Synthesis and antitumor activity evaluation of 2-arylisoquinoline-1,3(2H, 4H)-diones in vitro and in vivo

Article abstract of DOI:10.1007/s00044-013-0734-x

Six 2-(2-acylaminobenzothiazol-6-yl)isoquinoline-1,3(2H,4H)-diones (1a-1f) and five 2-arylisoquinoline-1,3(2H,4H)-diones (1g-1k) were synthesized by refluxing homophthalic anhydrides with 2-acylaminobenzothiazolyl-6-amine or substituted aniline in glacial acetic acid. The cytotoxic activities of 1a-1k were evaluated via MTT method against A431, A549, and PC3. Compound 1b relatively displayed a higher cytotoxic activity than the others. The antitumor effect of 1b were evaluated in established nude mice PANC-1 xenograft model. The results suggest that compound 1b could potentially inhibit tumor growth.

Full text of DOI:10.1007/s00044-013-0734-x

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0734-x
ORIGINAL RESEARCH
Synthesis and antitumor activity evaluation of 2-arylisoquinoline-
1,3(2H,4H)-diones in vitro and in vivo
•
Bo-Rui Kang Juan Wang Huan Li Yan Li
•
•
•
•
Qi-Bing Mei San-Qi Zhang
Received: 28 February 2013 / Accepted: 17 August 2013
Ó Springer Science+Business Media New York 2013
Abstract Six 2-(2-acylaminobenzothiazol-6-yl)isoquino-
line-1,3(2H,4H)-diones (1a–1f) and five 2-arylisoquino-
line-1,3(2H,4H)-diones (1g–1k) were synthesized by
refluxing homophthalic anhydrides with 2-acylamino-
benzothiazolyl-6-amine or substituted aniline in glacial
acetic acid. The cytotoxic activities of 1a–1k were evalu-
ated via MTT method against A431, A549, and PC3.
Compound 1b relatively displayed a higher cytotoxic
activity than the others. The antitumor effect of 1b were
evaluated in established nude mice PANC-1 xenograft
model. The results suggest that compound 1b could
potentially inhibit tumor growth.
diones is relatively less active and reported. Recent years,
Hashimoto group synthesized a series of 2-arylisoquino-
line-1,3(2H,4H)-diones and found that 4-(4,4-diethyl-3,
4-dihydro-1,3-dioxoquinolin-2(1H)-yl)benzonitrile (DE-
PIQ-4CN) shows the most potent inhibitory activity against
progesterone receptor (Nakagawa et al., 2008) and 2-(2,6-
diethylphenyl)-1,2,3,4-tetrahydroisoquinoline-1,3-dione
(PIQ-22) displays potent aminopeptidase-inhibiting activ-
ity (Komoda et al., 2001). Meanwhile, some other deriv-
atives exhibit inhibitory activity against nitric oxide
synthase (Noguchi et al., 2004). Youssef group reported
that 2-arylisoquinoline-1,3(2H,4H)-dione derivatives dis-
play some potential antimicrobial and antioxidant activity
(Youssef and Amin, 2010). Murthy observed that 2-alkyl-
isoquinoline-1,3(2H,4H)-diones can lower serum choles-
terol and triglyceride levels in mice (Murthy et al., 1986).
Moreover, 2-arylisoquinoline-1,3(2H,4H)-diones are useful
intermediates to synthesize new derivatives (Semple et al.,
1996) and heterocyclic compounds (Nishijima et al., 1998).
However, among the reported isoquinoline-1,3(2H,4H)-
diones, few derivatives with substituted groups at 5, 6, 7,
8-position were involved.
Keywords Benzothiazole derivatives ꢀ Isoquinoline-1 ꢀ
3(2H,4H)-diones ꢀ Cytotoxic activity ꢀ Antitumor effect
Introduction
Isoquinolinone is an important drug scaffold. Isoquinolin-
1-one derivatives were designed, synthesized, and evalu-
ated to find active compounds. The results indicate that
isoquinolin-1-one derivatives exhibit a broad spectrum of
biological activities (Roth et al., 2008; Seitz et al., 2008;
Ukita et al., 2001). Compared with isoquinoline-1-one
derivatives, the research on isoquinoline-1,3(2H,4H)-
The derivatives of benzothiazole exhibit a broad spec-
trum of biological activities such as antitumor, antimicro-
bial, anti-inflammatory, anticonvulsant and antidiabetic
activity. Khokra reviewed the progress on the synthesis and
biological activities of benzothiazole derivatives in 2011
(Khokra et al., 2011). Shi reported that pyridinyl-2-amine
coupled with benzothiazole-2-thiol compounds exhibit
potent and broad-spectrum inhibitory activities against
human tumor cell lines (Shi et al., 2012). D’Angelo dis-
B.-R. Kang ꢀ H. Li ꢀ Y. Li ꢀ S.-Q. Zhang (&)
Department of Pharmacy, School of Medicine, Xi’an Jiaotong
University, Xi’an 710061, People’s Republic of China
e-mail: sqzhang@mail.xjtu.edu.cn; sqzhang@xjtu.edu.cn
covered
that
2-acetylamino-6-pyridinylbenzothiazole
J. Wang ꢀ Q.-B. Mei
derivatives display PI3K and mTOR dual inhibitory
activity (D’Angelo et al., 2011). Caputo reported benzo-
thiazole derivatives bearing arylurea moiety at C-2 also
Center for Pharmacological Evaluation and Research, Shanghai
Institute of Pharmaceutical Industry, Shanghai 200437, People’s
Republic of China
123

Med Chem Res
show significant growth inhibitory activity on several
human tumor cell lines (Caputo et al., 2012). Our group
reported that 1-(2-acetylaminobenzothiazol-6-yl)-3-(4-(1-
methylpiperazine-4-carbinyl)phenyl)urea display a potent
cytotoxic activity against A549 (Xuan et al., 2013). There
are two hydrogen-bond acceptors and one hydrogen-bond
donor in the 2-acetylaminobenzothiazole. Thus it is a
desired fragment in drug design.
et al., 1995). The yields of target compounds were dis-
tinctly improved when the reaction was carried out in
glacial acetic acid.
All the newly synthesized compounds gave satisfactory
analyses for the proposed structures, which were charac-
1
terized on the basis of their H NMR, 13C NMR, HRMS,
and IR.
It has been a focus of concern for research in medicinal
chemistry to find novel and efficient compounds for cancer
treatment. Yoshida et al. reported that 2,6-dichloro-N-(2-
cyclopropanylcarboxamino)benzothiazol-6-yl)benzamide
(compound A) exhibit potent cytotoxic and antitumor
effect (Yoshida et al., 2005). As part of our efforts to
discover a novel scaffold of antitumor agent, we try to
combine the 6-aminobenzothiazole frament or other aryl-
amines with isoquinoline-1,3(2H,4H)-diones scaffold into
one molecule to explore 2-arylisoquinoline-1,3-dione as a
potential antitumor agent. In this work, we synthesized
2-arylisoquinoline-1,3-diones and evaluated their antitu-
mor effects in vitro and in vivo (Fig. 1).
Cytotoxic assays
Compounds 1a–1k were evaluated for their cytotoxic
activities in vitro against human cancer cell lines, including
A431(human epithelial carcinoma cell line), A549 (human
lung adenocarcinoma epithelial cell line), and PC-3
(human prostate carcinoma cell line) by applying the MTT
colorimetric assay. Gefitinib and compound A were used as
positive controls. Compounds were tested over a range of
concentrations from 10-4 to 10-8 M, and the calculated
IC50 values were reported differently according to different
cancer cells. The results are summarized in Table 1.
Data in the Table 1 show that some synthesized com-
pounds exhibited distinct cytotoxic activity against the
three human cancer cell lines in vitro, especially against
A431. Compounds 1a–1f were found to be more potent
than compounds 1g–1k. This result indicate that the cyto-
toxic activity is related to the substituted group at 2-posi-
tion of isoquinoline-1,3(2H,4H)-diones. Compound 1f
exhibited less inhibitory activity than compounds 1a–1e.
This connotes methoxyl or fluoro at 6, 7, 8-position of
isoquinoline-1,3-dione may contribute the cytotoxic activ-
ity. 1b (2-cyclopropanylcarboxamino) displayed a higher
potency than 1a (2-acetylamino) against three cell lines.
That suggests the presence of 2-cyclopropanylcarboxamino
at benzothiazole may improve the activity of target com-
pounds. The IC50 of compounds 1g (2-(4-MeOPh)), 1h (2-
(4-MePh)), and 1i (2-(4-F3CPh)) are 78.91 lM, 47.60, and
32.75 lM, respectively, suggesting that the activity is
related to the electronic nature of the substituent, and an
electron-withdrawing substituent at 4-position of 2-phenyl
can improve the cytotoxic activity. Unexpectedly, com-
pounds 1a–1k did not display a strong activities than the
positive controls.
Results and discussion
Synthesis
Our synthetic approach for the targeted compounds is
outlined in Scheme 1. The commercially available substi-
tuted cinnamic acid was reduced by hydrogenation in the
presence of Pd–C (5 %) to give substituted phenylpropa-
noic acid (2). Then 2 was cyclized in polyphosphoric acid
to give 2,3-dihydroinden-1-one (3). Acylation of 3 with
diethyl oxalate, subsequent oxidation with alkaline hydro-
gen peroxide, according to Bhakta’s conditions (Bhakta
1986) afforded homophthalic acid (4). Cyclization of 4 into
5 was accomplished with acetic anhydride in hot toluene
(Matstuda et al., 1988) and 5 was isolated directly from the
reaction mixture as a white powder. The synthesis of
compounds 1a–1k was achieved by condensation of
homophthalic anhydride 5 with corresponding 2-acyla-
mino-6-benzothiazolylamine or substituted aniline (Cheng
Fig. 1 The structures of
compound A and target
compounds
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Med Chem Res
Scheme 1 Synthesis of title compounds. Reagents and conditions: a 5 % Pd/C, H2; b PPA; c diethyl oxalate, NaOMe, then H2O2; d Ac2O,
reflux; e ArNH2, HOAc, reflux
Table 1 IC50 values of 1a–1k
against three cancer cell lines
Compd.
IC50 (lM)a
Compd.
IC50 (lM)a
A431
A549
PC
A431
A549
PC
1a
1b
1c
1d
1e
1f
11.92
7.01
11.96
7.58
8.64
46.80
ntb
20.51
12.73
20.70
16.23
12.56
22.30
9.00
11.25
7.70
1g
1h
1i
78.91
47.60
32.75
62.53
60.35
[100
43.61
32.15
[100
[100
[100
21.03
17.12
45.32
28.89
10.50
20.59
11.66
16.74
2.01
a
1j
Values were expressed as
mean of IC50 of the triplicate
experiment. Variability around
the mean values was 10–40 %
1k
A
gefitinib
1.89
8.51
2.80
b
Not tested
Antitumor effects in vivo
To preliminarily test the antitumor effects of the synthe-
sized compounds in vivo, a study using PANC-1 (human
pancreatic carcinoma cell line) xenograft model was per-
formed. Compound 1b displayed distinct activities against
the three carcinoma cell lines and was chosen to evaluate
its antitumor effect in vivo. 1b was dosed orally at 5 or
25 mg/kg for 13 days. The control group was adminis-
trated orally with solvent alone. Tumor volumes were
measured at intervals of 4 days (Fig. 2). In this model,
treatment with 5 and 25 mg/kg of compound 1b resulted in
statistically significant antitumor activity, characterized as
tumor growth delay (p \ 0.01 vs. solvent group based on
Dunnett’s test on day 13).
Fig. 2 In vivo efficacy for 1b in PANC-1 xenograft tumor model
when dosed orally at 5 and 25 mg/kg on a once daily schedule.
*p \ 0.01 compared with the control group
Mice body weights and tumor weights are listed in
Table 2. Figure 2 and data in Table 2 show that 1b display
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Med Chem Res
Table 2 1b suppress tumor growth in weight in PANC-1 xenograft tumor model ðxꢀꢁ s; n ¼ 5Þ
Groups
Dosage (mg/kg)
Schedule
Mice weight(g) (tumor removed)
Tumor weights (g) xꢀ ꢁ SD
Inhibition rate (%)
Solvent
20.12 1.25
17.74 2.71
18.02 1.59*
1.73 0.21
1b
5
ig*13
ig*13
1.32 0.23*
1.18 0.30**
23.74
31.51
25
* p \ 0.05 versus solvent group, ** p \ 0.01 versus solvent group
Chemistry
a dose-dependent tumor suppression activity. 1b can sup-
press tumor growth with 23.74 %, 31.51 % in weight when
administered at 5 or 25 mg/kg once a day compared with
the control group, respectively. These data suggest that
compound 1b could potentially inhibit tumor growth. Mice
body weight loss of tested animals was observed in two
dosages groups.
3-(3,5-Dimethoxyphenyl) propionic acid (2a)
The mixture of 3-(3,5-dimethoxyphenyl)acrylic acid
(50.0 g, 0.24 mol) and Pd–C (5.0 g, 5 %) in ethanol
(150 ml), methanol (75 ml), and THF (200 ml) was stirred
under atmosphere of hydrogen for 30 h at ambient tem-
perature. The suspension was filtrated and the solid was
washed with THF for three times. The combined filtrate
was concentrated to give 50.0 g of 2a as a white solid,
which was used for the next step without further purifica-
tion. Yield 99.0 %. mp 58.0–61.0 °C. IR (KBr): 3,350
Conclusions
Six 2-(2-acylaminobenzothiazol-6-yl)isoquinoline-1,3(2H,
4H)-diones (1a–1f) and five 2-arylisoquinoline-1,3(2H,
4H)-diones (1g–1k) were synthesized. 1a–1e exhibited
distinct cytotoxic activitiy and 1f–1k displayed weak
cytotoxic activitiy against A431, A549, and PC3. Com-
pound 1b relatively displayed a higher activity than the
others. The antitumor effects of 1b were evaluated in
established nude mouse PANC-1 xenograft model. The
results suggest that compound 1b could potentially inhibit
tumor growth.
1
(mO–H), 1,721(mC=O)/cm. H NMR (300 MHz, CDCl3) d:
2.67 (t, J = 6.4 Hz, 2H, –CH2), 2.88 (t, J = 6.4 Hz, 2H,
–CH2), 3.77 (s, 6H, –OCH392), 6.32 (s, 1H, Ar–H), 6.36
(s, 2H, Ar–H). 13C NMR (100 MHz, CDCl3) d: 34.0 (C-3),
36.2 (C-2), 55.6 (OCH3), 55.6 (OCH3), 97.2 (C-40), 103.6
(C-20), 103.6 (C-60), 140.5 (C-10), 161.1(C-30), 161.1(C-50),
174.3 (C-1). MS (m/z): 210.1 (M), 165.0.
Compounds 2b–2e were synthesized according to the
procedure described above.
Experimental
3-(3-Methoxyphenyl) propionic acid (2b)
Unless specified otherwise, all starting materials, reagents
and solvents were commercially available. All reactions
were monitored by thin-layer chromatography on silica gel
plates (GF-254) and visualized with UV light. All the
melting points were determined on a Beijing micromelting-
point apparatus and thermometer was uncorrected. 1H-
NMR spectra were recorded on a 300 MHz or 400 Bruker
NMR spectrometer with tetramethylsilane as an internal
reference. All chemical shifts are reported in parts per
million (ppm). High-resolution exact mass measurements
were performed using electrospray ionization (positive
mode) on a quadrupole time-of-flight mass spectrometer
(Maxis Q-TOF, Bruker Inc.). Mass spectra were performed
on a Shimadzu GC–MS-QP2010.
Yield 95.2 %. mp 48.0–50.0 °C. IR (KBr): 3350 (mO–H),
1722 (mC=O)/cm. H NMR (400 MHz,CDCl3) d: 2.70 (t, 2
1
H, J = 7.4 Hz, –CH2), 2.91 (t, 2H, J = 7.4 Hz, –CH2),
3.90 (s, 3H, –OCH3), 7.00 (s, 1H, Ar–H), 7.10 (d, 1H,
J = 8.8 Hz, Ar–H), 7.60 (t, 1H, J = 8.8 Hz, Ar–H), 7.80
(d, 1H, J = 8.8 Hz, Ar–H). 13C NMR (100 MHz, CDCl3)
d: 33.6 (C-3), 36.1 (C-2), 55.9 (OCH3), 110.6 (C-40), 111.2
(C-20), 119.5 (C-60), 139.8 (C-10), 160.0 (C-30), 128.6 (C-
50), 174.3 (C-1). MS (m/z): 180.1 (M), 135.0.
3-(3,4,5-Trimethoxyphenyl) propionic acid (2c)
Yield 98.2 %. mp 100.0–101.5 °C. IR (KBr): 3346 (mO–H),
1
The mice were purchased from Experiment Animal
Center of Shanghai Institute of Pharmaceutical Industry
and were raised in the same place. The experimental pro-
tocol was approved by the Ethics Committee of Shanghai
Institute of Pharmaceutical Industry.
1722 (mC=O)/cm. H NMR (400 MHz, CDCl3) d: 2.69 (t,
2H, J = 7.8 Hz, –CH2), 2.91 (t, 2H, J = 7.8 Hz, –CH2),
3.83 (s, 3H, –OCH3), 3.85 (s, 6H, –OCH392), 6.43 (s, 2H,
Ar–H). 13C NMR (100 MHz, CDCl3) d: 33.6 (C-3), 36.2
(C-2), 56.2 (OCH3), 56.2 (OCH3), 57.8 (OCH3), 104.6 (2C,
123

Med Chem Res
C-20, C-60), 135.4 (C-40), 132.6 (C-10), 149.5 (C-30), 149.5
(C-50), 174.2 (C-1). MS (m/z): 240.1 (M), 195.0.
J = 5.8 Hz, –CH2), 3.09 (t, 2H, J = 5.8 Hz, –CH2), 3.89
(s, 3H, –OCH3), 6.91 (s, 2H, Ar–H), 7.69 (s, 1H, Ar–H).
13C NMR (100 MHz, DMSO-d6) d: 25.8 (C-3), 36.8 (C-2),
55.8 (OCH3), 110.0 (C-6), 111.2 (C-4), 128.1 (C-7), 135.1
(C-8), 156.7 (C-9), 166.5 (C-5), 203.2 (C-1). MS (m/z):
163.0 (M?1).
3-(4-Fluorophenyl) propionic acid (2d)
Light brown liquid. IR (KBr): 3344 (mO–H), 1720 (mC=O)/
cm. 1H NMR(400 MHz, CDCl3) d: 2.68 (t, 2H,
J = 7.4 Hz, –CH2), 2.98 (t, 2H, J = 7.4 Hz, –CH2), 7.38
(d, 2H, J = 8.2 Hz, Ar–H), 7.63 (t, 2H, J = 8.2 Hz, Ar–
H). 13C NMR (100 MHz, CDCl3) d: 33.3 (C-3), 36.0 (C-2),
113.6 (C-30), 113.6 (C-50), 128.2 (C-20), 128.2 (C-60), 135.8
(C-10), 159.3 (C-40), 174.0 (C-1). MS (m/z): 174.0 (M),
123.0.
5,6,7-Trimethoxy-2,3-dihydroinden-1-one (3c)
Yield 81.9 %. mp 110.0–111.5 °C. IR (KBr): 1718 (mC=O)/
cm. 1H NMR (400 MHz, CDCl3) d: 2.66 (t, 2H,
J = 6.0 Hz, –CH2), 3.02 (t, 2H, J = 6.0 Hz, –CH2), 3.85
(s, 3H, –OCH3), 3.94 (s, 3H, –OCH3), 4.05 (s, 3H, –OCH3),
6.68 (s, 1H, Ar–H). 13C NMR (100 MHz, CDCl3) d: 25.6
(C-3), 36.8 (C-2), 55.8 (OCH3), 59.0 (OCH3), 60.6
(OCH3), 102.7 (C-4), 105.0 (C-8), 136.3 (C-9), 149.2(C-7),
155.5 (C-6), 157.3 (C-5), 202.1 (C-1). MS (m/z): 223.2
(M?1).
3-Phenylpropionic acid (2e)
Colorless liquid. IR (KBr): 3350 (mO–H), 1723 (mC=O)/cm.
1H NMR (400 MHz, CDCl3) d: 2.68 (t, 2H, J = 7.4 Hz,
–CH2), 2.98 (t, 2H, J = 7.4 Hz, –CH2), 7.30 (d, 2H,
J = 7.6 Hz, Ar–H), 7.40 (t, 2H, J = 7.4 Hz, Ar–H), 7.68
(t, 1H, J = 7.5 Hz, Ar–H). 13C NMR (100 MHz, CDCl3)
d: 33.4 (C-3), 35.8 (C-2), 124.6 (C-40), 126.8 (2C, C-20,
C-60), 127.2 (C-30), 127.5 (C-50), 134.3 (C-10), 174.0 (C-1).
MS (m/z): 150.1 (M), 105.0.
6-Fluoro-2,3-dihydroinden-1-one (3d)
1
Orange semi-solid. IR (KBr): 1721 (mC=O)/cm. H NMR
(400 MHz, DMSO-d6) d: 2.67 (t, 2H, J = 5.7 Hz, CH2),
3.09 (t, 2H, J = 5.7 Hz, CH2), 7.38 (m, 1H, Ar–H), 7.40
(m, 1H, Ar–H), 7.63 (b, 1H, Ar–H). 13C NMR (100 MHz,
DMSO-d6) d: 25.3 (C-3), 36.3 (C-2), 112.1 (C-5), 117.8
(C-7), 128.3 (C-4), 138.1 (C-8), 151.2 (C-9), 160.5 (C-6),
203.6 (C-1). MS (m/z): 151.0 (M?1).
5,7-Dimethoxy-2,3-dihydroinden-1-one (3a)
The mixture of 3-(3,5-dimethoxyphenyl) propionic acid 2a
(10.0 g, 47.6 mmol) and poly phosphoric acid (120 g) was
stirred at 80 °C under nitrogen for 5 h, cooled to ambient
temperature and poured onto crushed-ice (300 ml) slowly.
The aqueous mixture was extracted with ethyl acetate
(150 ml 94). The combined organic layers were washed
with saturated sodium carbonate aqueous solution
(50 ml 92), brine (50 ml) and dried over anhydrate
sodium sulfate. After evaporation of solvent, the crude
product was purified with flash-chromatography (PE:
EA = 3: 1, v/v) to give 9.35 g of 3a. Yield 97.4 %. mp
98.5–99.5 °C. IR (KBr): 1720 (mC=O)/cm. 1H NMR
(300 MHz, DMSO-d6) d: 2.50 (t, J = 6.0 Hz, 2H, –CH2),
2.95 (t, J = 6.0 Hz, 2H, –CH2), 3.79 (s, 3H, –OCH3), 3.84
(s, 3H, –OCH3), 6.42 (s, 1H, Ar–H), 6.62 (s, 1H, Ar–H).
13C NMR (100 MHz, DMSO-d6) d: 25.8 (C-3), 37.0 (C-2),
55.9 (OCH3), 56.3 (OCH3), 97.8 (C-6), 102.7 (C-4), 119.1
(C-8), 159.2 (C-9), 160.5 (C-7), 166.9 (C-5), 201.8 (C-1).
MS (m/z): 193.1 (M?1).
2,3-Dihydroinden-1-one (3e)
1
Orange semi-solid. IR (KBr): 1719 (mC=O)/cm. H NMR
(400 MHz, DMSO-d6) d: 2.67 (t, 2H, J = 5.8 Hz, –CH2),
3.09 (t, 2H, J = 5.8 Hz, –CH2), 7.20 (d, 1H, J = 7.4 Hz,
Ar–H), 7.35 (t, 1H, J = 7.4 Hz, Ar–H), 7.65 (t, 1H,
J = 7.6 Hz, Ar–H), 8.02 (d, 1H, J = 7.6 Hz, Ar–H). 13C
NMR (100 MHz, DMSO-d6) d: 25.6 (C-3), 36.6 (C-2),
125.7 (C-7), 126.9 (C-4), 127.8 (C-6), 132.1 (C-5),134.8
(C-8), 153.2 (C-9), 204.1 (C-1). MS (m/z): 133.1 (M?1).
2-(Carboxymethyl)-4,6-dimethoxybenzoic acid (4a)
To a freshly prepared solution of sodium methoxide
(0.46 g, 20.0 mmol of sodium in 40 ml of absolute meth-
anol) was added dropwise a solution of 3a and diethyl
oxalate (2.19 g, 15.0 mmol) in toluene (20 ml) at 2 °C.
The mixture was stirred at ambient temperature overnight.
Solvent was evaporated, the residue was added 5 %
hydrochloric acid (200 ml). The precipitate was collected,
recrystallized from methanol–water (70 ml, 2:1, v/v) to
yield a solid. To the suspension of the solid in water
(30 ml) was added dropwise an aqueous solution of
potassium hydroxide (2.24 g, 40.0 mmol of KOH in 10 ml
Compounds 3b–3e were synthesized according to the
procedure described above.
5-Methoxy-2,3-dihydroinden-1-one (3b)
Yield 87.5 %. mp 108.0–109.5 °C. IR (KBr): 1723 (mC=O)/
cm. 1H NMR (400 MHz, DMSO-d6) d: 2.67 (t, 2H,
123

Med Chem Res
2-(Carboxymethyl)benzoic acid (4e)
of water) at 2 °C. After the addition, hydrogen peroxide
solution (18.0 g, 30 %) was added dropwise around 5 °C
and the mixture was stirred for 2 h at ambient temperature,
and for 3 h at 50 °C, cooled, acidified with concentrate
hydrochloric acid and extracted with ethyl acetate (100 ml,
50 ml 93). The organic layers were combined, washed
with brine (40 ml), dried (Na2SO4), filtered, and concen-
trated under reduced pressure to afford 1.81 g of 4a. Yield
75.0 %. mp 168.0–170.0 °C. IR (KBr): 1705 (mC=O), 1688
(mC=O)/cm. 1H NMR (300 MHz, DMSO-d6) d: 3.57 (s, 2H,
CH2), 3.76 (s, 3H, –OCH3), 3.77 (s, 3H, –OCH3), 6.47 (s,
1H, Ar–H), 6.53 (s, 1H, Ar–H). 13C NMR (100 MHz,
DMSO-d6) d: 39.2 (CH2), 55.8 (OCH3), 56.2 (OCH3), 97.7
(C-5), 108.4 (C-3), 117.8 (C-1), 135.2 (C-2), 158.2 (C-6),
161.1 (C-4), 168.6 (C=O), 172.3 (C=O). MS (m/z): 241.0
(M?1).
Yield 44.0 %. mp 173.0–174.5 °C. IR (KBr): 1709 (mC=O),
1
1687 (mC=O)/cm. H NMR (400 MHz, DMSO-d6) d: 3.94
(s, 2H, –CH2), 7.32 (d, 1H, J = 7.6 Hz, Ar–H), 7.38 (t, 1H,
J = 7.4 Hz, Ar–H), 7.51 (t, 1H, J = 7.4 Hz, Ar–H), 7.90
(d, 1H, J = 7.6 Hz, Ar–H). 13C NMR (100 MHz, DMSO-
d6) d: 39.1 (CH2), 130.6 (C-4), 126.3 (C-6), 127.2 (C-3),
132.4 (C-1), 135.4 (C-2), 128.7 (C-5), 168.4 (C=O), 173.2
(C=O). MS (m/z): 181.0 (M?1).
6,8-Dimethoxy-4H-isochromene-1,3-dione (5a)
The mixture of 4a (5.19 g, 21.6 mmol), acetic anhydride
(3.33 g, 32.4 mmol), and toluene (14 ml) was refluxed
under nitrogen for 3 h and cooled for 4 h at 2 °C. The
yellow needle crystal was collected with suction, washed
with petroleum ether to produce 4.05 g of 5a. Yield
84.4 %. mp 159.0–160.0 °C. IR (KBr): 1847 (mC=O), 1775
(mC=O)/cm. 1H NMR (300 MHz, DMSO-d6) d: 3.88 (s, 6H,
–OCH392), 4.16 (s, 2H, -CH2), 6.58 (s, 1H, Ar–H), 6.62 (s,
1H, Ar–H). 13C NMR (100 MHz, DMSO-d6) d: 37.8 (C-4),
55.6 (OCH3), 56.3 (OCH3), 98.4 (C-7), 105.5 (C-5), 106.3
(C-9), 136.3 (C-10), 161.8 (C-8), 162.9 (C-6), 163.8 (C-1),
168.4 (C-3). MS (m/z): 223.1 (M?1).
Compounds 4b–4e were synthesized according to the
procedure described above.
2-(Carboxymethyl)-4-methoxybenzoic acid (4b)
Yield 68.7 %. mp 196.5–197.5 °C. IR (KBr): 1703(mC=O),
1
1685 (mC=O)/cm. H NMR (400 MHz, DMSO-d6): d 3.81
(s, 3H, –OCH3), 3.91 (s, 2H, –CH2), 6.91 (s, 1H, Ar–H),
6.92 (d, 1H, J = 8.0 Hz, Ar–H), 7.89 (d, 1H, J = 8.0 Hz,
Ar–H). 13C NMR (100 MHz, DMSO-d6) d: 39.1 (CH2),
55.7 (OCH3), 109.2 (C-5), 111.5 (C-3), 121.3 (C-1), 130.7
(C-6), 137.5 (C-2), 157.4 (C-4), 168.4 (C=O), 174.3 (C=O).
MS (m/z): 211.1 (M?1).
Compounds 5b–5e were synthesized according to the
procedure described above.
6-Methoxy-4H-isochromene-1,3-dione (5b)
Yield 84.7 %. mp 169.0–170.5 °C. IR (KBr): 1850 (mC=O),
1
1778 (mC=O)/cm. H NMR (400 MHz, DMSO-d6): d 3.87
6-(Carboxymethyl)-2,3,4-trimethoxy benzoic acid (4c)
Yield 42.0 %. mp 138.5–140.0 °C. IR (KBr): 1708 (mC=O),
(s, 3H, –OCH3), 4.24 (s, 2H, –CH2), 6.99 (s, 1H, Ar–H),
7.06 (d, 1H, J = 8.8 Hz, Ar–H), 7.98 (d, 1H, J = 8.8 Hz,
Ar–H). 13C NMR (100 MHz, DMSO-d6) d: 38.0 (C-4),
55.8 (OCH3), 112.7 (C-7), 113.6 (C-5), 133.6 (C-9), 130.8
(C-10), 123.4 (C-8), 153.6 (C-6), 164.8 (C-1), 168.6 (C-3).
MS (m/z): 193.1 (M?1).
1
1686 (mC=O)/cm. H NMR (400 MHz, CDCl3) d: 3.90 (s,
3H, –OCH3), 3.95 (s, 3H, –OCH3), 4.00 (s, 5H, –CH2,
–OCH3), 6.68 (s, 1H, Ar–H). 13C NMR (100 MHz, DMSO-
d6) d: 39.2 (CH2), 55.7 (OCH3), 55.7 (OCH3), 56.2
(OCH3), 105.5 (C-5), 110.3 (C-1), 129.8 (C-6), 151.4 (C-
2), 156.5 (C-3), 157.3 (C-4), 168.6 (C=O), 172.3 (C=O).
MS (m/z): 271.1 (M?1).
6,7,8-Trimethoxy-4H-isochromene-1,3-dione (5c)
Yield 82.3 %. mp 175.5–177.0 °C. IR (KBr): 1846 (mC=O),
1772 (mC=O)/cm. 1H NMR (400 MHz, CDCl3) d: 3.89 (s, 3H,
–OCH3), 3.96 (s, 3H, –OCH3), 4.00 (s, 5H, –CH2, –OCH3),
6.54 (s, 1H, Ar–H). 13C NMR (100 MHz, DMSO-d6) d: 38.2
(C-4), 56.8 (OCH3), 61.2 (OCH3), 61.2 (OCH3), 107.2 (C-5),
110.7 (C-9), 138.6 (C-10), 152.6 (C-7), 155.4 (C-6), 156.2
(C-8), 164.6 (C-1), 168.6 (C-3). MS (m/z): 253.1 (M?1).
2-(Carboxymethyl)-5-fluoro benzoic acid (4d)
Yield 42.0 %. mp 167.5–169.5 °C. IR (KBr): 1709 (mC=O),
1
1688 (mC=O)/cm. H NMR (400 MHz, DMSO-d6) d: 3.93
(s, 2H, –CH2), 7.38 (s, 1H, Ar–H), 7.40 (d, 1H, J = 9.6 Hz,
Ar–H), 7.63 (d, 1H, J = 9.6 Hz, Ar–H). 13C NMR
(100 MHz, DMSO-d6) d: 38.7 (CH2), 113.1 (C-4), 114.1
(C-6), 129.2 (C-3), 130.8 (C-1), 132.2 (C-2), 160.6 (d,
J = 250 Hz, C-5), 168.6 (C=O), 172.3 (C=O). MS (m/z):
199.0 (M?1).
7-Fluoro-4H-isochromene-1,3-dione (5d)
Yield 55.2 %. mp 143.0–144.0 °C. IR (KBr): 1844 (mC=O),
1
1775 (mC=O)/cm. H NMR (400 MHz, CDCl3) d: 4.13 (s,
123

Med Chem Res
2H, –CH2), 7.58 (d, 1H, J = 8.5 Hz, Ar–H), 7.77 (s, 1H,
Ar–H), 8.16 (d, 1H, J = 8.5 Hz, Ar–H). 13C NMR
(100 MHz, DMSO-d6) d: 37.6 (C-4), 113.4(C-8), 114.7 (C-
6), 130.7 (C-5), 131.6 (C-9), 132.4 (C-10), 156.6 (d,
J = 250 Hz, C-7), 164.5 (C-1), 168.7 (C-3). MS (m/z):
181.1 (M?1).
(100 MHz, DMSO-d6) d: 9.3 (CH2), 9.3 (CH2), 14.3 (CH),
56.2 (OCH3), 56.5 (OCH3); benzo[d]thiazole ring: 170.2
(C-2), 127.9 (C-4), 122.8 (C-5), 132.2 (C-6), 120.8 (C-7),
132.0 (C-8), 148.5 (C-9); isoquinoline-1,3(2H,4H)-dione
ring: 163.0 (C-1), 164.5 (C-3), 38.0 (C-4), 104.6 (C-5),
162.7 (C-6), 98.4 (C-7), 159.1 (C-8), 107.7 (C-9), 140.3 (C-
10); 173.4 (C=O). HRMS calc’d for C22H19N3NaO5S
(M?Na): 460.0943; found 460.0931.
4H-Isochromene-1,3-dione (5e)
Yield 76.5 %. mp 157.5–159.0 °C. IR (KBr): 1843 (mC=O),
1778 (mC=O)/cm. H NMR (400 MHz, DMSO-d6) d: 4.20
N-(6-(6-methoxy-1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-
1
yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide(1c)
(s, 2H, –CH2), 7.30 (d, 1H, J = 7.8 Hz, Ar–H), 7.40 (t, 1H,
J = 7.4 Hz, Ar–H), 7.56 (t, 1H, J = 7.4 Hz, Ar–H), 8.00
(d, 1H, J = 7.8 Hz, Ar–H). 13C NMR (100 MHz, DMSO-
d6) d: 37.5 (C-4), 126.5 (C-8), 129.4 (C-6), 125.7 (C-5),
132.4 (C-9), 136.2 (C-10), 128.8 (C-7), 164.5 (C-1), 168.4
(C-3). MS (m/z): 163.1 (M?1).
Yield 62.9 %. mp 265.0–267.0 °C. IR (KBr): 3471(mN–H),
1721 (mC=O), 1670 (mC=O), 1650 (mC=O)/cm. 1H NMR
(300 MHz, DMSO-d6) d: 0.97 (s, 2H, –CH2), 0.98 (d,
J = 3.9 Hz, 2H, –CH2), 1.99 (s, 1H, –CH), 3.88 (s, 3H,
–OCH3), 4.27 (s, 2H, –CH2), 6.88 (s, 1H, Ar–H), 7.07 (d,
J = 8.4 Hz, 1H, Ar–H), 7.28(d, J = 7.8 Hz, 1H, Ar–H), 6.65
(s, 1H, Ar–H), 7.80 (d, J = 7.3 Hz, 1H, Ar–H), 7.84 (d,
J = 7.5 Hz, 1H, Ar–H), 12.76 (s, 1H, CONH). 13C NMR
(100 MHz, DMSO-d6) d: 9.3 (CH2), 9.3 (CH2), 14.3 (CH),
56.2 (OCH3); benzo[d]thiazole ring: 170.8 (C-2), 127.7 (C-4),
122.7 (C-5), 132.0 (C-6), 120.9 (C-7), 131.8 (C-8), 148.7 (C-
90); isoquinoline-1,3(2H,4H)-dione ring: 163.9 (C-1), 165.1
(C-3), 37.4 (C-4), 114.8 (C-5), 159.2 (C-6), 112.1 (C-7), 130.8
(C-8), 118.5 (C-9), 138.5 (C-10); 173.4 (C=O). HRMS calc’d
for C20H17N3NaO5S (M?Na): 434.0787; found 434.0773.
Generalsynthesisfor1a–1l. Themixtureof5 (10.0 mmol),
2-acylamino-6-benzothiazolylamine (10.0 mmol)or substi-
tuted aniline (10.0 mmol) and acetic acid (5 ml) was refluxed
under nitrogen for 4–8 h, cooled to ambient temperature,
pouredintowater. The solidwascollected, recrystallizedfrom
methanol to give a off-white solid.
N-(6-(6,8-dimethoxy-1,3-dioxo-3,4-dihydroisoquinolin-
2(1H)-yl)benzo[d]thiazol-2-yl) acetamide (1a)
Yield 36.0 %. mp 255.5–257.0 °C. IR (KBr): 3470(mN–H),
1720 (mC=O), 1668 (mC=O), 1652 (mC=O)/cm. 1H NMR
(300 MHz, CDCl3) d: 2.31 (s, 3H, –CH3), 3.91 (s, 6H,
–OCH392), 4.17 (s, 2H, –CH2), 6.40 (s, 1H, Ar–H), 6.48
(s, 1H, Ar–H), 7.67 (s, 1H, Ar–H), 7.26 (d, 1H, J = 7.5 Hz,
Ar–H), 7.83 (d, 1H, J = 7.5 Hz, Ar–H). 13C NMR
(100 MHz, DMSO-d6) d: 23.3 (CH3), 56.20 (OCH3), 56.5
(OCH3); benzo[d]thiazole ring: 170.2 (C-2), 127.9 (C-4),
122.8 (C-5), 131.9 (C-6), 120.8 (C-7), 132.2 (C-8), 148.5
(C-9); isoquinoline-1,3(2H,4H)-dione ring: 163.0 (C-1),
164.5 (C-3), 38.0 (C-4), 104.6 (C-5), 162.7 (C-6), 98.4 (C-
7), 159.2 (C-8), 107.6 (C-9), 140.3 (C-10); 170.0 (C=O).
HRMS calc’d for C20H17N3NaO5S (M?Na): 434.0787;
found 434.0773.
N-(6-(6,7,8-trimethoxy-1,3-dioxo-3,4-dihydroisoquinolin-
2(1H)-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide(1d)
Yield 54.4 %. mp 270.0–271.0°C. IR (KBr): 3470 (mN–H),
1719 (mC=O), 1670 (mC=O), 1653 (mC=O)/cm. 1H NMR
(300 MHz, DMSO-d6) d: 0.97 (s, 2H, –CH2), 0.98 (d,
J = 3.3 Hz, 2H, –CH2), 1.99 (s, 1H, –CH), 3.75 (s, 6H,
–OCH392), 3.91 (s, 3H, –OCH3), 4.20 (s, 2H, –CH2), 6.95(s,
1H, Ar–H), 7.26 (d, J = 7.5 Hz, 1H, Ar–H), 7.79 (d,
J = 7.6 Hz, 1H, Ar–H), 7.82 (s, 1H, Ar–H), 12.75 (s, 1H,
CONH). 13C NMR (100 MHz, DMSO-d6) d: 9.3 (CH2), 9.3
(CH2), 14.3 (CH), 56.7 (OCH3), 61.2 (OCH3), 61.9 (OCH3);
benzo[d]thiazole ring: 170.8 (C-2), 127.9 (C-4), 122.8 (C-5),
133.8 (C-6), 120.9 (C-7), 132.0 (C-8), 148.6 (C-9); iso-
quinoline-1, 3(2H,4H)-dione ring: 162.8 (C-1), 162.8 (C-3),
37.6 (C-4), 107.3 (C-5), 159.2 (C-6), 157.8 (C-7), 155.4 (C-
8), 112.6 (C-9), 142.2 (C-10); 173.4 (C=O). HRMS calc’d
for C20H17N3NaO5S (M?Na): 490.1049; found 490.1040.
N-(6-(6,8-dimethoxy-1,3-dioxo-3,4-dihydroisoquinolin-
2(1H)-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide(1b)
Yield 75.2 %. mp 252.0–254.0 °C. IR (KBr): 3472 (mN–H),
1718 (mC=O), 1669 (mC=O), 1651 (mC=O)/cm. 1H NMR
(300 MHz, CDCl3) d: 1.02 (d, J = 4.5 Hz, 2H, –CH2),
1.26 (s, 2H, –CH2), 1.75 (s, 1H, –CH), 3.91 (s, 6H,
–OCH392), 4.16 (s, 2H, –CH2), 6.40 (s, 1H, Ar–H), 6.48
(s, 1H, Ar–H), 7.25 (d, J = 7.0 Hz, 1H, Ar–H) 7.67 (s, 1H,
Ar–H), 7.83 (d, J = 7.2 Hz, 1H, Ar–H). 13C NMR
N-(6-(7-fluoro-1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-
yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide(1e)
Yield 39.6 %. mp 268.2–270.0 °C. IR (KBr): 3465 (mN–H),
1716 (mC=O), 1665 (mC=O), 1650 (mC=O)/cm. 1H NMR
123

Med Chem Res
6,8-Dimethoxy-2-(4-methylphenyl)isoquinoline-1,3(2H,4H)-
dione (1h)
(300 MHz, DMSO-d6) d: 0.92 (s, 2H, –CH2), 0.99 (s, 2H,
–CH2), 1.99 (s, 1H, –CH), 4.29 (s, 2H, –CH2), 7.31 (d,
J = 6.6 Hz, 1H, Ar–H), 7.60 (t, J = 5.1 Hz, 1H, Ar–H),
7.62 (d, J = 8.4 Hz, 1H, Ar–H), 7.77 (d, J = 8.7 Hz, 1H,
Ar–H), 7.82 (d, J = 6.6 Hz, 1H, Ar–H), 7.87 (s, 1H, Ar–
H), 12.78 (s, 1H, CONH). 13C NMR (100 MHz, DMSO-d6)
d: 9.3 (CH2), 9.3 (CH2), 14.3 (CH), 173.5 (C=O);
benzo[d]thiazole ring: 170.7 (C-2), 127.6 (C-4), 122.6 (C-
5), 132.4 (C-6), 121.0 (C-7), 132.1 (C-8), 148.8 (C-9);
isoquinoline-1,3(2H,4H)-dione ring: 159.3 (C-1), 164.7 (C-
3), 37.6 (C-4), 130.6 (C-5), 114.4 (C-6), 162.3 (d,
J = 250 Hz, C–F), 114.1 (C-8), 130.7 (C-9), 131.5 (C-10).
HRMS calc’d for C20H14FN3NaO3S (M?Na) 418.0638;
found 418.0628.
Yield 64.3 %. mp 160.0–163.0 °C. IR (KBr): 1719 (mC=O),
1664 (mC=O)/cm. 1H NMR (300 MHz, CDCl3) d: 2.38 (s, 3H,
–CH3), 3.98 (s, 6H, –OCH392), 4.11 (s, 2H, –CH2), 6.37 (s,
1H, Ar–H), 6.45 (s, 1H, Ar–H), 7.05 (d, 2H, J = 7.2 Hz, Ar–
H), 7.26 (d, 2H, J = 7.2 Hz, Ar–H). 13C NMR (100 MHz,
DMSO-d6) d: 56.2 (OCH3), 56.4 (OCH3); isoquinoline-
1,3(2H,4H)-dione ring: 164.4 (C-1), 170.0 (C-3), 37.9 (C-4),
104.5 (C-5), 162.9 (C-6), 98.4 (C-7), 162.4 (C-8), 107.7 (C-
9), 140.3 (C-10); 2-phenyl: 134.2 (C-1), 129.6 (C-2), 129.4
(C-3), 137.5 (C-4), 129.4 (C-5), 129.6 (C-6). HRMS, calc’d
for C18H17NNaO4 (M?Na): 334.1055; found 334.1036.
6,8-Dimethoxy-2-(4-trifluoromethylphenyl)isoquinoline-1,
N-(6-(1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)benzo[d]
3(2H,4H)-dione (1i)
thiazol-2-yl)cyclopropanecarboxamide(1f)
Yield 54.7 %. mp 182.5–184.5 °C. IR (KBr): 1720 (mC=O),
1666 (mC=O)/cm. H NMR (300 MHz, CDCl3) d: 3.91 (s,
Yield 56.0 %. mp 233.0–235.2 °C. IR (KBr): 3471
(mN–H), 1720 (mC=O), 1668 (mC=O), 1652 (mC=O)/cm. 1H
NMR (300 MHz, DMSO-d6): d 0.97 (s, 2H, –CH2–), 0.98
(d, J = 3.3 Hz, 2H, –CH2–), 1.99 (s, 1H, –CH–), 4.31 (s,
2H, –CH2–), 7.31 (dd, J = 7.5 Hz, 1H, Ar–H), 7.48 (d,
J = 6.0 Hz, 1H, Ar–H), 7.52 (d, J = 5.7 Hz, 1H, Ar–H),
7.73 (t, J = 5.6 Hz, 1H, Ar–H), 7.81 (d, J = 6.3 Hz, 1H,
Ar–H), 7.86 (d, J = 1.2 Hz, 1H, Ar–H), 8.07 (d,
J = 5.7 Hz, 1H, Ar–H), 12.76 (s, 1H, CONH). 13C NMR
(100 MHz, DMSO-d6) d: 9.3 (CH2), 9.3 (CH2), 14.3
(CH), 173.4 (C=O); benzo[d]thiazole ring: 170.8 (C-2),
128.2 (C-4), 122.6 (C-5), 132.0 (C-6), 120.9 (C-7), 131.7
(C-8), 148.7 (C-9); isoquinoline-1,3(2H,4H)-dione ring:
159.2 (C-1), 165.5 (C-3), 37.2 (C-4), 128.6 (C-5), 125.7
(C-6), 127.8 (C-7), 127.6 (C-8), 34.2 (C-9), 136.2 (C-10).
HRMS calc’d for C20H14FN3NaO3S (M?Na) 400.0732;
found 400.0726.
1
6H, 6H, –OCH392), 4.14 (s, 2H, –CH2), 6.39 (s, 1H, Ar–
H), 6.47 (s, 1H, Ar–H), 7.32 (d, 2H, J = 7.4 Hz, Ar–H),
7.74 (d, 2H, J = 7.2 Hz, Ar–H). 13C NMR (100 MHz,
DMSO-d6) d: 56.2 (OCH3), 56.4 (OCH3); isoquinoline-
1,3(2H,4H)-dione ring: 164.6 (C-1), 169.9 (C-3), 37.9 (C-
4), 104.7 (C-5), 163.1 (C-6), 98.4 (C-7), 162.3 (C-8), 106.4
(C-9), 140.9 (C-10); 2-phenyl: 140.2 (C-1), 126.3 (C-2),
130.9 (C-3), 126.4 (C-4), 130.9 (C-5), 126.3 (C-6); 128.5
(q, J = 186 Hz, CF3). HRMS calc’d for C20H14FN3NaO3S
(M?Na) 388.0773; found 388.0748.
6,8-Dimethoxy-2-(3-trifluoromethylphenyl)isoquinoline-1,
3(2H,4H)-dione (1j)
Yield 36.5 %. mp 174.5–175.5 °C. IR (KBr): 1721,
1667/cm. 1H NMR (300 MHz, CDCl3) d: 3.91 (s, 3H,
–OCH3), 3.92 (s, 3H, –OCH3), 4.15 (s, 2H), 6.39 (s, 1H,
Ar–H), 6.47 (s, 1H, Ar–H), 7.40 (d, 1H, J = 6.9 Hz, Ar–
H), 7.48 (s, 1H, Ar–H), 7.60 (t, 1H, J = 7.2 Hz, Ar–H),
7.67 (d, 1H, J = 6.9 Hz, Ar–H). 13C NMR (100 MHz,
DMSO-d6) d: 56.2 (OCH3), 56.4 (OCH3); isoquinoline-
1,3(2H,4H)-dione ring: 164.5 (C-1), 169.9 (C-3), 37.9 (C-
4), 104.6 (C-5), 163.1 (C-6), 98.4 (C-7), 162.2 (C-8), 107.4
(C-9), 140.3 (C-10); 2-phenyl: 133.9 (C-1), 117.2 (C-2),
132.0 (C-3), 117.4 (C-4), 119.6 (C-5), 130.7 (C-6); 130.8
(q, J = 186 Hz, CF3). HRMS, calc’d for C18H14F3NNaO4
(M?Na) 388.0773; found 388.0749.
6,8-Dimethoxy-2-(4-methoxyphenyl)isoquinoline-1,3(2H,
4H)-dione (1g)
Yield 84.8 %. mp 211.5–213.0 °C. IR (KBr): 1720
1
(mC=O), 1655 (mC=O)/cm. H NMR (300 MHz, CDCl3) d:
3.83 (s, 3H, –OCH3), 3.89 (s, 3H, –OCH3), 3.91 (s, 3H,
–OCH3), 4.13 (s, 2H, –CH2), 6.37 (s, 1H, Ar–H), 6.45 (s,
1H, Ar–H), 6.97 (d, 2H, J = 8.7 Hz, Ar–H), 7.09 (d, 2H,
Ar–H). 13C NMR (100 MHz, DMSO-d6) d: 55.8 (OCH3),
56.1 (OCH3), 56.4 (OCH3); isoquinoline-1,3(2H,4H)-
dione ring: 164.4 (C-1), 170.1 (C-3), 37.9 (C-4), 104.5
(C-5), 162.9 (C-6), 98.4 (C-7), 162.4 (C-8), 107.7 (C-9),
140.2 (C-10); 2-phenyl: 129.2 (C-1),114.4 (C-2), 130.6
(C-3), 150.9 (C-4), 130.6 (C-5), 114.4 (C-6). HRMS
calc’d for C20H14FN3NaO3S (M?Na) 334.1055; found
334.1036.
2-(3-Ethynylphenyl)-6,8-dimethoxy-isoquinoline-1,
3(2H,4H)-dione (1k)
Yield 78.8 %. mp 196.5–198.5 °C. IR (KBr): 2155, 1720,
1666/cm. 1H NMR (300 MHz, CDCl3) d: 3.07 (s, 1H,
123

Med Chem Res
–C:CH), 3.90 (s, 3H, –OCH3), 3.91 (s, 3H, –OCH3), 4.12
(s, 2H, –CH2), 6.38 (s, 1H, Ar–H), 6.46 (s, 1H, Ar–H), 7.17
(d, 1H, J = 7.8 Hz, Ar–H), 7.33 (s, 1H, Ar–H), 7.40 (t, 1H,
J = 7.6 Hz, Ar–H), 7.51 (d, 1H, J = 7.8 Hz, Ar–H). 13C
NMR (100 MHz, DMSO-d6) d: 56.2 (OCH3), 56.5
(OCH3), 81.8 (C:), 83.2 (:CH); isoquinoline-
1,3(2H,4H)-dione ring: 164.5 (C-1), 169.9 (C-3), 37.8 (C-
4), 104.6 (C-5), 163.3 (C-6), 98.4 (C-7), 162.3 (C-8), 107.9
(C-9), 140.3 (C-10); 2-phenyl: 131.6 (C-1), 129.6 (C-2),
137.2 (C-3), 133.0 (C-4), 130.6 (C-5), 122.6 (C-6). HRMS
calc’d for C19H15NNaO4 (M?Na): 344.0899, found
344.0880.
of the body, the neoplasm, and the volumes of neoplasm,
were measured and inhibitory ratios for tumor volume and
weight was calculated.
Acknowledgments Financial support from The National Natural
Science Foundation of China (Grant No. 21072156) is gratefully
acknowledged.
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