Design, synthesis, and inhibition of platelet aggregation for some 1-o-chlorophenyl-1,2,3,4-tetrahydroisoquinoline derivatives

Article abstract of DOI:10.1016/j.bmc.2004.09.028

Four analogs proved to be potential antiplatelet aggregation agents, and compound 9 (TQP-3, applying for patent), which inhibits ADP-induced human platelet aggregation with IC₅₀ values of approximately 0.206 nM was the most active. Based on ticlopidine active as an ADP receptor antagonist for inhibiting platelet aggregation in clinical test, and upon finding (±)-1,2-substituted-7-sulfonylamide/amide-1,2,3,4-tetrahydroisoquinoline (11-31) inhibited of platelet aggregation, a series of (±)-1-o- chlorophenyl-2-substituted-tetrahydroisoquinoline derivatives was designed and synthesized. Four analogs proved to be potential antiplatelet aggregation agents, and compound 9 (TQP-3, applying for patent) which inhibits ADP-induced human platelet aggregation with IC₅₀ values of approximately 0.206 nM was the most active. Compound 2 is more active than compound 1, which (Type I) is similar to ticlopidine. This is because there is a spacial hindrance in compound 1, and the o-chloro group of compound 2 may play the same a role as o-chloro group of ticlopidine. On the other hand, with the different substitutions at different positions on the 2-substituted phenylacyl group, their inhibition of platelet aggregation differs. These compounds with m-substituted group (5, 7, 9) showed a higher IC₅₀ value for inhibiting ADP-induced human platelet aggregation than those with o-substituted group (4, 6) or p-substituted group (3, 8). It was observed that their inhibition is bromine-substituted derivative (9), chlorine-substituted derivative (7), and nitro-substituted derivative (5) in turn. Moreover, these compounds (Type II) may be more similar to clopidogrel than to ticlopidine due to the acyl group at 2 position of the nucleus playing a role as the ester group of clopidogrel. It was conjectured that these analogs function as a potential antiplatelet aggregation role by acting as ADP receptor antagonists.

Full text of DOI:10.1016/j.bmc.2004.09.028

Bioorganic & Medicinal Chemistry 12 (2004) 6547–6557
Design, synthesis, and inhibition of platelet aggregation for some
1-o-chlorophenyl-1,2,3,4-tetrahydroisoquinoline derivativesq
Jie Yang,a,* Wei-Yi Hua,b Fu-Xiang Wang,a Zhi-Yuan Wanga and Xiang Wanga
aState Key Laboratory of Pharmaceutical Biotechnology, Department of Biochemistry, College of Life, 22 Hankou Road,
Nanjing University, Nanjing 210093, PR China
bCenter of New Drug, Chinese Pharmaceutical University, Nanjing 210009, PR China
Received 28 December 2003; accepted 13 September 2004
Available online 7 October 2004
Abstract—Based on ticlopidine active as an ADP receptor antagonist for inhibiting platelet aggregation in clinical test, and upon
finding ( )-1,2-substituted-7-sulfonylamide/amide-1,2,3,4-tetrahydroisoquinoline (11–31) inhibited of platelet aggregation, a series
of ( )-1-o-chlorophenyl-2-substituted-tetrahydroisoquinoline derivatives was designed and synthesized. Four analogs proved to
be potential antiplatelet aggregation agents, and compound 9 (TQP-3, applying for patent) which inhibits ADP-induced human
platelet aggregation with IC50 values of approximately 0.206nM was the most active. Compound 2 is more active than compound
1, which (Type I) is similar to ticlopidine. This is because there is a spacial hindrance in compound 1, and the o-chloro group of
compound 2 may play the same a role as o-chloro group of ticlopidine. On the other hand, with the different substitutions at different
positions on the 2-substituted phenylacyl group, their inhibition of platelet aggregation differs. These compounds with m-substituted
group (5, 7, 9) showed a higher IC50 value for inhibiting ADP-induced human platelet aggregation than those with o-substituted
group (4, 6) or p-substituted group (3, 8). It was observed that their inhibition is bromine-substituted derivative (9), chlorine-sub-
stituted derivative (7), and nitro-substituted derivative (5) in turn. Moreover, these compounds (Type II) may be more similar to
clopidogrel than to ticlopidine due to the acyl group at 2 position of the nucleus playing a role as the ester group of clopidogrel.
It was conjectured that these analogs function as a potential antiplatelet aggregation role by acting as ADP receptor antagonists.
Ó 2004 Published by Elsevier Ltd.
1. Introduction
of serious thromboembolic complications still occur,
highlighting the need for a more effective therapy.
Fibrinogen interactions with vascular endothelial cells
are implicated in various physiological and pathophysio-
logical events, including angiogenesis and wound heal-
ing.2 Fibrinogen has been identified in many prospective
clinical studies as an independent risk factor for arterial,
peripheral, and cerebrovascular events, which include
stroke, myocardial infarction, peripheral circulatory
deficiencies, angina, intermittent claudication, and deep
vein thrombosis.3 The binding of the glycoprotein IIb–
IIIa complex (GP IIb–IIIa or integrin aIIbb3) to the sym-
metrical molecules fibrinogen and/or vWF in solution
was shown to be essential for platelet aggregation and
thrombus growth. In addition, a variety of other platelet
activators, including adenosine diphosphate (ADP), col-
lagen, epinephrine, thromboxane A2, platelet-activating
factor (PAF), serotonin or thrombin, might be involved
in the physiological process of platelet stimulation lead-
ing finally to the functionalization of GP IIb–IIIa and to
platelet aggregation. Therefore, the blockade of GP IIb–
IIIa receptor might constitute a superior approach in
Cardiovascular and cerebrovascular diseases are still the
main cause of morbidity and mortality in the world. The
formation of platelet aggregates is an important patho-
genetic factor in widespread cardiovascular disease. The
sudden occlusion of an arterial vessel by formation of a
thrombotic plug is the crucial event leading to deficient
oxygen supply of important target organs like the heart
or the brain. Human blood platelets play a significant
role not only in normal hemostasis but also in arterial
thrombosis, particularly under conditions of high shear
stress.1 Currently used antiplatelet drugs, including aspi-
rin, ticlopidine, and others, are effective against certain
but not all of the many endogenous platelet activators.
Because of their limited efficacy, a significant number
Keywords: Tetrahydroisoquinoline; Antiplatelet aggregation; TQP-3.
q Project supported by NSFC (Nature Science Foundation of China,
Nos 30171094 and 30271497).
*
Corresponding author. Tel.: +86 25 83594060; fax: +86 25
83324605; e-mail: luckyjyj@sina.com.cn
0968-0896/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.bmc.2004.09.028

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J. Yang et al. / Bioorg. Med. Chem. 12 (2004) 6547–6557
effectively preventing arterial thrombus formation.1,3
There are some GP IIb–IIIa receptor antagonists, such
as a systematically active peptide analog (DMP 728) of
RGD motif,4 decorsin of 39-residue RGD–protein,5–8
ornatin,6,7,9 a nonpeptide antagonist XR300, an ethyl
ester prodrug of XR299.10
O
Cl
1.
R
NH2
R
CHO
2. Et3N, CH2Cl2
R
H
N
1.
R
Ticlopidine, an antiplatelet drug with a broad scope of
clinical applications, is claimed to be an antagonist of
adenosine diphosphate on platelet receptors. Thienopyr-
idine compounds, including ticlopidine and clopidog-
rel, have been found to selectively inhibit adenosine 50
diphosphate (ADP)-induced platelet aggregation and
adenylyl cyclase ex vivo, but the mechanism of their
antiplatelet action remains to be determined.11 The thera-
peutic efficacy of ticlopidine might be associated not
only with its delayed antiplatelet effects but also with
its immediate thrombolytic action, which is likely to be
mediated by endothelial prostacyclin and tissue plasmi-
nogen activator rather than by platelet mechanisms.12,13
Like ticlopidine, the ADP receptor antagonist clopidog-
rel is inactive in vitro and must be administered i.v. or
orally to exhibit antiaggregatory and antithrombotic
activities. The irreversible modification of the ADP
receptor site, which is responsible for the biological
activity could be explained by the formation of a disul-
fide bridge between the reactive thiol group of the active
metabolite and a cysteine residue of the platelet ADP
receptor.14,15 Platelet-dependent occlusive thrombosis
at sites of deep vessel wall injury elicited by electrical
stimulation of rat carotid arteries was significantly
reduced by thromboxane A2 (TXA2) synthetase
inhibition and/or TXA2/prostaglandin endoperoxide
receptor antagonism (ridogrel, dazoxiben, sulotroban),
by inhibition of ADP-dependent platelet responses (tic-
lopidine) and by anticoagulation (heparin, warfarin).
This points to an involvement of arachidonic acid
metabolites, ADP, and thrombin as modulators of the
thrombotic process. The antithrombotic effect of ridog-
rel was abolished by cyclooxygenase inhibition but
enhanced by cAMP phosphodiesterase inhibition,
demonstrating the importance of platelet inhibitory
prostanoids such as PGD2, and prostacyclin formed
after TXA2 synthetase inhibition. The antithrombotic
effect of ridogrel, when combined with ticlopidine or
heparin, exceeded that of the single compounds,
pointing to interactions between arachidonic acid
metabolites, ADP, and thrombin in the formation of
occlusive thrombosis at sites of arterial injury
(Fig. 1).16–19
O
2. -H2O;
3. CF3CO2H
M1
path A
POCl3
ht, 8hs
R
R
N
NH
R
path B
KBH4
ht, 3hs
R
M2
M3
C6H5COCl;
rt, 3hs
C6H5CH2Cl;
ht, 6hs
path C
path D
R
R
R
R
N
N
O
R
R
1-3
4-10
Scheme 1.
2. Chemistry
Two synthetic schemes were used to make the 2-unsub-
stituted tetrahydroisoquinolines. If the phenethylamine
had a substituent, which activated the position ortho
to the ethylamine side chain, such as methoxy group,
the Pictet–Spengler reaction (Scheme 1, path A) was
used. Trifluoroacetic acid proved to be a much better
cyclization catalyst than the usual acids used in this
reaction. When there was no activation ortho to the eth-
ylamine, the Bischler–Napieralski reaction20,21 (Scheme
1, path B) was used. The representative synthesis of 10
tetrahydroisoquinoline derivatives (1–10) were prepared
by Scheme 1, path C or path D. The 21 tetrahydroiso-
quinoline derivatives (11–31) were prepared by Scheme
2, path F or path G. Table 1 lists 10 analogs of 1-o-chlo-
rophenyl-1,2,3,4-tetrahydroisoquinoline (M3) while
Table 2 lists 21 tetrahydroisoquinoline derivatives with
different substitutes at position 1, 2, and 7 of the tetra-
hydroisoquinoline nucleus used to make the various
analogs. Table 3 lists the structural and spectrum
parameters of 21 tetrahydroisoquinoline derivatives
(11–31).
Here, on the basis of the principles of isosterism and
rational drug design, and in view of the structural
features of ticlopidine, clopidogrel, R-(+)-trimetoquinol
and some tetrahydroisoquinoline alkaloids posses-
sing antiplatelet aggregation activities, as well as some
synthesized antiplatelet aggregating agents ( )-1-
phenyl-2-substituted-7-sulfonylamide/amide-1,2,3,4-tetra-
3. Results and discussion
3.1. Antiplatelet aggregation activity in vitro
hydroisoquinoline (11–31, Table 2),
a series of
1-o-chlorophenyl-2-substituted-1,2,3,4-tetrahydroisoqui-
noline derivatives were designed and synthesized
in order to search for new type of platelet anti-
aggregants.
The effects of 10 tetrahydroisoquinoline derivatives
upon ADP-induced (121.0lmolLꢀ1, 20lL) platelet
aggregation in human platelet-rich plasma (PRP)
were evaluated by a turbidimetric method. Inhibitory

J. Yang et al. / Bioorg. Med. Chem. 12 (2004) 6547–6557
6549
Scheme 2.
concentrations (IC50) of these compounds for antiplate-
let aggregation measured with human platelet-rich plas-
ma (PRP) are listed in Table 1. It seemed to reveal that
four derivatives (2, 5, 7, 9) showed platelet aggrega-
tion inhibitory activities with a range of potencies. Con-
centrations of these compounds as low as 1.0lM
inhibited human platelet aggregation induced by
121.0lM ADP. The inhibitory concentration (IC50) val-
ues for 2, 5, 7, and 9 were 60.60nM, 2.080lM, 54.21,
and 0.206nM, respectively. Furthermore, human platelet
aggregation induced by ADP was inhibited by TQP-3
(9) with an IC50 of approximately 0.206nM; complete
inhibition of aggregation was observed at a concentra-
tion of 1lM. Further evaluation is under investigation.

6550
J. Yang et al. / Bioorg. Med. Chem. 12 (2004) 6547–6557
Table 1. Information concerning seven new compounds
No.
Type Substituent at 1 Substituent at 2
Procedure Yield (%) Mp (°C), solvent Formula, MW
IC50 (lM)*
(nmol/L)
a
1
2, TQP-1
I
o-C6H5Cl
o-C6H5Cl
o-C6H5Cl
o-C6H5Cl
o-C6H5Cl
o-C6H5Cl
o-C6H5Cl
o-C6H5Cl
o-C6H5Cl
o-C6H5Cl
o-Cl–C6H5CH2
C6H5CH2
C
12.28
15.90
51.77
47.02
41.94
15.58
11.23
14.68
11.06
12.44
168–169, Ethanol C22H19NCl2, 368.30
118–119, Ethanol C22H20NCl, 333.90
I
C
60.60 25.23
3
4
5
6
I
p-NO2–C6H5CH2
o-NO2–C6H5CO
m-NO2–C6H5CO
o-Cl–C6H5CO
m-Cl–C6H5CO
p-Cl–C6H5CO
m-Br–C6H5CO
C6H5SO2
C
104–106, Ethanol C21H19N2O2Cl, 378.857 >10lM
143–145, Ethanol C22H17N2O3Cl, 392.841 >10lM
115–117, Ethanol C22H17N2O3Cl, 392.841 2.080lM
II
II
II
D
D
D
D
D
D
D
b
178–180, Ethanol C22H17NOCl2, 382.30
7, TQP-2 II
II
9, TQP-3 II
160–162, Ethanol C22H17NOCl2, 382.30
174–176, Ethanol C22H17NOCl2, 382.30
120–122, Ethanol C22H17NOBrCl, 426.70 0.206 0.033
54.21 18.72
c
8
c
10
Aspirin
II
98–100, Ethanol C21H18NO2SCl, 383.90
9.673 3.285
Note: The inhibitory concentrations (IC50) of these compounds for antiplatelet aggregation were evaluated by a turbidimetric method based on ADP-
induced (2.0lM, 5lL) platelet aggregation in rabbit platelet-rich plasma (PRP).
a The compound at 0.882lmol/L possesses antiplatelet aggregation activity with aggregation inhibition rate of 26.02% while at 0.0882lmol/L shows
accelerating platelet aggregation.
b–d The compound at approximately 10ꢀ6 mol/L shows accelerating platelet aggregation.
Table 2. Information concerning 21 new compounds
No. R7
CH3SO2NH
R1
R2
Path Yield (%) Mp (°C), solvent Formula, MW
IC50 (lM)*
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
C6H5
C6H5
C6H5
o-NO2–C6H5CO
p-NO2–C6H5CO
CH3CH2OCO
F
F
F
F
F
F
F
F
F
F
F
F
F
F
G
G
G
G
G
G
G
42.39
38.29
38.63
43.53
61.34
55.44
46.19
33.18
43.34
40.51
49.34
26.76
26.53
20.49
20.10
35.56
48.29
29.53
58.56
39.99
50.15
208–210, Acetone C23H21N3O5S, 451.427
135–137, Acetone C23H21N3O5S, 451.427
145–146, Acetone C19H22N2O4S, 374.454
130–132, Acetone C23H20N3O5SCl, 485.927
147–149, Acetone C23H20N3O5SCl, 485.927
121–123, Acetone C23H20N3O5SCl, 485.927
148–150, Acetone C19H21N2O4SCl, 408.954
149–151, Acetone C28H23N3O5S, 513.544
225–227, Acetone C28H23N3O5S, 513.544
0.0229
0.0763
0.543
0.428
0.171
0.199
2.040
0.156
>10
CH3SO2NH
CH3SO2NH
CH3SO2NH
CH3SO2NH
CH3SO2NH
CH3SO2NH
C6H5SO2NH
C6H5SO2NH
C6H5SO2NH
C6H5SO2NH
C6H5SO2NH
CH3SO2NH
C6H5SO2NH
p-C6H5Cl o-NO2–C6H5CO
p-C6H5Cl p-NO2–C6H5CO
p-C6H5Cl m-NO2–C6H5CO
p-C6H5Cl CH3CH2OCO
C6H5
C6H5
C6H5
m-NO2–C6H5CO
p-NO2–C6H5CO
3,5-(NO2)2–C6H5CO
>250, Acetone C28H22N4O7S, 558.554
185–187, Acetone C28H22N3O5SCl, 548.012 >10
>10
p-C6H5Cl o-NO2–C6H5CO
C6H5
C6H5
C6H5
CH3CH2OCO
125–127, Acetone C24H24N2O4S, 436.514
153–155, Acetone C20H24N2O4S, 388.474
122–124, Acetone C25H26N2O4S, 450.544
107–109, Ethanol C25H23N3O5, 455.45
257–259, Ethanol C29H22N4O6, 522.50
111–113, Ethanol C29H22N4O6, 522.50
145–147, Ethanol C29H22N4O6, 522.50
224–226, Ethanol C29H22N4O6, 522.50
113–115, Ethanol C29H22N4O6, 522.50
223–225, Ethanol C29H21N5O8, 567.50
>10
1.710
CH3CH2OCOCH2
CH3CH2OCOCH2
CH3CH2OCO
2.287
1.500
0.730
1.720
2.420
p-NO2–C6H5CONH C6H5
o-NO2–C6H5CONH C6H5
o-NO2–C6H5CONH C6H5
o-NO2–C6H5CONH C6H5
p-NO2–C6H5CONH C6H5
p-NO2–C6H5CONH C6H5
p-NO2–C6H5CONH C6H5
o-NO2–C6H5CO
p-NO2–C6H5CO
m-NO2–C6H5CO
p-NO2–C6H5CO
o-NO2–C6H5CO
3,5-(NO2)2–C6H5CO
>10
>10
0.869
Note: *The inhibitory concentrations (IC50) of these compounds for antiplatelet aggregation were evaluated by a turbidimetric method based on
ADP-induced (2.0lM, 5lL) platelet aggregation in rabbit platelet-rich plasma (PRP). The anticoagulant blood was taken from the auricular artery
of rabbits, and platelet-rich plasma (PRP) and platelet-poor plasma (PPP) were prepared with centrifugation. Platelet aggregation was studied at
37°C using BornÕs method21 in a platelet aggregation module (DAM-1, Danyang Institute of Electronic Research, Suzhou, China). A final
concentration of ADP 2.0lmolLꢀ1 was used in a volume of 5lL. The new compound 0.05mL at different concentrations and normal saline were
added to 0.45mL PRP, respectively. After 5min, ADP (2.0lmolLꢀ1, 5lL) was given. Maximal change in light transmission was assumed to
represent maximal platelet aggregation. Platelet aggregation was measured and the maximal deflection was obtained after 5min of curve registration
computed as a percentage of maximal aggregation.

J. Yang et al. / Bioorg. Med. Chem. 12 (2004) 6547–6557
Table 3. Structural Information concerning 21 new compounds
6551
No.
Yield %
42.39
Mp (°C) solvent
Formula MW
IR (KBr) (cmꢀ1
)
1H NMR (CDCl3, d)
MS, m/z
11
208–210, Acetone
C23H21N3O5S, 451.427
3267 (NH), 1616 (C@O),
1523, 1341 (NO2), 1335,
1146 (SO2–N)
2.90 (s, 3H, CH3SO2), 3.30
(m, 4H, ArCH2CH2N), 6.80
(s, 1H, C1–H), d 7.00–8.30
(m, 12H, aromatic), 9.40 (s,
1H, NH)
452 (M+1
)
12
13
14
15
16
17
38.29
38.63
43.53
61.34
55.44
46.19
135–137, Acetone
145–146, Acetone
130–132, Acetone
147–149, Acetone
121–123, Acetone
148–150, Acetone
C
23H21N3O5S, 451.427
3398 (NH), 3094 (ArH),
3206 (C@O double),
1610 (C@O), 1516, 1340
(NO2), 1340, 1146 (SO2–
N), 1275 (CN)
2.90 (s, 3H, CH3SO2), 3.35
(m, 4H, ArCH2CH2N), 6.90
(s, 1H, C1–H), 7.10–8.00 (m,
12H, aromatic), 9.45 (s, 1H,
NH)
452 (M+1
375 (M+1
487 (M+1
487 (M+1
487 (M+1
)
)
)
)
)
C19H22N2O4S, 374.454
3306 (NH), 1724, 1668
(C@O), 1371, 1227
(SO2–N), 1101 (C–O)
1.25 (t, 3H, CH3), 2.90 (s,
3H, CH3SO2), 2.70–3.50 (m,
4H, ArCH2CH2N), 4.10 (q,
2H, CH2O), 6.40 (s, 1H, C1–
H), d 7.30 (m, 8H, aromatic)
3.00 (s, 3H, CH3), 3.30 (m,
4H, ArCH2CH2N), 6.8 (s,
1H, C1–H), 7.30–7.90 (m,
11H, aromatic)
C23H20N3O5SCl, 485.927
C23H20N3O5SCl, 485.927
C23H20N3O5SCl, 485.927
C19H21N2O4SCl, 408.954
3022 (ArH), 2878 (CH);
1678 (C@O), 1528, 1360
(NO2), 1483, 1412
(aromatic), 1360, 1133
(SO2–N), 1290 (CN)
3246 (NH), 1624 (C@O),
1518, 1347 (NO2), 1316,
1142 (SO2–N)
2.90 (s, 3H, CH3), 3.40 (m,
4H, ArCH2CH2N), 7.0 (s,
1H, C1–H), 7.20–8.30 (m,
11H, aromatic), 9.50 (s, 1H,
NH)
3246 (NH), 3084 (ArH),
2934 (CH); 1616 (C@O),
1529, 1348 (NO2), 1481,
1442 (aromatic), 1317,
1148 (SO2–N)
3.00 (s, 3H, CH3), 3.40 (m,
4H, ArCH2CH2N), 7.0 (s,
1H, C1–H), 7.20–8.30 (m,
11H, aromatic)
2918 (CH); 1634 (C@O),
1346, 1163 (SO2–N),
1285 (CN)
1.30 (t, 3H, CH3), 2.90 (s,
3H, CH3SO2), 2.70–3.40 (m,
4H, ArCH2CH2N), 4.10 (m,
H, CH2O), 6.30 (s, 1H, C1–
H), 7.20 (m, 7H, aromatic),
7.80 (s, 1H, NH)
373 (MꢀCl,
base peak)
18
19
33.18
43.34
149–151, Acetone
225–227, Acetone
C
28H23N3O5S, 513.544
3437 (NH), 1662 (C@O),
1341, 1164 (SO2–N),
1079 (C–O)
2.70–3.40 (m, 4H,
513 (M)
513 (M)
ArCH2CH2N), 6.90 (s, 1H,
C1–H), 7.20–8.30 (m, 17H,
aromatic), 10.00 (s, 1H, NH)
2.70–4.60 (m, 4H,
C28H23N3O5S, 513.544
3435 (NH), 3099, 3049
(ArH), 2920 (CH), 1666
(C@O), 1529, 1427
(aromatic), 1339, 1159
(SO2–N), 1097 (C–O),
1003, 932, 864 (CH)
3084 (ArH), 2920 (CH),
1639 (C@O), 1539, 1371
(NO2), 1344, 1173
ArCH2CH2N), 6.90 (s, 1H,
C1–H), 7.10–8.30 (m, 17H,
aromatic), 9.90 (s, 1H, NH)
20
21
22
40.51
49.34
26.76
>250, Acetone
C28H22N4O7S, 558.554
2.80–3.70 (m, 4H,
557 (Mꢀ1
547 (Mꢀ1
435 (Mꢀ1
)
)
)
ArCH2CH2N), 6.70 (s, 1H,
C1–H), 6.90–9.00 (m, 16H,
aromatic)
(SO2–N)
185–187, Acetone
125–127, Acetone
C28H22N3O5SCl, 548.012
2.60–3.60 (m, 4H,
ArCH2CH2N), 6.85 (s, 1H,
C1–H), 7.20–8.10 (m, 16H,
aromatic)
C24H24N2O4S, 436.514
1686 (C@O), 1445, 1414
(aromatic), 1375, 1167
(SO2–N), 1232 (CN),
1084 (C–O), 933 (CH)
1.25 (t, 3H, CH3), 2.90 (m,
4H, ArCH2CH2N), 4.20 (m,
2H, CH2O), 6.35 (s, 1H,
C1–H), 6.80–7.90 (m, 13H,
aromatic)
(continued on next page)

6552
J. Yang et al. / Bioorg. Med. Chem. 12 (2004) 6547–6557
Table 3 (continued)
No.
Yield %
26.53
Mp (°C) solvent
Formula MW
IR (KBr) (cmꢀ1
)
1H NMR (CDCl3, d)
MS, m/z
23
153–155, Acetone
C20H24N2O4S, 388.474
3491 (NH), 2991, 2924
(CH), 1730 (C@O), 1493,
1416 (aromatic), 1366,
1271 (SO2–N), 1161,
1109 (C–O), 974, 930,
872 (CH)
1.25 (t, 3H, CH3), 2.90 (s,
3H, CH3SO2), 3.00–3.50 (m,
6H, ArCH2CH2N, CH2N),
4.15 (q, 2H, CH2O), 6.70 (s,
1H, C1–H), 7.10–7.65 (m,
8H, aromatic)
388 (M)
24
25
26
27
28
20.49
20.10
35.56
48.29
29.53
122–124, Acetone
107–109, Ethanol
257–259, Ethanol
111–113, Ethanol
145–147, Ethanol
C
C
25H26N2O4S, 450.544
3464 (C@O double),
1732 (C@O), 1491, 1445
(aromatic), 1375, 1167
(SO2–N)
1.20 (t, 3H, CH3), 2.70–3.60
(m, 8H, ArCH2CH2N,
CH2N, CH2O), 6.70 (s, 1H,
C1–H), 7.10–8.00 (m, 13H,
aromatic)
449 (Mꢀ1
)
25H23N3O5, 455.45
3294 (NH), 1690, 1661
(C@O), 1535, 1339
(NO2), 1501, 1431
1.30 (t, 3H, CH3), 2.70–3.30
(m, 4H, ArCH2CH2N), 4.20
(m, 2H, CH2O), 6.30 (s, 1H,
C1–H), 7.20–8.40 (m, 12H,
aromatic)
445 (M)
(aromatic), 1231 (C–N)
C29H22N4O6, 522.50
3170 (NH), 1676 (C@O),
1595, 1437 (aromatic),
1523, 1342 (NO2), 1244
(C–N), 1197 (C–O),
2.70–3.50 (m, 4H,
523 (M+1
523 (M+1
523 (M+1
)
)
)
ArCH2CH2N), 7.00 (s, 1H,
C1–H), 7.30–8.30 (m, 16H,
aromatic), 10.05 (s, 1H, NH)
1021, 886 (CH)
C
C
29H22N4O6, 522.50
2854 (CH), 1649 (C@O),
1529, 1346 (NO2), 1411
(aromatic), 1259 (C–N),
1164, 1077 (C–O), 1020,
853 (CH)
2.70–3.60 (m, 4H,
ArCH2CH2N), 6.90 (s, 1H,
C1–H), 7.10–8.30 (m, 16H,
aromatic), 10.30 (s, 1H, NH)
29H22N4O6, 522.50
3101 (NH), 2950 (CH),
1681 (C@O), 1512, 1345
(NO2), 1477, 1406
2.70–3.60 (m, 4H,
ArCH2CH2N), 6.90 (s, 1H,
C1–H), 7.10–8.30 (m, 16H,
aromatic), 10.15 (s, 1H, NH)
(aromatic), 1258 (C–N),
1062 (C–O), 893 (CH)
3284 (NH), 1665 (C@O),
1591, 1423 (aromatic),
1516, 1340 (NO2), 1300
(C–N), 932, 848 (CH)
2867 (CH), 1686 (C@O),
1526, 1348 (NO2), 1479,
1411 (aromatic), 1263
(C–N), 1067 (C–O), 895
(CH)
29
30
58.56
39.99
224–226, Ethanol
113–115, Ethanol
C
C
29H22N4O6, 522.50
29H22N4O6, 522.50
2.70–3.60 (m, 4H,
523 (M+1
523 (M+1
)
)
ArCH2CH2N), 7.00 (s, 1H,
C1–H), 7.20–8.30 (m, 16H,
aromatic), 10.19 (s, 1H, NH)
2.70–3.60 (m, 4H,
ArCH2CH2N), 7.00 (s, 1H,
C1–H), 7.30–8.30 (m, 16H,
aromatic), 10.20 (s, 1H, NH)
31
50.15
223–225, Ethanol
C
29H21N5O8, 567.50
3291 (NH), 2985 (CH),
1624 (C@O), 1587, 1408
(aromatic), 1513, 1393
(NO2), 1240 (C–N), 1153
(C–O), 900, 863 (CH)
2.70–3.60 (m, 4H,
568 (M+1
)
ArCH2CH2N), 6.80 (s, 1H,
C1–H), 7.30–8.90 (m, 15H,
aromatic), 10.35 (s, 1H, NH)
3.2. Design of 1-o-chlorophenyl-2-substituted-1,2,3,4-
tetrahydroisoquinoline derivatives
sine 50 diphosphate (ADP)-induced platelet aggregation
and adenylyl cyclase ex vivo.11 The ( )-1-o-chlorophen-
yl-1,2,3,4-tetrahydroisoquinoline nucleus (M3) is similar
to ticlopidine, and tetrahydroisoquinoline nucleus and
thienopyridine are biological isosteres. So, we designed
and synthesized some analogs of ( )-1-o-chlorophenyl-
1,2,3,4-tetrahydroisoquinoline nucleus (M3) with several
substituent groups at position 2 of the nucleus.
A series of 1-o-chlorophenyl-2-substituted-1,2,3,4-tetra-
hydroisoquinoline derivatives were designed and synthe-
sized in order to search for a new type of platelet
antiaggregants on the basis of the principles of isoster-
ism and rational drug design, and in view of the
structural features of ticlopidine, clopidogrel, R-(+)-
trimetoquinol, and some tetrahydroisoquinoline alka-
loids possessing antiplatelet aggregation activities, as well
as some synthesized antiplatelet aggregating agents
( )-1-phenyl-2-substituted-7-sulfonylamide/amide-1,2,3,4-
tetrahydroisoquinoline (11–31, Table 2).
Fifteen synthesized ( )-1-phenyl-2-substituted-7-sulfon-
ylamide/amide-1,2,3,4-tetrahydroisoquinoline
com-
pounds (11–31, Table 2) inhibited of platelet
aggregation, PLS (partial least-square method) analysis
result shows that the CoMFA model based upon super-
position of the 15 compounds with compound 11 as the
template produced a valid model. CoMFA analysis of
these compounds was performed on a Silicon Graphics
Thienopyridine compounds, including ticlopidine and
clopidogrel, have been found to selectively inhibit adeno-

J. Yang et al. / Bioorg. Med. Chem. 12 (2004) 6547–6557
6553
Figure 1. Steric field contribution contour map based on the superposition of the 15 compounds using compound 11 as the template. CoMFA results
reveal that the steric interactive energy is a major contribution to antiplatelet aggregatory activity, and the sulfonylamide group is necessary to the
activity. Here a small group favorable area exists near the 7 position of the tetrahydroisoquinoline nucleus, which means that the smaller substituent
at the 7 position of the tetrahydroisoquinoline nucleus, the more inhibition of platelet aggregation.
Iris Indigo XZ4000 (SGI Inc., Silicon, CA, USA) work-
station using the QSAR/CoMFA module within SYBYL
V 6.3 software (Tripos Inc., St. Louis, MI, USA). The
CoMFA study reveals that the steric interactive energy
is a major contribution to antiplatelet aggregatory activ-
ity, and the sulfonylamide group is necessary for activity
(Fig. 1). An area accommodating a small group exists
near the 7 position of the tetrahydroisoquinoline
nucleus. Smaller substituent at the 7 position of the
tetrahydroisoquinoline nucleus, favor platelet aggrega-
tion inhibitory activity. It seems to show that removing
a substituent from the 7 position of the tetrahydroiso-
quinoline nucleus would improve antiplatelet aggrega-
tion activity. So, we designed a type of ( )-1-phenyl-2-
substituted-1,2,3,4-tetrahydroisoquinoline derivatives,
which is similar to ticlopidine.
opidine, which has a o-chlorobenzyl group at the 2
position of the thienopyridine nucleus. This is because
there are steric hindrance to both o-chloro groups of
o-chlorophenyl at the 1 position and of o-chlorobenzyl
at the 2 position of the nucleus of compound 1. The o-
chloro group of o-chlorophenyl at the 1 position of the
tetrahydroisoquinoline nucleus in compound 2 may play
the same role as o-chloro group of o-chlorobenzyl at the
2 position of the thienopyridine nucleus in ticlopidine.
This may be the reason that compound 2 is superior
to compound 1.
On the other hand, compound with the different substi-
tutions at position 2 of the nucleus (such as 2-substituted
phenylacyl group), have different effects on activity.
These compounds of 2-substituted phenylacyl group
with m-substituted group (5, 7, 9) showed a higher
IC50 values for inhibiting ADP-induced human platelet
aggregation than those with o-substituted group (4, 6)
or p-substituted group (3, 8), where these substituents
were chlorine, bromine, and nitro group. Of these com-
pounds, bromine-substituted derivative (TQP-3, 9)
exhibited the highest IC50 value. The bromine-substi-
tuted derivative (TQP-3, 9) was more potent than that
of two other derivatives, namely the chlorine-substituted
derivative (7) and the nitro-substituted derivative (5).
Moreover, compound 7 was more active than com-
pound 5, ( )-1-o-chlorophenyl-2-substituted phenyl-
acyl-1,2,3,4-tetrahydroisoquinoline analogs (Type II
4–10) is more similar to clopidogrel than to ticlopidine.
This is due to the acyl group at 2 position of the nucleus,
which plays the role of the ester group of clopidogrel. It
was conjectured that these analogs could take on a
potential antiplatelet aggregation role acting as ADP
receptor antagonists.
From 10 new compounds, ( )-1-phenyl-2-substituted-
1,2,3,4-tetrahydroisoquinoline (1–10), it is clear that
four analogs, of which ( )-1-o-chlorophenyl-2-m-
bromicophenylacyl-1,2,3,4-tetrahydroisoquinoline (9,
TQP-3) was the most active, proved to be potential anti-
platelet aggregation agents. It seemed to reveal that four
derivatives (2, 5, 7, 9) showed, which inhibited human
platelet aggregation induced by 121.0lM ADP with
IC50 values ranging over 0.206nM–2.080lM. The com-
pound TQP-3 (9) inhibits ADP-induced human platelet
aggregation with IC50 values of approximately
0.206nM. Here, ( )-1-phenyl-2-o-chlorobenzyl/benzyl-
1,2,3,4-tetrahydroisoquinoline (Type I) compounds 1
and 2 are similar to ticlopidine because there are o-chlo-
robenzyl or benzyl at the 2 position of the nucleus. How-
ever, compound 2 with benzyl at the 2 position of the
tetrahydroisoquinoline nucleus is more active than com-
pound 1 with o-chlorobenzyl. This is different from ticl-

6554
J. Yang et al. / Bioorg. Med. Chem. 12 (2004) 6547–6557
4. Conclusion
anhydrous magnesium sulfate was used. For column
chromatography, silica gel (Merck silica gel 60). Ele-
mental analysis was performed with PK2400CHN
instrument, and C, H, and N results were within 0.4%
of theoretical values.
Ten tetrahydroisoquinoline derivatives were designed
and synthesized by the aid of computer drug design,
basis on the principles of isosterism and the reported
SAR (structure–activity relationship) of synthesized
tetrahydroisoquinoline derivatives22. It was found that
compound TQP-3 possessed more potent antiplatelet
aggregatory activity with an IC50 values of approxi-
mately 0.206nM. 2-Benzyl-1,2,3,4-tetrahydroisoquino-
line compounds 1 and 2 are similar to ticlopidine, and
compound 2 with benzyl at the 2 position of the tetra-
hydroisoquinoline nucleus is more active than com-
pound 1 with o-chlorobenzyl. This is because there is a
steric interaction between o-chlorophenyl and o-chloro-
benzyl of compound 1, and the o-chloro group of o-
chlorophenyl of compound 2 may play a role as o-chloro
group of o-chlorobenzyl of ticlopidine. The 2-substi-
tuted phenylacyl group, their inhibition of platelet with
m-substituted group (5, 7, 9) showed a higher IC50 value
of inhibiting ADP-induced human platelet aggregation
than those with o-substituted group (4, 6) or p-substi-
tuted group (3, 8). Of these compounds, bromine-substi-
tuted derivative (TQP-3, 9) exhibited the highest IC50
value. It is observed that their inhibition is bromine-sub-
stituted derivative, chlorine-substituted derivative (7),
and nitro-substituted derivative (5) in turn. ( )-1-o-
5.2. Synthesis of N-phenylethyl o-chlorophenylamide
(M1)
o-Chlorophenylformyl acid (16.0g, 0.11mol) was dis-
solved in 50mL dry CH2Cl2, and 10.0mL SOCl2 was
added to the solution at 0°C. The mixture was stirred
at room temperature for 1h and concentrated (<30°C)
to give the unstable chloride, which was used in the next
reaction without purification. The fresh chloride
(17.5mL, 14.6g, 0.10mol) dissolved in 20mL CH2Cl2
was added dropwise to a solution containing a mixture
of b-phenylethylamine (12.0g, 0.10mol) and triethyl-
amine (14.0mL, 0.10mol) in 100mL dry CH2Cl2 at ice
bath. The resultant mixture was stirred at room temper-
ature for 3h. After being concentrated under reduced
pressure, the reaction mixture was cooling and 150mL
ether was added. The colorless powders were separated
out and were filtered off. The filtrate was washed with
water and ether, dried, and 23.8g (92.90%) of N-phenyl-
ethyl o-chlorophenylamide (M1) was given as white
needles: mp 99–101°C (acetone).
Chlorophenyl-2-substituted
phenylacyl-1,2,3,4-tetra-
hydroisoquinoline analogs is more similar to clopidogrel
than to ticlopidine due to the acyl group at 2 position of
the nucleus playing a role as the ester group of
clopidogrel.
5.3. 1-o-Chlorophenyl-3,4-dihydroisoquinoline intermedi-
ates (M2)
According to Bischler–Napieralski reaction,20,21 a mix-
ture of compound M1 (20g, 0.077mol) with anhydrous
methylbenzene (50mL) and fresh POCl3 (30mL) was
refluxed for 8h in a nitrogen atmosphere. The solvent
was evaporated under reduced pressure. The concen-
trated solution was added to a 10mL acetone solution,
poured into ice water, neutralized with strong aqua
ammonia to pH9–10, and extracted with 250mL ether
three times. The extractant was washed with water,
dried with anhydrous MgSO4, filtered, and concen-
trated. The crude product was to give 11.2g (46.38%)
of 1-o-chlorophenyl-3,4-dihydroisoquinoline (M2) as
light yellow needles, which was used in the next reaction
It was conjectured that these analogs could take on a
potential antiplatelet aggregation role acting as ADP
receptor antagonists. The results may be useful for fur-
ther investigation on antiplatelet aggregatory activity
and mechanism of tetrahydroisoquinoline compounds.
5. Experimental
5.1. General
1
Ten
1-o-chlorophenyl-1,2,3,4-tetrahydroisoquinoline
without purification. H NMR (CDCl3): d 2.75 (m, 2H,
derivatives (1–10) with different substitutes at position
2 of the nucleus were designed and synthesized. The
structures of the new compounds synthesized were iden-
tified by means of elemental analysis, MS, H NMR, and
IR. Reactions using anhydrous solvents that had been
dried by sodium thread were carried out in a nitrogen
atmosphere. Melting points were determined on a DX-
5 double-eyes micro-melting point apparatus and are
uncorrected. Infrared (IR) spectra were taken with a
Bruker IFS-48 FT-IR or Nexus 870 FT-IR spectropho-
tometer. Proton nuclear magnetic resonance (1H NMR)
spectra were recorded on a FX-90Q or FX-900 spec-
trometer using deuteriochloroform unless otherwise sta-
ted with tetramethylsilane as an internal or external
(D2O) reference. Mass spectra (MS) were obtained on
a Finnigan FTMS-2000 mass spectrometer or ZAB-HS
(VG) inversion double-focusing high-definition mass
spectrometer. To dry the organic extraction solutions,
CH2N), d 3.70 (m, 2H, ArCH2), d 7.45 (m, 8H,
aromatic).
5.4. 1-o-Chlorophenyl-1,2,3,4-tetrahydroisoquinoline
(M3)
The above intermediate (3.5g, 0.014mol) was dissolved
in 40mL anhydrous methanol, adjusted to pH8.5 with
diethylamine, and KBH4 (1.5g, 0.027mol) was slowly
added under 50°C. The mixture was stirred at 50–
70°C for 4h. After evaporating solvent, addition of
water can decompose KBH4. The extraction with ether
was washed with brine and water, dried with MgSO4, fil-
tering, and concentration, to produce next intermediate,
namely
1-o-chlorophenyl-1,2,3,4-tetrahydroisoquino-
lines (M3) as light yellow oleaginous dope: 1.7g
(48.57%), which was used in next reaction without
purification.

J. Yang et al. / Bioorg. Med. Chem. 12 (2004) 6547–6557
6555
5.5. Synthesis of 1-o-chlorophenyl-2-o-chlorobenzyl-
1,2,3,4-tetrahydroisoquinoline (1)
ArCH2CH2N), 7.0 (s, 1H, C1–H), 7.20–8.20 (m, 12H,
aromatic); MS, m/z 393 (M). Analyses (C22H17N2O3Cl)
C, H, N.
The above intermediate (M3, 3.50g, 0.014mol) was dis-
solved in 50mL anhydrous ethanol, added a little trieth-
ylamine and fresh o-chlorobenzyl chloride (2.20g,
0.014mol), and stirred at reflux for 6h. After evaporat-
ing solvent, 5mL acetone was added to the concentrated
solution, poured into water, and extracted with 250mL
CHCl3 three times. The extraction was washed with
brine and water, dried with MgSO4, colored with active
carbon, filtering, and concentration. The crude product
was crystallized with 40mL anhydrous alcohol to give
0.64g (12.28%) 1-o-chlorophenyl-2-o-chlorobenzyl-
1,2,3,4-tetrahydroisoquinolines (1) as white powders:
mp 168–169°C (EtOH); IR (KBr) 2912, 2863, 1616
(CH2), 1489, 1471, 1451 (aromatic), 1244 (C–N), 1021,
5.9. 1-o-Chlorophenyl-2-m-nitrophenylacyl-1,2,3,4-tetra-
hydroisoquinoline (5)
A light yellow powder: 0.59g (41.94%); mp 115–117°C
(EtOH); IR (KBr) 1673, 1622 (C@O), 1528, 1344 (NO2),
1479, 1429 (aromatic), 1234 (C–N), 1084 (C–Cl) cmꢀ1
;
1H NMR (CDCl3): d 2.70–3.70 (m, 4H, ArCH2CH2N),
7.0 (s, H, C1–H), 7.20–8.30 (m, 12H, aromatic); MS, m/z
393 (M). Analyses (C22H17N2O3Cl) C, H, N.
5.10. 1-o-Chlorophenyl-2-o-chlorophenylacyl-1,2,3,4-
tetrahydroisoquinoline (6)
1
886 (CH) cmꢀ1; H NMR (CDCl3): d 2.619 (m, 2H,
o-Chlorophenyl formyl chloride (fresh) 1.5g (0.014mol)
dissolved in 5mL CH2Cl2 was added to a solution con-
taining 1-o-chlorophenyl-1,2,3,4-tetrahydroisoquinoline
(M3, 3.50g, 0.014mol) and 2.0mL triethylamine in
80mL CH2Cl2 at 0°C. The mixture was stirred at room
temperature for 3h. The reaction mixture was concen-
trated. Then, the concentrated solution was added
5mL acetone solution, poured into water, and extracted
with 250mL CH2Cl2 three times. The combined extracts
were washed with brine and water, dried with MgSO4,
colored with active carbon, filtering, and concentration.
The crude product was crystallized with 40mL anhy-
drous alcohol to give 0.86g (15.58%) 1-o-chlorophenyl-
2-o-chlorobenzoyl-1,2,3,4-tetrahydroisoquinolines (6)
as white powder: mp 178–180°C (EtOH); IR (KBr)
Ar–CH2–C(H2)–), d 3.066 (m, 2H, Ar–C(H2)–CH2–N–),
d 3.621 (m, 2H, –N–CH2–Ar), d 5.361 (s, 1H, C1–H),
d 6.744 (d, 1H, C7–H), d 7.134 (m, 1H, C5–H of 1-o-
chlorophenyl), d 7.206 (m, 6H, C5–H, C8–H, C4–H,
and C6–H of 1-o-chlorophenyl, C4–H and C6–H of 2-
o-chlorobenzyl), d 7.281 (m, 1H, C5–H of 2-o-chloro-
benzyl), d 7.397 (m, 2H, C3–H of 1-o-chlorophenyl,
C3–H of 2-o-chlorobenzyl), d 7.523 (d, 1H, C6–H);
MS, m/z 369 (M+1), 368 (M), 367 (Mꢀ1). Analyses
(C22H19NCl2) C, H, N.
5.6. 1-o-Chlorophenyl-2-benzyl-1,2,3,4-tetrahydroiso-
quinoline (2)
A white powder: 0.78g (15.90%); mp 118–119°C
(EtOH); IR (KBr) 2938 (–CH2–), 2861 (–CH2–), 1603,
1644 (C@O), 1588, 1488, 1455 (aromatic) cmꢀ1 1H
;
NMR (CDCl3): d 2.193 (s, 1H, C1–H), d 2.780 (m, 2H,
Ar–CH2–C(H2)–), d 3.076 (m, 2H, Ar–C(H2)–CH2–N–),
d 6.157 (s, 1H, C7–H), d 6.390 (s, 1H, C8–H), d 6.557
(m, 2H, C5–H, C6–H), d 6.947 (m, 2H, C4–H and C6–
H of 1-o-chlorophenyl), d 7.183 (m, 2H, C3–H and
C5–H of 1-o-chlorophenyl), d 7.313 (m, 2H, C4–H and
C5–H of 2-o-chlorobenzoyl), d 7.434 (m, 2H, C3–H
and C6–H of 2-o-chlorobenzoyl); MS, m/z 381 (Mꢀ1),
382 (M). Analyses (C22H17NOCl2) C, H, N.
1495, 1456 (aromatic), 757, 707 (CH) cmꢀ1
;
1H
NMR (CDCl3): d 2.501 (m, 2H, Ar–CH2–C(H2)–), d
3.093 (m, 2H, Ar–C(H2)–CH2–N–), d 3.282 (d, 2H,
–N–CH2–Ar), d 5.311 (s, 1H, C1–H), d 6.767 (d, 1H,
C7–H), d 7.134 (m, 1H, C5–H of 1-o-chlorophenyl), d
7.194 (m, 2H, C5–H, C8–H), d 7.226 (m, 2H, C4–H
and C6–H of 1-o-chlorophenyl), d 7.258 (d, 1H, C4–H
of 2-benzyl), d 7.306 (d, 4H, C2–H, C3–H, C5–H, and
C6–H of 2-benzyl), d 7.417 (d, 1H, C3–H of 1-o-chloro-
phenyl), d 7.486 (m, 1H, C6–H); MS, m/z 333 (Mꢀ1), 334
(M), 335 (M+1). Analyses (C22H20NCl) C, H, N.
5.11. 1-o-Chlorophenyl-2-m-chlorophenylacyl-1,2,3,4-
tetrahydroisoquinoline (7)
5.7. 1-o-Chlorophenyl-2-p-nitrobenzyl-1,2,3,4-tetrahydro-
isoquinoline (3)
A white powder: 0.61g (11.23%); mp 159–160°C
(EtOH); IR (KBr) 2945, 2836 (–CH2–), 1637 (C@O),
1
1593, 1475, 1455 (aromatic) cmꢀ1; H NMR (CDCl3):
A light yellow powder: 0.42g (51.77%); mp 104–106°C
(EtOH); IR (KBr) 1661 (C@O), 1512, 1340 (NO2),
d 2.193 (s, 1H, C1–H), d 2.826 (m, 2H, Ar–CH2–
C(H2)–N–), d 3.446 (m, 2H, Ar–C(H2)–CH2–N–), d
6.890 (s, 1H, C7–H), d 7.067 (s, 1H, C5–H), d 7.138
(m, 5H, C6–H, C8–H, 3H at C4–H, C5–H, and C6–H
of 1-o-chlorophenyl), d 7.341 (m, 5H, C3–H of 1-o-chlo-
rophenyl, C2–H, C4–H, C5–H, and C6–H of 2-m-chloro-
benzoyl); MS, m/z 381 (Mꢀ1), 382 (M), 383 (M+1).
Analyses (C22H17NOCl2) C, H, N.
1
1086 (C–O), 1013, 851 (CH) cmꢀ1; H NMR (CDCl3):
d 2.40–3.90 (m, 6H, ArCH2CH2N, ArCH2), 6.70 (s,
1H, C1–H), 6.90–8.10 (m, 12H, aromatic); MS, m/z
379 (M). Analyses (C22H19N2O2Cl) C, H, N.
5.8. 1-o-Chlorophenyl-2-o-nitrophenylacyl-1,2,3,4-tetra-
hydroisoquinoline (4)
5.12. 1-o-Chlorophenyl-2-p-chlorophenylacyl-1,2,3,4-
tetrahydroisoquinoline (8)
A light yellow powder: 0.78g (47.02%); mp 143–145°C
(EtOH); IR (KBr) 3059 (ArH), 2912 (CH), 1634
(C@O), 1522, 1340 (NO2), 1481, 1431 (aromatic), 1228
A white powder: 0.82g (14.68%); mp 174–176°C
(EtOH); IR (KBr) 1640 (C@O), 1591, 1488, 1455
1
(C–N) cmꢀ1; H NMR (CDCl3): d 2.70–3.40 (m, 4H,

6556
J. Yang et al. / Bioorg. Med. Chem. 12 (2004) 6547–6557
(aromatic) cmꢀ1; 1H NMR (CDCl3): d 2.820 (s, 1H, C1–
H), d 3.438 (s, 2H, Ar–CH2–C(H2)–), d 3.843 (s, 2H, Ar–
C(H2)–CH2–N–), d 6.871 (m, 1H, C7–H), d 6.901 (s, 2H,
C5–H, C8–H), d 7.133 (m, 4H, C6–H of tetrahydroiso-
quinoline, C4–H, C5–H, and C6–H of 1-o-chlorophenyl),
d 7.280 (m, 4H, C3–H of 1-o-chlorophenyl, C3–H, C4–H,
and C5–H of 2-p-chlorobenzoyl), d 8.085 (d, 1H, C6–H
of 2-p-chlorobenzoyl); MS, m/z 381 (Mꢀ1), 382 (M).
Analyses (C22H17NOCl2) C, H, N.
1min with stirring (1200rpm), and then a saline solution
of the test compound (30lL) or saline was added.
Exactly 2min later, a solution of ADP (20lL, 121lM)
was added to each of the samples, and the changes in
light transmission were recorded, with the light trans-
mission for PRP and PPP taken as 0% and 100%,
respectively, and the maximum light transmission after
addition of ADP as the maximum aggregations. Platelet
aggregation was measured and the maximal deflection
was obtained after 5min of curve registration computed
as a percentage of maximal aggregation. The percent
inhibition of platelet aggregation (Pi) was expressed as
the difference between 1 and the ratio of the maximum
aggregation with the test compounds to that with the
saline.
5.13. 1-o-Chlorophenyl-2-m-bromicophenylacyl-1,2,3,4-
tetrahydroisoquinoline (9)
A white powder: 0.68g (11.06%); mp 120–122°C
(EtOH); IR (KBr) 1673 (C@O), 1595, 1469, 1434 (aro-
1
matic) cmꢀ1; H NMR (CDCl3): d 2.191 (s, 1H, C1–
H), d 3.226 (m, 2H, Ar–CH2–C(H2)–), d 3.843 (m, 2H,
Ar–C(H2)–CH2–N–), d 7.254 (m, 3H, C5–H, C7–H,
C8–H), d 7.315 (d, 1H, C6–H of 1-o-chlorophenyl), d
7.490 (m, 4H, C6–H, C3–H, C4–H, and C5–H of
1-o-chlorophenyl), d 7.534 (m, 1H, C5–H of 2-m-bro-
micobenzoyl), d 7.763 (d, 2H, C4–H and C6–H of
Acknowledgements
This work is supported by NSFC (Nature Science Fund
of China, Nos 30171094 and 30271497). We appreciate
Prof. H. Z. Gu at Jiangsu Hospital of Chinese Tradi-
tional Medicine and Prof. D. Y. Zhu at Department
of Medicinal Chemistry, Chinese Pharmaceutical Uni-
versity for their help in pharmacology. We thank Prof.
H. L. Jiang at Shanghai Institute of Materia Medica,
CAS for help in QSAR and CoMFA.
2-m-bromicobenzoyl),
d 7.992 (s, 1H, C2–H of
2-m-bromicobenzoyl); MS, m/z 426 (Mꢀ1), 427 (M).
Analyses (C22H17NOBrCl) C, H, N.
5.14. 1-o-Chlorophenyl-2-phenylsulfonyl-1,2,3,4-tetra-
hydroisoquinoline (10)
The residue was chromatographed on silica gel with oil
ether/EtOAc (5/1) as effluent to give 0.68g (12.44%) of 1-
o-chlorophenyl-2-phenylsulfonyl-1,2,3,4-tetrahydroiso-
quinoline (10) as a light yellow powder: mp 98–100°C
(EtOH); IR (KBr) 1603, 1487, 1444 (aromatic), 1307
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