Phenylhomophthalimide-type NOS inhibitors derived from thalidomide

Article abstract of DOI:10.1016/j.bmcl.2004.06.026

Thalidomide shows moderate inhibitory activity toward neuronal nitric oxide synthase (nNOS) and inducible NOS (iNOS), but not toward endothelial NOS (eNOS). Structural development studies of thalidomide yielded novel phenylhomophthalimide-type NOS inhibitors with enhanced activity and different subtype selectivity.

Full text of DOI:10.1016/j.bmcl.2004.06.026

Bioorganic & Medicinal Chemistry Letters 14 (2004) 4141–4145
Phenylhomophthalimide-type NOS inhibitors
derived from thalidomide
Tomomi Noguchi, Hiroko Sano, Rumiko Shimazawa, Aya Tanatani,
Hiroyuki Miyachi and Yuichi Hashimoto*
Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
Received 24 May 2004; revised 9 June 2004; accepted 10 June 2004
Available online 2 July 2004
Abstract—Thalidomide shows moderate inhibitory activity toward neuronal nitric oxide synthase (nNOS) and inducible NOS
(iNOS), but not toward endothelial NOS (eNOS). Structural development studies of thalidomide yielded novel phenylhomoph-
thalimide-type NOS inhibitors with enhanced activity and different subtype selectivity.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Thalidomide (1: Fig. 1) is a sedative/hypnotic drug,
which was withdrawn from the market because of its
severe teratogenicity.13;14 In spite of this, research into
thalidomide was not halted, and the drug has been
established to be effective for the treatment of various
diseases, including leprosy, myeloma, AIDS, and oth-
ers.15–17 The drug was approved in the United States for
the treatment of leprosy in 1998, and clinical studies of
its use for the treatment of various cancers, including
multiple myeloma, colon cancer, prostate tumor, and
breast cancer are on-going. The molecular mechanisms
of the multiple pharmacological actions elicited by
thalidomide are not clear, but its tumor necrosis factor
(TNF)-a production-inhibitory activity has been well
documented.16–18
Nitric oxide (NO) is a biologically important regulator/
messenger, which is produced by oxidation of
catalyzed by nitric oxide synthase (NOS).1 NOS com-
prises constitutive NOS (cNOS), which requires Ca2þ
L-arginine
/
calmodulin for its activation, and inducible NOS
(iNOS), which is independent of Ca2þ/calmodulin, and
cNOS has been further divided into neuronal NOS
(nNOS) found in the brain, and endothelial NOS
(eNOS) found in the vascular endothelium. nNOS has
been shown to regulate neuronal transmission and
cerebral blood flow, while eNOS is implicated in vas-
cular tone and platelet aggregation.2;3 Excessive induc-
tion of iNOS, which is mainly expressed in activated
macrophages, plays a role in the over-production of NO
that is associated with inflammatory diseases.4;5 The
We have demonstrated that the TNF-a production-
regulating activity of thalidomide is bidirectional, and
that thalidomide is a multi-target drug.16;17;19 We have
been engaged in structural development studies of tha-
lidomide, and have obtained TNF-a production regu-
lators (including bi-directional ones and pure inhibitors
classical NOS inhibitors are limited to
logs, such as NG-nitro- -arginine (NNA),6 NG-mono-
methyl- -arginine ( -argi-
-NMMA),7 and NG-nitro-
L-arginine ana-
L
L
L
L
nine methyl ester.8 Some of these compounds have been
investigated in clinical trials. Although natural products
such as flavonoids,9 coumarins,10 and diterpenes,11 as
well as some synthetic oxazolidine derivatives,12 have
been reported to inhibit NOS, there is little structural
variation of known NOS inhibitors.
O
N
O
NH
O
O
1: Thalidomide
Keywords: Thalidomide; NOS inhibitors; Structural development.
* Corresponding author. E-mail: bmcyfh@iam.u-tokyo.ac.jp
Figure 1. Structure of thalidomide (1).
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.06.026

4142
T. Noguchi et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4141–4145
and enhancers),16;17;20 androgen antagonists,16;17;20–22
peptidase glucosidase inhibi-
inhibitors,16;17;23–25
-
-
-
100
90
tors,16;17;26;27 thymidine phosphorylase inhibitors,28 and
cyclooxygenase (COX) inhibitors.16;17;29 We suspected
that NOS is another target molecule of thalidomide,
because the drug is effective against various diseases,
including diabetes, in which NOS plays an important
pathophysiological role. Recently, we have reported that
thalidomide shows moderate inhibitory activity toward
nNOS.30 Preliminary structural development studies
based on nNOS-inhibiting activity were also reported in
the same paper.30 In this paper, we report the inhibitory
activity of thalidomide (1) toward the three subtypes of
NOS, and the results of structural development studies.
PIQ-11 (6)
80
-
-
70
60
-
-
-
-
50
40
30
L-NMMA
PIQ-10 (3)
20
10
0
NNA
-
-
PIQ-20 (12)
Thalidomide (1)
10
100
1000
2. Results and discussion
CONCENTRATION OF ADDED COMPOUND (µM)
First we investigated the NOS-inhibitory activity of
thalidomide (1) using commercially available nNOS,
iNOS, and eNOS (Cayman Co., Ltd). Inhibitory activity
was assayed by monitoring nitrite/nitrate production
Figure 2. Inhibition of nNOS by PIQ-10 (3) and PIQ-11 (6).
Thalidomide (1) inhibited nNOS and iNOS with mod-
erate potency (32–33% at 450 lM), but not eNOS (Table
1). Though the activity is less potent than that of L-
NMMA at the same concentration [but slightly more
potent than that of NNA (Fig. 2)], the inhibitory activity
of thalidomide (1) toward nNOS/iNOS might explain at
least some of the versatile pharmacological effects of the
drug.
from L-arginine by NOS, using Ichimori’s protocol with
slight modifications.30;31 Although the quantitative val-
ues differed from experiment to experiment, the results
were basically reproducible. Typical sets of data from
inhibitory activity assays of thalidomide and other
compounds, as well as L-NMMA, a well-known NOS
inhibitor (positive control), at the concentration of
450 lM are presented in Table 1. The concentration was
determined so as to the inhibiting efficacy of thalidomide
Next we investigated the NOS-inhibitory activity of
phenylphthalimide and phenylhomophthalimide deriv-
and L-NMMA being in the range of 30–60%.
Table 1. NOS-inhibitory activity of thalidomide (1) and phenylhomophthalimide derivatives (2–18)
m
p
o
O
m'
R
N
o'
O
Compounds
R
Inhibitory activity at 450 lM (%) and relative activitya
nNOS
iNOS
eNOS
L
-NMMA
––
––
59 (1.0)a
33 (1.0)a
60 (1.0)a
92 (1.0)a
79 (1.0)a
64 (1.0)a
96 (1.0)a
52 (1.0)a
76 (1.0)a
76 (1.0)a
82 (1.0)a
62 (1.0)a
92 (1.0)a
85 (1.0)a
69 (1.0)a
83 (1.0)a
66 (1.0)a
32 (1.0)a
26 (1.0)a
81 (1.4)a
32 (1.0)a
42 (0.7)a
80 (0.9)a
64 (0.8)a
49 (0.8)a
77 (0.8)a
36 (0.6)a
88 (1.2)a
88 (1.2)a
73 (0.8)a
10 (0.2)a
84 (0.9)a
57 (0.7)a
61 (0.9)a
69 (0.8)a
50 (0.8)a
26 (0.8)a
Inactive (0)a
22 (0.4)a
Thalidomide (1)
PIQ-00 (2)
PIQ-10 (3)
Inactive (0)a
64 (1.1)a
H
o-CH3
m-CH3
77 (0.8)a
PIQ-01 (4)
PIQ-001 (5)
PIQ-11 (6)
31 (0.4)a
p-CH3
62 (1.0)a
o,o0-(CH3)2
m,m0-(CH3)2
o,m-(CH3)2
o,p-(CH3)2
o,m0-(CH3)2
m,p-(CH3)2
o-C2H5
80 (0.8)a
PIQ-0101 (7)
PIQ-11000 (8)
PIQ-101 (9)
PIQ-1001 (10)
PIQ-011 (11)
PIQ-20 (12)
PIQ-02 (13)
PIQ-002 (14)
PIQ-30 (15)
PIQ-03 (16)
PIQ-003 (17)
PIQ-004 (18)
55 (1.1)a
58 (0.8)a
58 (0.8)a
50 (0.6)a
Inactive (0)a
57 (0.6)a
m-C2H5
p-C2H5
34 (0.4)a
4 (0.1)a
o-CH(CH3)2
m-CH(CH3)2
p-CH(CH3)2
p-C(CH3)3
34 (0.4)a
Inactive (0)a
Inactive (0)a
Inactive (0)a
a Values in parenthesis are the relative activity of each compound when the activity toward nNOS of that compound is defined as 1.0.

T. Noguchi et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4141–4145
4143
atives, which have been chosen as lead compounds
based on our previous studies on enzyme inhibitors
derived from thalidomide.16–29 These compounds were
prepared by routine organic synthetic methods that is,
condensation of appropriate amines with phthalic or
homophthalic anhydride. The structures of all the
compounds were confirmed by spectroscopic (1H NMR
and mass) analysis, and the analytical data were con-
sistent with expectation.32 Phenylphthalimide deriva-
tives investigated were inactive at the concentration
range (up to 1 mM) examined (data not shown), but the
ring-expanded analogs that is, phenylhomophthalimide
derivatives (PIQs), showed NOS-inhibitory activity.
Among PIQs examined, some analogs showed more
effect of a para-substituent, the sensitivity of the
enzymes seems to decrease in the order of eNOS >
iNOS > nNOS. Consequently, para-substituted analogs,
PIQ-002 (14), PIQ-003 (17), and PIQ-004 (18) inhibit
NOSs with the following decreasing order of potency:
nNOS > iNOS > eNOS. A similar, but less marked,
tendency was observed for meta-substituted analogs.
The different sensitivities of the NOS subtypes to sub-
stituents resulted in the appearance of NOS-subtype
selectivity. The selectivity indices (values in parenthesis
in Table 1, defined as the relative inhibitory activity
compared with that toward nNOS for each compound)
of the majority of the PIQs fall into the range of 0.6–1.2
that is, almost nonselective. Some PIQs, especially those
with meta- and/or para-substituent(s), showed selectivity
indices of less than 0.4 for iNOS and/or eNOS [e.g., (i)
the meta,para-dimethyl analog (PIQ-011: 11) showed a
selectivity index of 0.2 for iNOS and was inactive to-
ward eNOS, so it is nNOS-selective, (ii) the para-tert-
butyl analog (PIQ-004: 18) is an nNOS-selective inhib-
itor, though it is less potent than thalidomide (1), (iii)
the meta- and para-iso-propyl analogs (PIQ-03: 16 and
PIQ-003: 17) are inactive toward eNOS, and the meta-
methyl, meta-ethyl, and para-ethyl analogs (PIQ-01: 4,
PIQ-02: 13 and PIQ-002: 14) showed selectivity indices
of 0.4, 0.4, and 0.1, respectively, for eNOS, so these five
compounds are nNOS/iNOS-selective inhibitors]. The
ortho-iso-propyl analog (PIQ-30: 15) also seems to be
slightly selective for nNOS/iNOS.
potent activity than -NMMA at 450 lM, as follows:
L
i: Toward nNOS PIQ-10 (3), PIQ-11 (6), PIQ-1001 (10),
PIQ-20 (12), PIQ-02 (13), and PIQ-30 (15) showed po-
tent inhibitory activity toward nNOS (82–96% inhibi-
tion), while
L-NMMA showed 59% inhibition [dose–
response curves for nNOS inhibition with PIQ-10 (3),
PIQ-11 (6), and PIQ-20 (12) are shown in Figure 2, as
well as data for thalidomide (1), L-NMMA and NNA].
These structure–activity relationships are consistent
with those we previously reported.30
ii: Toward iNOS PIQ-11000 (8) and PIQ-101 (9) inhib-
L-NMMA showed
ited iNOS to the extent of 88%, while
81% inhibition.
iii: Toward eNOS PIQ-10 (3) and PIQ-11 (6) showed 77–
80% inhibition of eNOS, while
22% inhibition.
In conclusion, thalidomide was found to inhibit nNOS
and iNOS, but not eNOS, which might in part explain
the multiple pharmacological effects elicited by the drug.
Some potent phenylhomophthalimide-type NOS inhib-
L-NMMA gave only
The most potent and the second most potent inhibitors
among the examined compounds for each subtype of
NOS are: PIQ-11 (6) (96%) and PIQ-10 (3)/PIQ-20 (12)
(92%) for nNOS, PIQ-11000 (8)/PIQ-101 (9) (88%) and
PIQ-20 (12) (84%) for iNOS, and PIQ-11 (6) (80%) and
PIQ-10 (3) (77%) for eNOS. All of these potent inhibitors
possess an ortho-substituent of the N-phenyl moiety in
common, suggesting that introduction of an alkyl group
at the ortho-position on the N-phenyl moiety is critical
for potent activity. The activity of regio-isomers of
mono-alkylated analogs decreased in the order of ortho-
isomer > meta-isomer > para-isomer [e.g., the mono-
methyl analogs: 3 > 4 > 5, with the exception of eNOS.
Mono-ethyl analogs: 12 > 13 > 14. Mono-iso-propyl
analogs: 15 > 16 > 17 (in the case of eNOS, 16 and 17 are
inactive)]. Among the mono-ortho-substituted analogs, a
rather small alkyl group (a methyl or an ethyl group)
seems to be superior for potent activity [e.g., methyl
(3) ¼ ethyl (12) > iso-propyl (15) for nNOS, 12 > 3 > 15
for iNOS, and 3 > 12 > 15 for eNOS]. Similar tendencies
were observed for meta- and para-substituted analogs.
itors with higher potency than L-NMMA and with some
degree of NOS-subtype selectivity were derived from
thalidomide, and their structure–activity relationships
were partly interpreted. Further structural development
studies aiming at inhibitors with higher potency and
selectivity are in progress.
Acknowledgements
The work described in this paper was partially sup-
ported by Grants-in-Aid for Scientific Research from
The Ministry of Education, Culture, Sports, Science,
and Technology, Japan, and Japan Society for the
Promotion of Science.
References and notes
Introduction of an alkyl group larger than an ethyl
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to decrease the inhibitory activity of the compounds
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(18: inactive toward iNOS and eNOS), PIQ-003 (17:
inactive toward eNOS) and PIQ-002 (14: almost inactive
toward eNOS). Concerning this activity-decreasing
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2-(4-Methylphenyl)-1,2,3,4-tetrahydroisoquinoline-1,3-di-
one (PIQ-001: 5): mp 174–175 °C. 1H NMR (500 MHz,
CDCl3/d): 8.25 (d, J ¼ 7:7 Hz, 1H), 7.64 (t, J ¼ 7:7 Hz,
1H), 7.48 (t, J ¼ 7:7 Hz, 1H), 7.34 (d, J ¼ 7:7 Hz, 1H),
7.31 (d, J ¼ 8:1 Hz, 2H), 7.09 (d, J ¼ 8:1 Hz, 2H), 4.21 (s,
2H), 2.41 (s, 3H).
2-(2,6-Dimethylphenyl)-1,2,3,4-tetrahydroisoquinoline-
1,3-dione (PIQ-11: 6): mp 129–130.4 °C. 1H NMR
(500 MHz, CDCl3/d): 8.27 (d, J ¼ 7:7 Hz, 1H), 7.67 (t,
J ¼ 7:7 Hz, 1H), 7.49 (t, J ¼ 7:7 Hz, 1H), 7.38 (d,
J ¼ 7:7 Hz, 1H), 7.25 (t, J ¼ 7:3 Hz, 1H), 7.18 (d,
J ¼ 7:3 Hz, 2H), 4.25 (s, 2H), 2.10 (s, 6H).
2-(3,5-Dimethylphenyl)-1,2,3,4-tetrahydroisoquinoline-
1,3-dione (PIQ-0101: 7): mp 129–130 °C. 1H NMR
(500 MHz, CDCl3/d): 8.24 (d, J ¼ 7:7 Hz, 1H), 7.63 (t,
J ¼ 7:7 Hz, 1H), 7.47 (t, J ¼ 7:7 Hz, 1H), 7.34 (d,
J ¼ 7:7 Hz, 1H), 7.07 (s, 1H), 6.82 (s, 2H), 4.21 (s, 2H),
2.36 (s, 6H).
2-(2,3-Dimethylphenyl)-1,2,3,4-tetrahydroisoquinoline-
1,3-dione (PIQ-11000: 8): mp 145–146 °C. 1H NMR
(500 MHz, CDCl3/d): 8.25 (d, J ¼ 7:7 Hz, 1H), 7.65 (t,
J ¼ 7:7 Hz, 1H), 7.49 (t, J ¼ 7:7 Hz, 1H), 7.36 (d,
J ¼ 7:7 Hz, 1H), 7.20–7.24 (m, 2H), 6.95 (d, J ¼ 7:0 Hz,
1H), 4.24 (s, 2H), 2.35 (s, 3H), 2.02 (s, 3H).
2-(2,4-Dimethylphenyl)-1,2,3,4-tetrahydroisoquinoline-
1,3-dione (PIQ-101: 9): mp 170.5–171 °C. 1H NMR
(500 MHz, CDCl3/d): 8.25 (d, J ¼ 7:7 Hz, 1H), 7.65 (t,
J ¼ 7:7 Hz, 1H), 7.48 (t, J ¼ 7:7 Hz, 1H), 7.36 (d,
J ¼ 7:7 Hz, 1H), 7.17 (m, 1H), 7.16 (d, J ¼ 7:9 Hz, 1H),
6.98 (d, J ¼ 7:9 Hz, 1H), 4.23 (s, 2H), 2.37 (s, 3H), 2.09 (s,
3H).
2-(2,5-Dimethylphenyl)-1,2,3,4-tetrahydroisoquinoline-
1,3-dione (PIQ-1001: 10): mp 125–126 °C. 1H NMR
(500 MHz, CDCl3/d): 8.25 (d, J ¼ 7:7 Hz, 1H), 7.65 (t,
J ¼ 7:7 Hz, 1H), 7.49 (t, J ¼ 7:7 Hz, 1H), 7.36 (d,
J ¼ 7:7 Hz, 1H), 7.24 (d, J ¼ 7:7 Hz, 1H), 7.16 (d,
J ¼ 7:7 Hz, 1H), 6.92 (t, J ¼ 7:7 Hz, 1H), 4.23 (s, 2H),
2.35 (s, 3H), 2.08 (s, 3H).
2-(3,4-Dimethylphenyl)-1,2,3,4-tetrahydroisoquinoline-
1,3-dione (PIQ-011: 11): mp 105–107 °C. 1H NMR
(500 MHz, CDCl3/d): 8.25 (d, J ¼ 7:7 Hz, 1H), 7.63 (t,
J ¼ 7:7 Hz, 1H), 7.47 (t, J ¼ 7:7 Hz, 1H), 7.34 (d,
J ¼ 7:7 Hz, 1H), 7.27 (d, J ¼ 8:1 Hz, 1H), 6.97 (s, 1H),
6.94 (d, J ¼ 8:1 Hz, 1H), 4.21 (s, 2H), 2.31 (s, 3H), 2.29 (s,
3H).
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32. 2-Phenyl-1,2,3,4-tetrahydroisoquinoline-1,3-dione (PIQ-
00: 2): mp 187–188 °C. 1H NMR (500 MHz, CDCl3/d):
8.25 (d, J ¼ 7:7 Hz, 1H), 7.65 (t, J ¼ 7:7 Hz, 1H), 7.49 (m,
5H), 7.36 (t, J ¼ 7:7 Hz, 1H), 7.21 (d, J ¼ 7:7 Hz, 1H),
4.24 (s, 2H).
2-(2-Ethylphenyl)-1,2,3,4-tetrahydroisoquinoline-1,3-di-
one (PIQ-20: 12): mp 123–124 °C. 1H NMR (500 MHz,
CDCl3/d): 8.25 (d, J ¼ 7:7 Hz, 1H), 7.66 (t, J ¼ 7:7 Hz,
1H), 7.49 (t, J ¼ 7:7 Hz, 1H), 7.41–7.42 (m, 2H), 7.37 (d,
J ¼ 7:7 Hz, 1H), 7.31–7.35 (m, 2H), 4.24 (s, 2H), 2.45 (q,
J ¼ 7:6 Hz, 2H), 1.16 (t, J ¼ 7:6 Hz, 3H).
2-(3-Ethylphenyl)-1,2,3,4-tetrahydroisoquinoline-1,3-di-
one (PIQ-02: 13): mp 76.5–78 °C. 1H NMR (500 MHz,
CDCl3/d): 8.25 (d, J ¼ 7:7 Hz, 1H), 7.64 (t, J ¼ 7:7 Hz,
1H), 7.42 (t, J ¼ 7:7 Hz, 1H), 7.35 (d, J ¼ 7:7 Hz, 1H),
7.30 (s, 1H), 7.29 (d, J ¼ 8:0 Hz, 1H), 7.06 (t, J ¼ 8:0 Hz),
7.03 (d, J ¼ 8:0 Hz, 1H), 4.23 (s, 2H), 2.72 (q, J ¼ 8:0 Hz,
2H), 1.17 (t, J ¼ 8:0 Hz, 3H).
2-(2-Methylphenyl)-1,2,3,4-tetrahydroisoquinoline-1,3-di-
one (PIQ-10: 3): mp 107–108 °C. 1H NMR (500 MHz,
2-(4-Ethylphenyl)-1,2,3,4-tetrahydroisoquinoline-1,3-di-
1
one (PIQ-002: 14): mp 139–140 °C. H NMR (500 MHz,

T. Noguchi et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4141–4145
4145
CDCl3/d): 8.25 (d, J ¼ 7:7 Hz, 1H), 7.64 (t, J ¼ 7:7 Hz,
1H), 7.48 (d, J ¼ 7:7 Hz, 1H), 7.35 (d, J ¼ 7:7 Hz, 1H),
7.31 (d, J ¼ 8:1 Hz, 2H), 7.12 (d, J ¼ 8:1 Hz, 2H), 4.22
(s, 2H), 2.72 (q, J ¼ 7:6 Hz, 2H), 1.28 (t, J ¼ 7:6 Hz,
3H).
1H), 7.33 (m, 2H), 7.06 (s 1H), 7.02 (d, J ¼ 7:7 Hz,
1H), 4.22 (s, 2H), 2.96 (m, 1H), 1.28 (d, J ¼ 6:9 Hz,
6H).
2-(4-Isopropylphenyl)-1,2,3,4-tetrahydroisoquinoline-1,3-
dione (PIQ-003: 17): mp 170–172 °C. 1H NMR (500 MHz,
CDCl3/dÞ: 8.25 (d, J ¼ 7:7 Hz, 1H), 7.64 (t, J ¼ 7:7 Hz,
1H), 7.47 (t, J ¼ 7:7 Hz, 1H), 7.36 (d, J ¼ 7:7 Hz, 1H),
7.35 (d, J ¼ 8:1 Hz, 2H), 7.12 (d, J ¼ 8:1 Hz, 2H), 4.23 (s,
2H), 2.97 (m, 1H), 1.29 (d, J ¼ 6:9 Hz, 6H).
2-(2-Isopropylphenyl)-1,2,3,4-tetrahydroisoquinoline-1,3-
1
dione (PIQ-30: 15): mp 158–160 °C. H NMR (500 MHz,
CDCl3/d): 8.26 (d, J ¼ 7:7 Hz, 1H), 7.66 (t, J ¼ 7:7 Hz,
1H), 7.50 (t, J ¼ 7:7 Hz, 1H), 7.42–7.48 (m, 1H), 7.37 (d,
J ¼ 7:7 Hz, 1H), 7.26–7.33 (m, 3H), 4.24 (s, 2H), 2.70 (m,
1H), 1.17 (d, J ¼ 6:9 Hz, 6H).
2-(4-tert-Butylphenyl)-1,2,3,4-tetrahydroisoquinolin-1,3-
dione (PIQ-004: 18): mp 170–173 °C. 1H NMR (500 MHz,
CDCl3/dÞ: 8.25 (d, J ¼ 7:7 Hz, 1H), 7.64 (t, J ¼ 7:7 Hz,
1H), 7.52 (t, J ¼ 7:7 Hz, 1H), 7.48 (d, J ¼ 7:7 Hz, 1H),
7.35 (d, J ¼ 8:1 Hz, 2H), 7.13 (d, J ¼ 8:1 Hz, 2H), 4.23 (s,
2H), 1.39 (s, 9H).
2-(3-Isopropylphenyl)-1,2,3,4-tetrahydroisoquinoline-1,3-
dione (PIQ-03: 16): mp 98–100 °C. 1H NMR (500 MHz,
CDCl3/d): 8.25 (d, J ¼ 7:7 Hz, 1H), 7.64 (t, J ¼ 7:7 Hz,
1H), 7.48 (t, J ¼ 7:7 Hz, 1H), 7.43 (d, J ¼ 7:7 Hz,