Antiplatelet activity of benzylisoquinoline derivatives oxidized by cerium(IV) ammonium nitrate

Article abstract of DOI:10.1016/S0960-894X(03)00477-3

Oxidation of 1-benzyl-3,4-dihydroisoquinolines with cerium(IV) ammonium nitrate (CAN) under mild condition yielded the mixture of corresponding 1-benzylisoquinolines (b-type) and 1-benzoylisoquinolines (a- or c-type) in an equal yields. The selective oxidation products (c-type) can be prepared by using MeCN instead of MeOH. In the antiplatelet assays, four inducers were employed, including AA, Col, PAF, and Thr. In the PAF or Col induced platelet aggregation, compounds belonging to a- and b-type showed stronger inhibitory effects than aspirin.

Full text of DOI:10.1016/S0960-894X(03)00477-3

Bioorganic & Medicinal Chemistry Letters 13(2003) 2789–2793
Antiplatelet Activity of Benzylisoquinoline Derivatives Oxidized
by Cerium(IV) Ammonium Nitrate
Reen-Yen Kuo, Fang-Rong Chang, Chin-Chun Wu, Ramesh Patnam,
Wei-Ya Wang, Ying-Chi Du and Yang-Chang Wu*
Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 807, Taiwan
Received 24 February 2003; accepted 23 April 2003
Abstract—Oxidation of 1-benzyl-3,4-dihydroisoquinolines with cerium(IV) ammonium nitrate (CAN) under mild condition yielded
the mixture of corresponding 1-benzylisoquinolines (b-type) and 1-benzoylisoquinolines (a- or c-type) in an equal yields. The
selective oxidation products (c-type) can be prepared by using MeCN instead of MeOH. In the antiplatelet assays, four inducers
were employed, including AA, Col, PAF, and Thr. In the PAF or Col induced platelet aggregation, compounds belonging to a- and
b-type showed stronger inhibitory effects than aspirin.
# 2003Elsevier Ltd. All rights reserved.
Benzylisoquinolines showed variable biological activ-
ities, such as smooth muscle relaxant,1 adreno-recep-
tor antagonist,2 antiplatelet3 and vasorelaxing
actions.3 In our previous investigation of the anti-
platelet agents, pyrrolo-benzylisoquinolines were syn-
thesized and some of them exhibited selective
antiplatelet activity.4 Now we report, herein, the oxi-
dation of 1-benzyl-3,4-dihydroisoquinolines (1–9) to
the corresponding 1-benzoylisoquinolines (1a–9a), 1-
benzylisoquinolines (1b–9b), and 1-benzoy-3,4-dihy-
drolisoquinolines (1c–9c) by cerium(IV) ammonium
nitrate (CAN) (Scheme 1). The reaction mechanism,
antiplatelet activity, and the structure–activity rela-
tionship of them are also revealed.
give the methoxylated products of methoxy-isochro-
mans, methoxy-isochromanones and d-oxoerythrinan
derivatives at the benzylic position,7 and the deprotec-
tion of dihydropyrans, cyclic ketals or acetals.8 Thus,
we start to study the oxidation of 1-benzyl-3,4-dihy-
droisoquinolines using CAN in mild conditions.
In a prototype experiment,9 a methanolic solution of 1
was treated with CAN (4 equiv) for 12 h to afford 1a, 1b,
and 1c in almost equal yield. When other substituted 1-
benzyl-3,4-dihydroisoquinolines (2–9) were treated with
same condition, the same three types (a–c) of products
were also obtained in the ca. equal yield. In entry 9, an
a-hydroxylbenzylisoquinoline 9d (13%) (Fig. 1) was
isolated, while this type of oxidative products was not
found in other entries.
Chemistry
Interestingly, the solvent contributes a strong effect on
the ratio of three different types of products. In the
prototype experiments (Table 1, entries 1–9), MeOH
was used as solvent and three types of products were
obtained at almost equal amounts. However, when
MeCN replaced MeOH as the solvent (Table 1, entries
10–18), the composition of the oxidative products dra-
matically changed. 3,4-Dihydro-1-benzoylisoquinolines
(1c–9c) were derived as major products, and 1-benzyl-
isoquinolines (1b–9b) were totally absent in these entries.
Therefore, solvent selection plays an important role in the
yields of these derivatives. Interestingly, selective oxida-
tion was also reported in a similar reaction with Pd/C.5
In previous reports, mostly Pd/C was used for the
preparation of 1-benzyl-3,4-dihydroisoquinoline to 1-
benzylisoquinoline5 and chromium reagents or DDQ
were used for the oxidation of 1-benzyl-3,4-dihy-
droisoquinoline to 1-benzoylisoquinolines.6 However,
in recent decades, CAN has received considerable
attention as an catalyst for selective organic reac-
tions,7,8 especially for the regioselective oxidations to
*Corresponding author. Tel.: +886-7-312-1101x2197; fax: +886-7-
311-4773; e-mail: yachwu@kmu.edu.tw
0960-894X/03/$ - see front matter # 2003Elsevier Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00477-3

2790
R.-Y. Kuo et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2789–2793
Scheme 1. Hypothetic mechanism of cerium(IV) ammonium nitrate catalyzed oxidation of 1-benzyl-3,4-dihydroisoquinolines.
Table 1. The yields and material recovered percentage of entries 1–
189
Entry
Subtrate
Solvent
RPa (%)
Yield (%)b
b
a
c
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
9
1
2
3
4
5
6
7
8
9
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
26
21
22
25
24
2325
25
2328
25
312
11
10
5
30
29
32
28
24
22
3
35
30
25
22
24
204
2320
251
36
33
30
36
Figure 1. Structures of 9d and pyrrolobenzylisoquinoline.
Although the mechanistic details of the reaction are not
clear,7 we have proposed a tentative mechanism to
explain the product formation (Scheme 1). The main
advantages of this methodology using CAN, a cheap,
stable and easily available chemical, in MeCN for selec-
tive oxidizing on 3,4-dihydrobenzylisoquinolines are
quite economical and tolerance to a wide range of func-
tional groups. All the products were fully characterized
by the spectral data (1H NMR, UV, IR, and MS).9
29
3
9
25
3 233
<375
<370
<367
<371
<367
<375
<369
<370
<370
10
11
12
13
14
15
16
17
18
10
12
10
8
15
10
12
13
4
15
20
25
18
aRP: Recovery percentage of starting material.
bYields were calculated base on the reacted material.
Pharmacological Evaluation and Discussion
Our previous studies indicated that benzylisoquinoline
possessed significant antiplatelet activity than cytotoxi-
city or adrenoceptor affinities.4 Therefore, we focused
on the antiplatelet aggregation activity of compounds
1a–9a, 1b–9b, 1c–9c and 9d. In the platelet aggregation
assays, four inducers were employed, including AA (ara-
chidonic acid), Col (collagen), PAF (platelet activating
factor), and Thr (thrombin), and aspirin was screened as
positivecontrol.Theresultsoftheantiplatelet aggregatory

R.-Y. Kuo et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2789–2793
2791
screening were presented in Table 2. While most com-
pounds inhibited Col-induced platelet aggregation, all
compounds were inactive toward Thr-induced aggrega-
tion. In comparison with the reference drug, aspirin and
these tested compounds, compound 8a showed an
almost equal activity to the aggregation induced by AA
and compounds 3b, 8a and 9b demonstrated almost
equal potency to the aggregation induced by Col.
Compounds 1a, 3a, 5a, 5c, 8a and 9a showed stronger
inhibition than aspirin toward the aggregation induced
by PAF. In our knowledge, aspirin inhibits the activity
of cycloxygenase and selectively blocks the AA- and
Col-induced aggregation. Based on our results men-
tioned above, these benzylisoquinoline derivatives have
a different inhibition pattern and mechanism of action
from the aspirin in the antiplatelet aggregation.
specific relationship further indicates the
importance of the benzylic ketone. In comparing
with our published study,4 the previously eval-
uated pyrrolo-benzylisoquinolines (Fig. 1) were
more potent than the current compounds
toward platelet aggregation induced by AA and
Col. However, the new a-type compounds
showed an additional inhibition to PAF-induced
aggregation. Therefore, incorporation of the
pyrrolo moiety increases the potency toward
AA- and Col-induced aggregation but reduces
the PAF-induced one. Such a structure rela-
tionship has not been studied before.
3. From the results mentioned above, substitutions
on the benzyl ring with different groups did not
improve their antiaggregatory effects. The type
and oxidation states of these benzylisoquinolines
contribute more than their substitution to the
antiplatelet aggregatory activity.
Several structure–activity relationships were summar-
ized from these results:
1. C-type derivatives obviously showed less activity
than other two types of compounds in the AA
induced aggregation, which suggested that the
presence of double bond at C3–C4 position in the
molecular is required for their activity.
In conclusion, a mild, efficient, and convenient metho-
dology for the preparation of benzylisoquinoline deri-
vatives with CAN was developed. By changing the
solvent from MeOH to MeCN, 1-benzoyl-3,4-dihy-
droisoquinolines (1c–9c) were obtained predominantly
over 1-benzoyl- (1a–9a) and 1-benzyl- (1b–9b) iso-
quinolines. In the further pharmacological studies, these
compounds showed wide range of inhibitory effects on
platelet aggregation induced by AA, Col, and PAF.
Some of them showed equal or even better potency than
the reference drug, aspirin. The mechanistic study of
their pharmacological effect is an ongoing work, and
these compounds merit further investigating as the drug
leads in continuing studies.
2. Except for 5c, all derivatives that inhibited
PAF-induced aggregation were a-type. The
Table 2. Antiplatelet aggregation activity of compounds 1a–9a, 1b–
9b, and 1c–9c10
IC50 (mM)a,b
AA (100 mM) Col (10 mg/mL) Thr (0.1 U) PAF (2 ng/mL)
Aspirin
1a
1b
1c
2a
2b
2c
3a
3b
3c
4a
4b
5a
5b
5c
6a
6b
6c
7a
7b
7c
8a
8b
8c
9a
9b
9c
34.6Æ1.0
77.1Æ8.6
>100 (34)
>100 (27)
>100 (35)
90.2Æ2.1
>100 (25)
>100 (11)
51.3Æ5.3
>100 (48)
>100 (49)
>100 (46)
>100 (35)
68.8Æ2.7
>100 (23)
>100 (22)
94.0Æ3.2
>100 (6)
>100 (50)
66.2Æ7.2
>100 (21)
37.7Æ1.5
>100 (39)
>100 (48)
>100 (20)
59.2Æ5.0
>100 (19)
>100 (44)
34.9Æ0.1
52.1Æ2.9
72.3Æ3.1
88.1Æ1.4
72.6Æ5.1
73.6Æ3.8
>100 (35)
89.2Æ10.3
32.7Æ0.3
66.1Æ2.3
77.3Æ8.9
99.2Æ5.7
69.0Æ0.7
48.9Æ10.0
74.5Æ4.4
>100 (36)
55.6Æ7.5
>100 (20)
>100 (39)
51.2Æ7.6
>100 (18)
39.1Æ3.1
>100 (46)
>100 (31)
97.0Æ20.7
36.7Æ3.9
87.0Æ15.0
58.9Æ2.4
>100 (81)c
>100 (30)
>100 (8)
>100 (9)
>100 (4)
>100 (18)
>100 (3)
>100 (9)
>100 (28)
>100 (18)
>100 (6)
>100 (7)
>100 (5)
>100 (8)
>100 (4)
>100 (5)
>100 (11)
>100 (4)
>100 (1)
>100 (8)
>100 (8)
>100 (46)
>100 (5)
>100 (14)
>100 (4)
>100 (26)
>100 (10)
>100 (9)
>100 (2)
82.0Æ1.9
>100 (13)
>100 (20)
>100 (47)
>100 (11)
>100 (32)
78.4Æ1.5
>100 (26)
>100 (22)
>100 (25)
>100 (8)
85.0Æ1.6
>100 (23)
75.8Æ2.7
>100 (44)
>100 (8)
>100 (10)
>100 (35)
>100 (20)
>100 (26)
73.0Æ3.7
>100 (12)
>100 (15)
64.7Æ2.9
>100 (52)
>100 (41)
>100 (18)
Acknowledgements
This investigation was supported by a grant from the
National Science Council of the Republic of China.
References and Notes
1. D’Ocon, P.; Blasco, R.; Candenas, L.; Ivorra, D.; Lopez,
S.; Villaverde, C.; Castedo, L.; Cortes, D. Eur.J.Pharmacol.
1991, 196, 183.
2. Costall, B.; Naylor, R. J. J.Med.Chem. 1977, 20, 190.
3. Chen, K. S.; Ko, F. N.; Teng, C. M.; Wu, Y. C. J.Nat.
Prod. 1996, 59, 531.
4. Kuo, R. Y.; Wu, C. C.; Chang, F. R.; Yeh, J. L.; Chen, I. J.;
Wu, Y. C. Bioorg.Med.Chem.Lett. 2003, 13, 821.
5. Andreu, I.; Cabedo, N.; Atassi, G.; Pierre, A.; Caignard,
D. H.; Renard, P.; Cortesa, D.; Bermejoa, A. Tetrahedron
Lett. 2002, 43, 757.
6. (a) Hufford, C. D.; Sharma, A. S.; Oguntimein, B. O. J.Pharm.
Sci. 1980, 69, 1180. (b) McMahon, R. M.; Thornber, C. W.;
Ruchirawat, S. J.Chem.Soc,. Perkin Trans.1 1982, 2163.
7. (a) Isobe, K.; Mohri, K.; Takeda, N.; Suzuki, K.; Hosoi, S.;
Tsuda, Y. Chem.Pharm.Bull. 1994, 42, 197. (b) Isobe, K.;
Takeda, N.; Mohri, K.; Tsuda, Y. Chem.Pharm.Bull. 1989,
37, 3390.
9d
aPlatelet were preincubated with DMSO (0.5%, control), aspirin or
tested compounds at 37 ꢀC for 3min, then four inducers was add.
bThe IC50 values were presented as meansÆSE (n=3).
cInhibition percentage was showed for compounds with IC50 higher
than 100 mM.
8. (a) Maity, G.; Roy, S. C. Synth.Commun. 1993, 23, 1667.
(b) Stefane, B.; Kocevar, M.; Polanc, S. Tetrahedron Lett.
1999, 40, 4429.

2792
R.-Y. Kuo et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2789–2793
9. General experimental procedure for the synthesis of com-
pounds 1a–9a, 1b–9b, 1c–9c, and 9d. Starting materials 1–9
were synthesized according to ref 4. To a methanolic solution
of 1–9 (0.5 mmol) was added a solution of CAN (2 mmol,
1.096 g) in methanol and the reaction mixture was stirred
overnight at room temperature, respectively (see Table 1). The
reaction was quenched by addition of water (40 mL) and the
diluted mixture was extracted with ethyl acetate (3Â40 mL).
The combined organic extracts were washed with water, brine
and dried over sodium sulfate. The solvent was evaporated at
reduced pressure. The residue was purified by column chro-
matography (Si-Gel) using EtOAc/hexane (1:2–1:1) mixture to
Ar–CH2), 4.00 and 3.91 (each 3H, s, 2ÂOMe); UV: 239, 312,
326 nm; IR (KBr): 1567, 1508, 1476, 1420, 1272, 1233, 1159,
1025 cmÀ1; EI–MS m/z: [358]+ 4c: d 7.62 (2H, m, Ar–H), 7.41
(2H, m, Ar–H), 7.32 and 6.73 (each 1H, s, Ar–H), 3.94 and
3.89 (each 3H, s, 2ÂOMe), 3.84 (2H, t, J=7.6 Hz, N–CH2),
2.74 (2H, t, J=7.6 Hz, Ar–CH2); UV: 232, 266 (sh), 237 nm;
IR (KBr): 1674, 1503, 1481, 1433, 1276, 1633, 1159,
1
1065 cmÀ1; EI–MS m/z: [374]+ 5a: H NMR: d 8.47 (1H, d,
J=5.8 Hz, Ar–H), 8.10 (1H, t, J=1.8 Hz, Ar–H), 7.89 (1H,
brd, J=7.6 Hz, Ar–H), 7.71 (3H, m, Ar–H), 7.36 (1H, t,
J=7.6 Hz, Ar–H), 7.15 (1H, s, Ar–H), 4.07 and 4.00 (each 3H,
2ÂOMe); UV: 237, 258 (sh), 331 nm; IR (KBr): 1664, 1561,
1503, 1479, 1370, 1263, 1232, 1157 cmÀ1; EI–MS m/z: [372]+
1
afford the oxidation products. The H spectrum was recorded
at 200 MHz using CDCl3 as solvent. 1a: 1H NMR: d 8.42 (1H,
d, J=5.4 Hz, Ar–H), 8.25 (1H, s, Ar–H), 7.66 (1H, d,
J=5.4 Hz, Ar–H), 7.60 (1H, m, Ar–H), 7.40 (3H, m, Ar–H),
7.14 (1H, s, Ar–H), 4.07 and 4.06 (each 3H, s, 2ÂOMe); UV:
233, 266 (sh), 346 nm; IR (KBr): 1674, 1503, 1480, 1433, 1277,
1262, 1234, 1071, 1039 cmÀ1; EI–MS m/z: [327]+ 1b: 1H
NMR: d 8.37 (1H, d, J=5.2 Hz, Ar–H), 7.46 (1H, s, Ar–H),
7.42 (1H, d, J=5.2 Hz, Ar–H), 7.26 (1H, s, Ar–H), 7.12 (1H,
m, Ar–H), 7.06 (3H, m, Ar–H), 4.71 (2H, s, Ar–CH2), 3.99
and 3.90 (each 3H, s, 2ÂOMe); UV: 238, 313, 325 nm; IR
(KBr): 1509, 1477, 1431, 1421, 1271, 1234, 1159 cmÀ1; EI–MS
m/z: [313]+ 1c: 1H NMR: d 7.69 (1H, d, J=6.0 Hz, Ar–H),
7.43 (3H, m, Ar–H), 7.25 and 6.74 (each 1H, s, Ar–H), 3.94
and 3.80 (each 3H, s, 2ÂOMe), 3.85 (2H, t, J=8.0, N–CH2),
2.74 (2H, t, J=8.0, Ar–CH2); UV: 213, 235 (sh), 265 (sh),
327 nm; IR (KBr): 1678, 1603, 1566, 1511, 1464, 1276,
5b: H NMR: d 8.35 (1H, d, J=5.2 Hz, Ar–H), 7.44 (2H, m,
1
Ar–H), 7.21 (4H, m, Ar–H), 7.05 (1H, s, Ar–H), 4.57 (1H, s,
Ar–CH2), 3.99 and 3.89 (each 3H, 2ÂOMe); UV: 236, 314,
326 nm; IR (KBr): 1566, 1509, 1477, 1430, 1420, 1272,
1
1159 cmÀ1; EI–MS m/z: [358]+ 5c: H NMR: d 8.17 (1H, d,
J=1.8 Hz, Ar–H), 7.96 (1H, dd, J=7.2, 1.8 Hz, Ar–H) 7.72
(1H, dd, J=7.2, 1.8 Hz, Ar–H), 7.36 (1H, t, J=7.2 Hz, Ar–H),
6.96 and 6.76 (each 1H, s, Ar–H), 3.94 and 3.80 (each 3H, s,
2ÂOMe), 3.93 (2H, t, J=7.8 Hz, N–CH2), 2.82 (2H, t,
J=7.8 Hz, Ar–CH2); UV: 216, 255 (sh), 277 (sh), 322 nm; IR
(KBr): 1674, 1565, 1515, 1271, 1143cm À1; EI–MS m/z: [374]+
1
6a: H NMR: d 8.45 (1H, d, J=5.2 Hz, Ar–H), 7.84 (2H, d,
J= 8.2 Hz, Ar–H), 7.70 (1H, s, Ar–H), 7.67 (1H, d, J=5.2 Hz,
Ar–H), 7.64 (2H, d, J= 8.2 Hz, Ar–H), 7.14 (1H, s, Ar–H),
4.06 and 3.39 (each 3H, s, 2ÂOMe); UV: 237, 267, 328 nm; IR
(KBr): 1665, 1504, 1479, 1265, 1233, 1158 cmÀ1; EI–MS m/z:
1
1
1148 cmÀ1; EI–MS m/z: [329]+ 2a: H NMR: d 8.47 (1H, d,
[372]+ 6b: H NMR: d 8.36 and 7.42 (each 1H, d, J=5.2 Hz,
J=4.4 Hz, Ar–H), 7.95 (1H, s, Ar–H), 7.85 (1H, d, J=8.0 Hz,
Ar–H), 7.71 (1H, s, Ar–H), 7.68 (1H, d, J= 4.4 Hz, Ar–H),
7.57 (1H, dd, J=2.8, 8.0 Hz, Ar–H), 7.42 (1H, t, J=8.0 Hz,
Ar–H), 7.16 (1H, s, Ar–H), 4.07 and 4.00 (each 3H, s,
2ÂOMe); UV: 237, 256 (sh), 334 nm; IR (KBr): 1666, 1619,
1565, 1504, 1433, 1264, 1158, 1052 cmÀ1; EI–MS m/z: [327]+
Ar–H), 7.37 (2H, d, J=8.8 Hz, Ar–H), 7.22 (1H, s, Ar–H )
7.1337 (2H, d, J=8.8 Hz, Ar–H), 7.06(1H, s, Ar–H), 4.54
(2H, s, Ar–CH2), 4.00 and 3.89 (each 3H, 2ÂOMe); UV: 239,
270, 312, 326 nm; IR (KBr): 1509, 1479, 1431, 1422, 1273,
1234, 1159 cmÀ1; EI–MS m/z: [358]+ 6c: 1H NMR: d 7.90 and
7.62 (each 2H, d, J=8.8 Hz, Ar–H), 6.95 and 6.75 (each 1H, s,
Ar–H), 3.93 and 3.80 (each 3H, s, 2ÂOMe), 3.88 (2H, t,
J=7.2 Hz, N–CH2), 2.80 (2H, t, J=7.2 Hz, Ar–CH2); UV:
215, 271, 328 nm; IR (KBr): 1672, 1584, 1567, 1515, 1276,
1
2b: H NMR: d 8.37 and 7.45 (each 1H, d, J=6.0 Hz, Ar–H),
7.16–7.26 (5H, m, Ar–H), 7.07 (1H, s, Ar–H), 4.57 (2H, s, Ar–
CH2), 4.01 and 3.90 (each 3H, 2ÂOMe); UV: 239, 312,
326 nm; IR: 1567, 1508, 1477, 1431, 1419, 1272, 1233,
1
1143cm À1; EI–MS m/z: [374]+ 7a: H NMR: d 8.37 (1H, d,
1
1159 cmÀ1; EI–MS m/z: [313]+ 2c: H NMR: d 8.03(1H, brs,
J=5.4 Hz, Ar–H), 7.91 (1H, s, Ar–H), 7.71 (1H, dd, J=7.4,
2.0 Hz, Ar–H), 7.60 (1H d, J=5.4 Hz, Ar–H), 7.52 (1H, td,
J=8.0, 2.0 Hz), 7.12 (1H, s Ar–H), 7.08 (1H, t, J=7.4 Hz, Ar–
H), 6.95 (1H, d, J=8.0 Hz, Ar–H), 4.06, 4.00 and 3.50 (each
3H, s, 3ÂOMe); UV: 235, 266, 327 nm; IR (KBr): 1663, 1597,
1503, 1480, 1434, 1233, 1158, 1040 cmÀ1; EI–MS m/z: [323]+
Ar–H), 7.94 (1H, d, J=7.4 Hz, Ar–H), 7.60 (1H, brd,
J=7.4 Hz, Ar–H), 7.45 (1H, t, J=7.4 Hz, Ar–H), 6.98 and
6.77 (each 1H, s, Ar–H), 3.95 (2H, t, J=7.7 Hz, N–CH2), 3.95
and 3.82 (each 3H, 2ÂOMe), 2.83(2H, t, J=7.7 Hz, Ar–CH2);
UV: 213, 232 (sh), 257, 311 (sh) nm; IR: EI–MS m/z: [329]+
3a: d 8.45 (1H, d, J=5.2 Hz, Ar–H), 7.92 (2H, d, J=8.8 Hz,
Ar–H), 7.69 (1H, s, Ar–H), 7.67 (1H, d, J=5.2 Hz, Ar–H),
7.45 (2H, d, J=8.8 Hz, Ar–H), 7.14 (1H, s, Ar–H), 4.05 and
3.98 (each 3H, 2ÂOMe); UV: 237, 266 (sh), 330 nm; IR (KBr):
1664, 1585, 1504, 1480, 1266, 1232, 1158 cmÀ1; EI–MS m/z:
[327]+ 3b: d 8.36 (1H, d, J=5.6 Hz, Ar–H), 7.44 (1H, d,
J=5.6 Hz, Ar–H), 7.22 (4H, m, Ar–H), 7.05 (1H, s, Ar–H),
4.55 (2H, s, Ar–CH2), 4.00 and 3.89 (each 3H, s, 2ÂOMe);
UV: 239, 313, 326 nm; IR (KBr): 1508, 1489, 1478, 1421, 1270,
1233, 1158 cmÀ1; EI–MS m/z: [313]+ 3c: d 7.98 (2H, d,
J=8.0 Hz, Ar–H), 7.45 (2H, d, J=8.0 Hz, Ar–H), 6.96 and
6.75 (each 1H, s, Ar–H), 3.99 and 3.80 (each 3H, s, 2ÂOMe),
3.89 (2H, t, J=7.4 Hz, N–CH2), 2.80 (2H, t, J=7.4 Hz, Ar–
CH2); UV: 239, 266, 325 nm; IR (KBr): 1671, 1585, 1567,
1510, 1274, 1143cm À1; EI–MS m/z: [329]+ 4a: 1H NMR: d
8.42 (1H, d, J=5.2 Hz, Ar–H), 8.30 (1H, s, Ar–H), 7.67 (1H,
d, J=5.2 Hz, Ar–H), 7.60 (2H, m, Ar–H), 7.45 (1H, td, J=7.2,
1.4 Hz, Ar–H), 7.36 (1H, td, J=7.2, 2.2 Hz, Ar–H), 4.08 and
4.07 (each 3H, s, 2ÂOMe); UV: 232, 266 (sh), 347 nm; IR
1
7b: H NMR: d 8.35 (1H, d, J=5.6 Hz, Ar–H), 7.45 (1H, s,
Ar–H), 7.40 (1H, d, J=5.6 Hz, Ar–H), 7.15 (1H, t, J=8.0 Hz,
Ar–H), 7.10 (1H, t, J=7.4 Hz, Ar–H), 7.02 (1H, d, J=8.0 Hz,
Ar–H), 6.79 (1H, td, J=7.4, 1.2 Hz, Ar–H), 4.59 (2H, s, Ar–
CH2), 3.98, 3.92 and 3.89 (each 3H, s, 3ÂOMe); UV: 238, 279,
312, 325 nm; IR (KBr): 1566, 1508, 1240, 1202, 1160,
1
1028 cmÀ1; EI–MS m/z: [309]+ 7c: H NMR: d 7.81 (1H, dd,
J=7.4, 1.6 Hz, Ar–H), 7.51 (1H, td, J=8.0, 1.6 Hz), 7.06 (1H,
t, Ar–H, J=8.0 Hz), 7.01 (1H, s, Ar–H), 6.92 (1H, d,
J=8.0 Hz, Ar–H), 6.74 (1H, s, Ar–H), 3.93, 3.76, and 3.66
(each 3H, s, 3ÂOMe) 3.76 (2H, t, J=5.6 Hz, N–CH2)d 2.73
(2H, t, J=5.6 Hz, Ar–CH2); UV: 219, 259, 316 nm; IR (KBr):
1666, 1597, 1513, 1463, 1281, 1246, 1146, 1039, 1020 cmÀ1; EI–
MS m/z: [325]+ 8a: 1H NMR: d 8.47 and 7.67 (each 1H, d,
J=5.4 Hz, Ar–H), 7.61 (1H, s, Ar–H), 7.55 and 7.44 (each 1H,
m, Ar–H), 7.36 (1H, t, J=8.2 Hz, Ar–H), 7.15 (1H, m, Ar–H)
7.14 (1H, s, Ar–H), 4.06, 3.97, and 3.86 (each 3H, s, 3ÂOMe);
UV: 235, 267, 317 nm; IR (KBr): 1661, 1501, 1479, 1431, 1263,
1232, 1148, 1039 cmÀ1; EI–MS m/z: [323]+ 8b: 1H NMR: d
8.37 and 7.47 (each 1H, d, J=6.0 Hz, Ar–H), 7.33 (1H, s, Ar–
H), 7.22 (1H, t, J=8.0 Hz, Ar–H), 7.07 (1H, s, Ar–H ), 6.89
(1H, d, J=7.8 Hz, Ar–H), 6.83(1H, brs, Ar–H), 6.72 (1H, dd,
J=7.8, 1.8 Hz, Ar–H), 4.62 (2H, s, Ar–CH2), 4.01, 3.89, and
(KBr): 1674, 1503, 1481, 1433, 1276, 1633, 1159, 1065 cmÀ1
;
EI–MS m/z: [372]+ 4b: 1H NMR: d 8.37 (1H, d, J=5.8 Hz,
Ar–H), 7.60 (1H, d, J=7.4 Hz, Ar–H), 7.45 (1H, d, J=5.8 Hz,
Ar–H), 7.23(1H, s, Ar–H), 7.06 (4H, m, Ar–H), 4.72 (2H, s,

R.-Y. Kuo et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2789–2793
2793
+
3,72 (each 3H, s, 3ÂOMe); UV: 234, 270, 313 (sh), 325 nm; IR
m/z: [3 23 ]9b: 1H NMR: d 8.36 and 7.42 (each 1H, d,
J=5.8 Hz, Ar–H), 7.31 and 7.04 (each 1H, s, Ar–H), 7.19 and
6.79 (each 2H, d, J=8.0 Hz, Ar–H), 4.53(2H, s, Ar–CH 2),
4.00, 3.90 and 3.74 (each 3H, s, 3ÂOMe); UV: 238, 278, 312,
326nm; IR (KBr): 1509, 1478, 1269, 1237, 1159 cmÀ1; EI–MS
(KBr): 1598, 1508, 1478, 1270, 1232, 1160, 1047 cmÀ1; EI–MS
1
m/z: [309]+ 8c: H NMR: d 7.56 (2H, m, Ar–H), 7.36 (1H, t,
J=8.2 Hz, Ar–H), 7.14 (1H, ddd, J=8.2, 2.6, 2.0 Hz, Ar–H),
6.92 and 6.75 (each 1H, s, Ar–H), 3.93, 3.88, and 3.78 (each
3 H s, 3ÂOMe), 3.91 (2H, t, J=7.4 Hz, N–CH2); and 2.81 (2H,
t, J=7.4 Hz, Ar–CH2); UV: 221, 268, 321 nm; IR (KBr): 1672,
1602, 1514, 1463, 1320, 1277, 1137, 1040 cmÀ1; EI–MS m/z:
[325]+ 9a: 1H NMR: d 8.45 (1H, d, J=5.8 Hz, Ar–H), 7.96
(2H, d, J=7.4 Hz, Ar–H), 7.64 (1H, d, J=5.8 Hz, Ar–H), 7.57
and 7.13(each 1H, s, Ar–H), 6.96 (2H, d, J=7.4 Hz, Ar–H),
4.05, 3.96, and 3.89 (each 3H, s, 3ÂOMe); UV: 236, 292, 329
(sh); IR: 1658, 1597, 1505, 1479, 1263, 1232, 1156 cmÀ1; EI–MS
+
m/z: [3 09] 9c: 1H NMR: d 8.02 and 6.94 (each 2H, d,
J=8.0 Hz, Ar–H), 6.92 and 6.74 (each 1H, s, Ar–H), 3.92,
3.86 and 3.77 (each 3H, s, 3ÂOMe), 3.91 (2H, t, J=7.6 Hz,
N–CH2), 2.80 (2H, t, J=7.6 Hz, Ar–CH2); UV: 209 (sh), 226,
290nm; IR (KBr): 1661, 1598, 1571, 1511, 1463, 1142 cmÀ1
;
EI–MS m/z: [325]+.
10. Antiplatelet aggregation assays: see: Chen, K. S.; Ko,
F. N.; Teng, C. M.; Wu, Y. C. Planta Med. 1996, 62, 133.