (% rel.
int.): 366 [M]+ (12), 310 (3), 183 (3), 113 (100), 70 (52). Anal. Calcd.
for C22H26N2O3 N 2HCl: C, 60.10; H, 6.40; N, 6.40. Found: C, 60.27;
H, 6.55; N, 6.05.
Physical data: see Table 3. IR (KBr) 1650, 1620 cm– 1 1H-NMR
.
(CDCl3-CD3OD) d (ppm):1.42 (t, 3H, J = 7.2 Hz, Me), 2.01 (m, 4H,
CH262), 3.09 (m, 4H, N(CH262)), 4.14 (t, 2H, J = 5.4 Hz, OCH2),
6.88 (d, 1H, J = 2.1 Hz, H-4), 6.93(dd, 1H, J = 8.7, 2.4 Hz, H-2), 7.37–
7.44 (m, 2H, H-6 and H-7), 7.70 (m, 1H, H-5), 8.19 (d, 1H, J = 8.7 Hz,
H-1), 8.27 (dd, 1H, J = 7.8, 1.2 Hz, H-8). 13C-NMR (CDCl3-CD3OD) d
(ppm): 10.8 (CH3), 22.9 (CH2), 25.9 (CH2), 42.8 (NCH2), 46.8 (NCH2),
67.5 (OCH2), 100.5 (C-4), 113.5 (C-2), 115.4 (C-9a), 117.6 (C-5), 121.4
(C-8a), 123.4 (C-7), 126.2 (C-8), 127.9 (C-1), 134.5 (C-6), 156.0 (C-
10a), 157.9 (C-4a), 164.2 (C-3), 176.7 (CO). EIMS (70 eV) m/z (% rel.
int.): 311 [M]+ (128). Anal. Calcd. for C19H21NO3 N HBr N H2O: C,
55.60; H, 5.90; N, 3.40. Found: C, 55.90; H, 5.60; N, 3.55.
3-(4-(n-Butylamino)butoxy)xanthone 14
Physical data: see Table 3. IR (KBr) 1645, 1625 cm– 1 1H-NMR
.
3-(4-Morpholinolbutoxy)xanthone hydrochloride 11
Physical data: see Table 3. IR (KBr) 1645, 1625 cm– 1
.
1H-NMR
(CDCl3) d (ppm): 0.92 (t, 3H, J = 7.2 Hz, Me), 1.39–1.74 (m, 4H,
CH262), 1.97 (m, 4H, CH262), 2.83-2.92 (m, 4H, N(CH2)62), 4.07
(CDCl3-CD3OD) d (ppm): 1.88 (m, 4H, CH262), 2.94 (m, 6H,
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2009, 342, 19–26
Antiplatelet and Vasorelaxing Xanthones
25
(t, 2H, J = 6.0 Hz, OCH2), 6.81 (d, 1H, J = 2.4 Hz, H-4), 6.90 (dd, 1H, J
= 9.0, 2.4 Hz, H-2), 7.31–7.42 (m, 2H, H-6 and H-7), 7.66 (m, 1H, H-
5), 8.21 (d, 1 H, J = 9.0 Hz, H-1), 8.29 (dd, 1H, J = 8.1, 1.5 Hz, H-8).
13C-NMR (CDCl3) d (ppm): 13.7 (Me), 20.3 (CH2), 24.5 (CH2), 26.6
(CH2), 29.7 (CH2), 48.4 (NCH2), 48.6 (NCH2), 67.9 (OCH2), 100.6 (C-
4), 113.4 (C-2), 115.8 (C-9a), 117.6 (C-5), 121.9 (C-8a), 123.8 (C-7),
126.6 (C-8), 128.3 (C-1), 134.2 (C-6), 156.1 (C-10a), 157.9 (C-4a),
164.2 (C-3), 176.2 (CO). EIMS (70 eV) m/z (% rel. int.): 339 [M]+ (5).
Anal. Calcd. for C21H25NO3 N HCl N H2O: C, 64.00; H, 7.20; N, 3.60.
Found: C, 64.15; H, 7.20; N, 3.49.
1H, J = 8.9, 2.7 Hz, H-2), 7.31–7.41 (m, 2H, J = H-6 and H-7), 7.63
(m, 1H, H-5), 8.19 (d, 1H, J = 8.9 Hz, H-1), 8.25 (dd, 1H, J = 7.9,
1.5 Hz, H-8). 13C-NMR (CDCl3) d (ppm): 10.2 (Me), 17.5 (Me), 23.6
(CH2), 27.6 (CH2), 27.8 (CH2), 28.6 (CH2), 45.7 (NH2), 55.3 (NCH),
68.2 (OCH2), 100.6 (C-4), 113.5 (C-2), 115.6 (C-9a), 117.6 (C-5), 121.8
(C-8a), 123.8 (C-7), 126.5 (C-8), 128.1 (C-1), 134.2 (C-6), 156.1 (C-
10a), 157.9 (C-4a), 164.4 (C-3), 176.2 (CO). EIMS (70 eV) m/z (% rel.
int.): 353 [M]+ (2). Anal. Calcd. for C22H27NO3 N HBr: C, 60.80; H,
6.50; N, 3.20. Found: C, 60.72; H, 6.82; N, 3.50.
Biological assays
Platelet aggregation
3-(4-(2-Hydroxyethyl)amino)butoxy)xanthone 15
Washed rabbit platelets were obtained from EDTA-anticoagu-
lated PrP according to procedures described previously. Human
PrP was obtained from the supernatant after centrifugation of a
1 : 9 mixture of blood and sodium citrate solution (3.8%). Plate-
let numbers were counted by using a Coulter Counter (Model
ZM; Beckman Coulter, USA) and adjusted to 4.56108 platelets/
mL. The platelet pellets were suspended in Tyrode's solution con-
taining (mM): NaCl (136.8), KCl (2.8), NaHCO3 (11.9), MgCl2 (2.1),
NaH2PO4 (0.33), CaCl2 (1.0), and glucose (11.2) with 0.35% BSA. All
glassware was siliconized. PrP or the platelet suspension was
stirred at 1200 rev/min 1 min before addition of the aggregation
inducer. Aggregation was measured by a turbidimetric method.
The absorbance platelet-poor plasma or platelet-free Tyrode's sol-
ution was taken as 100% aggregation. The aggregation was meas-
ured by means of a Lumi-aggregometer (Chrono-Log Co., USA)
connected to dual channel recorders [4].
1
Physical data: see Table 3. IR (KBr) 3420, 1645, 1625 cm– 1. H-
NMR (CDCl3-CD3OD) d (ppm): 1.78–1.94 (m, 4H, CH262), 2.79 (m,
4H, N(CH262)), 3.71 (t, 2H, J = 4.8 Hz, 2H, CH2OH), 4.14 (t, 2H, J =
6.3Hz, OCH2), 6.92 (d, 1H, J = 2.1 Hz, H-4), 6.97 (dd, 1H, J = 8.7, 2.4,
H-2), 7.40–7.50 (m, 2H, H-6 and H-7), 7.74 (t, 1H, J = 8.4 Hz, H-5),
8.22 (d, 1H, J = 8.7 Hz, H-1), 8.30 (dd, 1H, J = 7.8, 1.5, H-8). 13C-NMR
(CDCl3-CD3OD) d (ppm): 25.6 (CH2), 26.4 (CH2), 49.5 (CH2), 50.7
(CH2), 60.8 (CH2OH), 68.1 (OCH2), 100.5 (C-4), 113.2 (C-2), 115.4 (C-
9a), 117.6 (C-5), 121.4 (C-8a), 123.4 (C-7), 126.2 (C-8), 128.5 (C-1),
134.5 (C-6), 156.0 (C-10a), 158.0 (C-4a), 164.2 (C-3), 176.8 (CO).
ESIMS m/z 328 [M+1]+. HRESIMS: Calcd. for C19H22NO4: 328.1549.
Found: 328.1548.
3-(3-(sec-Butylamino)propoxy)xanthone 16
Physical data: see Table 3. IR (KBr) 1645, 1620 cm– 1 1H-NMR
.
(CDCl3-CD3OD) d (ppm): 0.91 (t, 3H, J = 7.4 Hz, Me), 1.28 (d, 3H, J =
6.62 Hz, CHCH3), 1.52 (m, 1H, CHH), 1.83 (m, 1H, CHH), 2.27 (m,
2H, CH2), 3.06 (m, 3H, NCH2 and NCH(CH3)C2H5), 3.23 (m, 1H, 1H,
NCH), 4.12 (t, 2H, J = 5.7 Hz, OCH2), 6.83 (d, 1H, J = 2.2 Hz, H-4),
6.87 (dd, 1H, J = 9.4, 2.4 Hz, H-2), 7.27–7.39 (m, 2H, H-6 and H-7),
7.62 (m, 1H, H-5), 8.09 (d, 1H, J = 9.4 Hz, H-1), 8.16 (dd, 1H, J = 7.9,
1.7 Hz, H-8). 13C-NMR (CDCl3-CD3OD) d (ppm): 9.4 (Me), 15.1 (Me),
25.6 (CH262), 42.0 (NCH2), 55.8 (NCH), 65.4 (OCH2), 100.7 (C-4),
113.4 (C-2), 115.6 (C-9a), 117.6 (C-5), 121.4 (C-8a), 123.9 (C-7), 126.2
(C-8), 128.0 (C-1), 134.5 (C-6), 156.1 (C-10a), 157.9 (C-4a), 163.8 (C-
3), 176.7 (CO). EIMS (70 eV) m/z (% rel. int.): 325 [M]+ (1). Anal.
Calcd. for C20H23NO3 N HBr: C, 59.10; H, 6.00; N, 3.40. Found: C,
59.31; H, 5.94; N, 3.42.
Aortic contraction
Wistar rats of either sex, 250–300 g, were killed by a blow to the
head. The thoracic aorta was isolated, excess fat and connective
tissue were removed and placed in organ bath containing 5 mL
Krebs solution, maintained at 378C, and bubbled with a 95% O2 /
5% CO2 mixture. Two stainless-steel hooks were inserted into the
aortic lumen, one was fixed while the other was connected to a
transducer. Aorta were equilibrated in the medium for 90 min
with three changes of Krebs solution and maintained under an
optimal tension of 1 g before specific experimental protocols
were initiated. Contractions were recorded isometrically via a
force displacement transducer connected to a Gould polygraph
(Model 2400; Gould Instruments,USA). The final concentration
of DMSO was fixed at 0.1% [4].
3-(4-(sec-Butyllamino)butoxy)xanthone 17
Physical data: see Table 3. IR (KBr) 1645, 1625 cm– 1 1H-NMR
.
(CDCl3) d (ppm): 1.00 (t, 3H, J = 7.2 Hz, Me), 1.48 (d, 3H, J = 6.6 Hz,
CHCH3), 1.72–2.23 (m, 6H, CH263), 3.09 (m, 2H, NCH2), 3.21 (m,
1H, NCH), 4.04 (t, 2H, J = 6.0 Hz, OCH2), 6.75 (d, 1H, J = 2.4 Hz, H-
4), 6.87 (dd, 1H, J = 9.0, 2.4 Hz, H-2), 7.28–7.38 (m, 2H, H-6 and H-
7), 7.63 (m, 1H, H-5), 8.18 (d, 1H, J = 9.0 Hz, H-1), 8.25 (dd, 1H, J =
7.8, 1.5 Hz, H-8). 13C-NMR (CDCl3) d (ppm): 10.2 (Me), 15.5 (Me),
23.0 (CH2), 25.8 (CH2), 26.5 (CH2), 44.3 (NCH2), 56.1 (NCH), 67.6
(OCH2), 100.6 (C-4), 113.3 (C-2), 115.8 (C-9a), 117.6 (C-5), 121.8 (C-
8a), 123.8 (C-7), 125.5 (C-8), 128.3 (C-1), 134.2 (C-6), 156.0 (C-10a),
157.8 (C-4a), 163.9 (C-3), 176.1 (CO). EIMS (70 eV) m/z (% rel. int.):
339 [M]+ (1). Anal. Calcd. for C21H25NO3 N HBr: C, 60.00; H, 6.20; N,
3.30. Found: C, 59.92; H, 6.24; N, 3.30.
Data analysis
Data are presented as means l S.E.M. One-way analysis was used
for multiple comparison, and if significant variation was
observed between the treatment groups and the inhibitor-
treated groups, they were then compared with the control group
by student's t-test. Values of P a 0.05 were considered statistically
significant.
References
[1] C. M. Teng, C. N. Lin, F. N. Ko, K. L. Cheng, T. F. Huang,
Biochem. Pharmacol. 1989, 38, 3791–3795.
3-(5-(sec-Butylamino)pentoxy)xanthone 18
Physical data: see Table 3. IR (KBr) 1645, 1620 cm– 1 1H-NMR
.
[2] F. N. Ko, C. N. Lin, S. S. Liou, T. F. Huang, C. M. Teng, Eur. J.
Pharmacol. 1991, 192, 133–139.
(CDCl3) d (ppm): 0.93 (t, 3H, J = 7.5 Hz, Me), 1.24 (d, 3H, J = 6.4 Hz,
CHCH3). 1.56–1.82 (m, 8H, CH264), 2.81 (m, 3H, NCH2 and NCH),
4.03 (t, 2H, J = 6.3 Hz, OCH2), 6.79 (d, 1H, J = 2.4 Hz, H-4), 6.89 (dd,
[3] I. J. Chen, S. J. Liou, S. S. Liou, C. N. Lin, Gen. Pharmacol.
1993, 24, 1425–1433.
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

26
K.-W. Lin et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 19–26
[4] C. N. Lin, S. S. Liou, S. C. Lai, H. C. Lin, et al., J. Pharm.
Pharmacol. 1995, 47, 588–594.
[8] S. S. Liou, C. M. Teng, F. N. Ko, C. N. Lin, J. Pharm. Sci. 1994,
83, 391–395.
[9] D. C. Macmillan, Nature 1966, 211, 140–145.
[5] L. W. Wang, J. J. Kang, I. J. Chen, C. M. Teng, C. N. Lin,
[10] J. R. A. Mitchell, A. A. Sharp, Br. J. Haematol. 1964, 10, 78–
Bioorg. Med. Chem. 2002, 10, 567–572.
93.
[6] M. F. Hsu, C. N. Lin, M. C. Lu, J. P. Wang, Naunyn Schmiede-
bergs Arch. Pharmacol. 2004, 369, 507–515.
[11] J. F. Mustard, D. W. Perry, R. L. Kinlough-Rathbone, M. A.
Packham, Am. J. Physiol. 1975, 228, 1757–1765.
[7] C. N. Lin, S. S. Liou, F. N. Ko, C. M. Teng, J. Pharm. Sci. 1993,
82, 11–16.
[12] C. M. Teng, W. Y. Chen, W. C. Ko, C. H. Ouyang, Biochim.
Biophys. Acta 1987, 924, 375–382.
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com