Novel dithiocarbamic acid esters derived from 6-aminomethyl-4- anilinoquinazolines and 6-aminomethyl-4-anilino-3-cyanoquinolines as potent EGFR inhibitors

Article abstract of DOI:10.1002/ardp.201200267

Two series of dithiocarbamic acid esters, 4-anilinoquinazoline-6- ylmethylcarbamodithioic acid esters and 3-cyano-4-anilinoquinolin-6- ylmethylcarbamodithioic acid esters, were designed and synthesized. The effect of the synthesized compounds on cell proliferation was evaluated by MTT assay against three human cancer cell lines: MDA-MB-468, SK-BR-3 and HCT-116. Most of the compounds are equally or more potent than the positive control lapatinib. Three compounds (14d, 14h and 14i) were identified as dual inhibitors of the EGFR and ErbB-2 kinases and two compounds (14b and 14c) were identified as multi-target kinase inhibitors, and they are very worthy of further study. Installation of the dithiocarbamic acid ester group at the 6-position of 4-anilinoquinazoline or 3-cyano-4-anilinoquinoline could improve the inhibitory activity. Different dithiocarbamic acid ester groups significantly affect the activities. Two series of dithiocarbamic acid esters were designed and synthesized. Compound 14d was found to have higher biological activity than lapatinib. Some useful structure-activity relationships were revealed. Copyright

Full text of DOI:10.1002/ardp.201200267

44
Arch. Pharm. Chem. Life Sci. 2013, 346, 44–52
Full Paper
Novel Dithiocarbamic Acid Esters Derived from
6-Aminomethyl-4-anilinoquinazolines and 6-Aminomethyl-
4-anilino-3-cyanoquinolines as Potent EGFR Inhibitors
Xin Zhang1,2,y, Ridong Li1,y, Kang Qiao1, Zemei Ge1, Liangren Zhang1, Tieming Cheng1,
and Runtao Li1
1 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences,
Peking University, Beijing, P. R. China
2 Department of Pharmacy, The First Affiliated Hospital of General Hospital of PLA, Beijing, P. R. China
Two series of dithiocarbamic acid esters, 4-anilinoquinazoline-6-ylmethylcarbamodithioic acid esters
and 3-cyano-4-anilinoquinolin-6-ylmethylcarbamodithioic acid esters, were designed and synthesized.
The effect of the synthesized compounds on cell proliferation was evaluated by MTT assay against
three human cancer cell lines: MDA-MB-468, SK-BR-3 and HCT-116. Most of the compounds are equally
or more potent than the positive control lapatinib. Three compounds (14d, 14h and 14i) were
identified as dual inhibitors of the EGFR and ErbB-2 kinases and two compounds (14b and 14c)
were identified as multi-target kinase inhibitors, and they are very worthy of further study.
Installation of the dithiocarbamic acid ester group at the 6-position of 4-anilinoquinazoline or
3-cyano-4-anilinoquinoline could improve the inhibitory activity. Different dithiocarbamic acid
ester groups significantly affect the activities.
Keywords: Dithiocarbamic acid ester / EGFR inhibitors / Structure–activity relationship / Synthesis
Received: July 2, 2012; Revised: September 14, 2012; Accepted: September 19, 2012
DOI 10.1002/ardp.201200267
Introduction
Lapatinib (3), a potent dual inhibitor of erbB1 and erbB2,
was approved in 2007 for treating breast cancer [4]. EKB-569 (4)
is a potent, selective, and irreversible inhibitor of EGFR that is
being developed as an anticancer agent [5, 6]. However, it has
been reported that somatic mutations in the tyrosine kinase
domain of the EGFR gene occur in a subset of patients with
lung cancer who showed a dramatic response to the EGFR
tyrosine kinase inhibitors 1 and 2 [7–9]. Therefore, it is still
necessary to develop novel EGFR targeting therapeutic agents
with enhanced potency that can overcome drug resistance.
In recent years, a number of dithiocarbamic acid esters with
cancer chemopreventive and anticancer activities have been
revealed. The natural product brassinin (Fig. 2, 5) isolated from
cabbage as indoleamine 2,3-dioxygenase (IDO) inhibitor [10]
and sulforamate (Fig. 2, 6) as phase II enzyme inducer have
demonstrated potential cancer chemopreventive action [11].
Some molecules that incorporated dithiocarbamic acid ester
groups as a key pharmacophore showed significant anticancer
activity, such as thalidomide dithiocarbamates [12], chromones
Tyrosine kinases are crucial enzymes involved in many cel-
lular processes such as cell proliferation, metabolism, sur-
vival, and apoptosis [1]. As a member of the erbB receptor
family of tyrosine kinases, overexpression of epidermal
growth factor receptor (EGFR) as well as the related human
epidermal growth factor receptor (HER-2, also known as erbB-
2) are markers for poor prognosis in many human cancers [2].
Therefore, EGFR as a target of anticancer drugs has received
much attention in the past decade. A series of EGFR inhibitors
with different molecular scaffolds have been discovered.
Meanwhile, most EGFR inhibitors are based on a 4-anilinoquin-
azoline or 3-cyano-4-anilinoquinolin core scaffold. As shown
in Fig. 1, gefitinib (1) and erlotinib (2) have been approved for
the treatment of non-small-cell lung cancer (NSCLC) [3].
Correspondence: Runtao Li, State Key Laboratory of Natural and
Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University,
Beijing 100191, P. R. China.
Additional corresponding author: Zemei Ge, E-mail: zmge@bjmu.edu.cn
yThese two authors made equal contributions to this work.
E-mail: lirt@bjmu.edu.cn
Fax: þ86-010-82716956
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Arch. Pharm. Chem. Life Sci. 2013, 346, 44–52
Dithiocarbamic Acid Esters as EGFR Inhibitors
45
F
HN
N
HN
N
O
Cl
O
O
O
O
O
O
N
N
N
(Erlotinib, Tarcera)
2
1 (Gefitinib, Iressa)
F
O
F
HN
Cl
H
HN
Cl
N
CN
HN
N
O
N
O
O
O
N
S
N
O
(Lapatinib)
3
Figure 1. Representative inhibitors of EGFR
(EKB569)
4
tyrosine kinase.
H
N
O
N
S
O
O
S
S
CH3
S
H
C
3
S
H
R
N
H
3C
S
O
O
N
H
Amine
S
5
6
7
(Brassinin)
(Sulforamate)
(Thalidomide dithiocarbamates)
S
S
S
O
N
O
S
R1
N
R1R2
S
N
S
N
H
NH
CH3
R2
X
R
O
O
O
10
8
9
(Butenolide dithiocarbamates)
(Chromones dithiocarbamates)
(Quinazolinone dithiocarbamates)
H
O
S
H
3C
R
N
O
CN
N
H
S
H
S
O
N
S
NMe2
H
O
N
S
RHN
S
13
12
(990207)
11
Figure 2. Structures of some dithiocarbamates
(Sugar dithiocarbamates)
with anticancer activities.
dithiocarbamates [13], quinazolinone dithiocarbamates [14],
butenolide dithiocarbamates [15] and sugar dithiocarbamates
[16] (Fig. 2, 7–11). In our research effort to develop new kinds of
anticancer drugs, a novel set of dithiocarbamate compounds 12
(990207) [17–19] and 13 (Fig. 2) were discovered to have potent
anticancer activity [20, 21]. More interestingly, it was found
that most of the dithiocarbamate derivatives from aromatic
and heteroaromatic methyl amines showed significant anti-
cancer activity, such as compounds 5, 9 and 13 (Fig. 2).
4-anilinoquinazolines or 4-anilinoquinoline-3-carbonitriles.
In particular, all target dithiocarbamic acid esters were
derived from 6-aminomethyl-4-anilinoquinazolines and
6-aminomethyl-4-anilino-3-cyanoquinolines. Here, we report
their syntheses and their activities against three kinds of
human cancer cell lines, MDA-MB-468, SK-BR-3 and HCT116.
R2
Based on the known structure–activity relationships (SAR)
of 4-anilinoquinazoline EGFR inhibitors [22–27], the C6 pos-
ition of 4-anilinoquinazolines still remains open for modifi-
cation and evaluation. Considering the research progress of
dithiocarbamic acid esters as anticancer agents, especially
that the aromatic and heteroaromatic methylaminodithio-
carbamic acid esters usually exhibited significant anticancer
activity, we designed a new kind of EGFR inhibitors 14
(Fig. 3) by the combination of dithiocarbamic acid esters with
S
HN
N
R1
R3
S
N
H
X
R4
X = N, C-CN
14
Figure 3. The structure of compounds 14.
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46
X. Zhang et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 44–52
Results and discussion
The synthesis of compounds 14g–14i is shown in Scheme 2.
Aza-Michael addition of 3-methoxy-4-methyl aniline (22) with
ethyl 2-cyanoacrylate provided ethyl 2-cyano-3-(3-methoxy-4-
methylphenylamino)acrylate (23), which transformed into
4-hydroxy-7-methoxy-6-methylquinoline-3-carbonitrile (24)
under thermal cyclization (Dowtherm) conditions [28].
Compound 24 was converted to 4-chloro-7-methoxy-6-
methylquinoline-3-carbonitrile (25) by treatment with an
excess of POCl3. The ensuing procedures to convert 25 to
the final compounds 14g–14i are similar to those that convert
18 to 14a–14f.
Chemistry
The synthesis of compounds 14a–14f is outlined in Scheme 1.
Reaction of 2-amino-5-methylbenzoic acid (15) with forma-
mide yielded the cyclized product 4-hydroxyl-6-methylquina-
zoline (16), which was treated with thionyl chloride to afford
4-chloro-6-methylquinazoline (17). Bromination of 17 with N-
bromosuccinimide induced by (PhCO)2O2 gave 4-chloro-6-bro-
momethylquinazoline (18). Reaction of 18 with potassium
phthalimide gave 2-((4-chloroquinazolin-6-yl)methyl)iso-
indoline-1,3-dione (19). Displacing the 4-chlorine of the
intermediate 19 with appropriate anilines provided the 2-
(4-anilinoquinazolin-6-yl)methyl)isoindoline-1,3-diones (20),
which were treated with methylamine in methanol at room
temperature to afford the key intermediate 6-aminomethyl-4-
anilinoquinazoline 21. Finally, the target compounds 14a–
14f were prepared according to our established method by
the reaction of compounds 21 with carbon disulfide and
different electrophilic agents.
Pharmacology
All synthesized compounds (14a–14i) were tested as EGFR
inhibitors for their ability to inhibit cellular proliferation
in three representative human cancer cell lines: MDA-MB-468
which overexpresses EGFR, SK-BR-3 which overexpresses ErbB-
2 and to a lesser extent EGFR, HCT-116 which is believed not
to express either EGFR or ErbB-2 to a significant extent. The
OH
Cl
H3C
COOH
NH2
H3C
H3C
b
c
a
N
N
N
N
15
16
17
Cl
O
Cl
N
N
d
e
Br
N
N
O
N
18
19
R2
R1
R2
R1
HN
N
O
HN
N
N
N
f
H2N
N
O
20a: R1 = Cl, R2 = 3-fluorobenzyloxy
20b: R1 = Cl, R2 = F
21a: R1 = Cl, R2 = 3-fluorobenzyloxy
21b: R1 = Cl, R2 = F
20c: R1 = Br, R2 = H
21c: R1 = Br, R2 = H
R2
S
HN
R1
g
R3
S
N
H
N
N
14a: R1 = Cl, R2 = 3-fluorobenzyloxy, R3X = 2-(2-bromoethyl)-1,3-dioxolane
14b: R1 = Cl, R2 = F, R3X = 2-(2-bromoethyl)-1,3-dioxolane
Scheme 1. Synthesis of compounds 14a–14f.
Reagents and conditions: (a) NH2CHO, reflux;
(b) SOCl2, DMF, reflux; (c) NBS, (PhCO)2O2,
CCl4, reflux; (d) potassium phthalimide, reflux;
(e) Ar-NH2, i-PrOH, reflux; (f) CH3NH2, MeOH,
r.t.; (g) R3X, CS2, Et3N, DMF, r.t.
14c: R1 = Br, R2 = H, R3X = 2-(2-bromoethyl)-1,3-dioxolane
14d: R1 = Cl, R2 = 3-fluorobenzyloxy, R3X = 3-bromopropanenitrile
14e: R1 = Cl, R2 = 3-fluorobenzyloxy, R3X = methyl acrylate
14f: R1 = Cl, R2 = 3-fluorobenzyloxy, R3X = ((2-bromoethylsulfonyl)methyl)benzene
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Arch. Pharm. Chem. Life Sci. 2013, 346, 44–52
Dithiocarbamic Acid Esters as EGFR Inhibitors
47
OH
N
H3C
NC
COOCH2CH3
H3C
H3C
CN
a
b
H3CO
N
H
H3CO
NH2
H3CO
23
22
24
Cl
Cl
N
CN
H3C
CN
Br
e
d
c
H3CO
N
H3CO
26
25
R2
R1
O
O
O
O
f
N
HN
g
N
Cl
N
CN
CN
H3CO
N
H3CO
27
28a: R1 = Cl, R2 = 3-fluorobenzyloxy
28b: R1 = Cl, R2 = F
28c: R1 = Br, R2 = H
R2
R1
R2
R1
Scheme 2. Synthesis of compounds 14g–14i.
Reagents and conditions: (a) ethyl (ethoxy-
methylene)cyanoacetate, toluene, reflux; (b)
Dowtherm, reflux; (c) POCl3, DMF, reflux; (d)
NBS, (PhCO)2O2, CCl4, reflux; (e) potassium
phthalimide, acetone, reflux; (f) aniline, i-PrOH,
reflux; (g) CH3NH2, MeOH, r.t.; (h) 2-(2-bro-
moethyl)-1,3-dioxolane, CS2, Et3N, DMF, r.t.
HN
N
S
HN
N
O
h
CN
CN
H2N
H3CO
S
N
H
O
H3CO
29a: R1 = Cl, R2 = 3-fluorobenzyloxy
14g: R1 = Cl, R2 = 3-fluorobenzyloxy
29b: R1 = Cl, R2 = F
14h: R1 = Cl, R2 = F
29c: R1 = Br, R2= H
14i: R1 = Br, R2= H
marketed drug lapatinib, a dual EGFR/ErbB-2 inhibitor, was
used as a positive control for the assay. The biological results
are shown in Table 1.
Compounds 14h (R1 ¼ Cl, R2 ¼ F) and 14i (R1 ¼ Br, R2 ¼ H)
with the 3-cyanoquinoline scaffold could highly selectively
inhibit the growth of the MDA-MB-468 and SK-BR-3 cell
lines. Compounds 14a and 14g with the same 4-amino
group, 4-(3-chloro-4-(3-fluorobenzyloxy))phenylamino group,
showed completely different selectivity, which is also due
to their different scaffolds. Compound 14a with the quinazo-
line scaffold showed high selectivity against the SK-BR-3
cell line (cell lines, IC50: MDA-MB-468, 18.74 mM; SK-BR-3,
5.46 mM; HCT116, 56.64 mM); however, compound 14g
with the 3-cyanoquinoline scaffold inhibited the growth of
the MDA-MB-468 cell line highly selectively (cell lines,
IC50: MDA-MB-468, 2.07 mM; SK-BR-3, 23.41 mM; HCT116,
16.41 mM).
The results indicated that all tested compounds showed
good activities with IC50 values in the mM range. Two com-
pounds (14b and 14c) inhibited the growth of all three cell
lines with IC50 < 10 mM. Except for two compounds (14a and
14g), all the compounds are more potent (IC50 < 5 mM) than
the positive control lapatinib against both MDA-MB-468 and
SK-BR-3 cell lines. For the MDA-MB-468 cell line, all com-
pounds are 1–10 times more potent than the positive control
lapatinib. Therefore, it is suggested that this kind of com-
pounds should be EGFR/ErbB-2 dual inhibitors or multi-target
inhibitors.
We designed compounds 14a–14c and 14g–14i in order
to identify a suitable 4-arylamino group of quinazoline
and 3-cyanoquinoline, as well as to compare the effects of
the two kinds of scaffolds, quinazoline and 3-cyanoquinoline,
on the activities. Three kinds of 4-arylamino groups were
selected from the known EGFR inhibitors, i.e., gefitinib (1),
lapatinib (3), and EKB-569 (4). Interestingly, the different scaf-
folds have obvious effects on the selectivity. Compounds 14b
(R1 ¼ Cl, R2 ¼ F) and 14c (R1 ¼ Br, R2 ¼ H) with the quinazo-
line scaffold have lower selectivity for the three cell lines.
The compounds 14a and 14d–14f contained different ester
moieties (R3) that were selected based on our previous
research results on arylmethylaminocarbodithiomates as
anticancer agents [20, 21]. Compared with lapatinib, all of
them showed equal or better activity and compound 14d
(R3 ¼ NCCH2CH2-) was found to be the most potent EGFR/
ErbB2 dual inhibitor (SK-BR-3, IC50 ¼ 2.62 mM; MDA-MB-468,
IC50 ¼ 2.71 mM) among them. Thus, the ester moiety in the
dithiocarbamate is crucial for the improvement of selectivity
and activity.
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48
X. Zhang et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 44–52
Table 1. Inhibitory effects of compounds 14a–14i on the growth of tumor cell lines.
R2
R1
S
HN
R3
S
N
H
X
R4
N
14
Compd.
X
R1
R2
R3
R4
Tumor cell IC50 (mM)a
MDA-MB-468b
SK-BR-3b
HCT116b
O
O
14a
14b
14c
N
N
N
Cl
Cl
Br
H
H
H
18.74
5.46
56.64
O
F
O
O
F
5.84
3.68
3.13
3.04
8.83
5.47
O
O
H
14d
14e
14f
N
N
N
Cl
Cl
Cl
H
H
H
2.71
4.28
4.67
2.62
3.35
3.68
25.48
17.72
11.60
O
O
O
N
C
F
F
F
H
3COOC
O
S
O
O
O
14g
14h
14i
C-CN
C-CN
C-CN
Cl
Cl
Br
OMe
OMe
OMe
2.07
3.01
23.41
2.50
16.41
25.81
O
F
O
O
F
O
O
H
4.69
3.27
4.34
35.45
42.36
Lapatinib
23.46
a
Dose-response curves were determined at five concentrations. The IC50 values are the concentrations in micromolar needed to
inhibit cell growth by 50% as determined from these curves.
b
Cell line MDA-MB-468 (breast carcinoma) overexpresses EGFR; cell line SK-BR-3 (breast carcinoma) overexpresses ErbB-2; HCT-116
(colon carcinoma) is believed not to express EGFR or ErbB-2 to a significant extent.
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Arch. Pharm. Chem. Life Sci. 2013, 346, 44–52
Dithiocarbamic Acid Esters as EGFR Inhibitors
49
CCl4 (10 mL) was refluxed for 0.5 h. The reaction mixture was
cooled to room temperature and filtered. The filtrate was concen-
trated and the residue was purified by column chromatography
(ethyl acetate/petroleum ¼ 1:15, v/v) to give product 18 as a
Conclusion
In summary, two series of novel dithiocarbamate esters, 4-
anilinoquinazoline-6-ylmethylcarbamodithioic acid esters
and 3-cyano-4-anilinoquinoline-6-ylmethylcarbamodithioic
acid esters, were designed and synthesized. The newly synthe-
sized compounds were evaluated for their activities against
three kinds of human cancer cell lines (MDA-MB-468, SK-BR-3
and HCT116). Most of the compounds are equally or more
potent than the positive control lapatinib. Three compounds
(14d, 14h and 14i) were identified as dual inhibitors of EGFR
and ErbB-2 kinases and two compounds (14b and 14c) were
identified as multi-target kinase inhibitors, and they are very
worthy of further study. Installation of the dithiocarbamic
acid ester group at the 6-position of 4-anilinoquinazolines or
3-cyano-4-anilinoquinolines improves the inhibitory activity.
Different dithiocarbamic acid ester groups significantly affect
the activities. Our results thus constitute a promising new
approach for the preparation of potent tyrosine kinase
inhibitors with dual or multiple targets.
1
white solid (0.60 g, 45%). mp: 118–1208C; MS (EI) 258.1. H NMR
(300 MHz, DMSO-d6): d ¼ 4.69 (s, 2H), 8.01 (d, J ¼ 8.7 Hz, 2.1 Hz,
1H), 8.09 (d, J ¼ 8.4 Hz, 1H), 8.26 (d, J ¼ 1.5 Hz, 1H), 9.07 (s, 1H).
2-((4-Chloroquinazolin-6-yl)methyl)isoindoline-1,3-dione
(19)
A mixture of 18 (1.03 g, 4 mmol) and potassium phthalimide
(0.74 g, 4 mmol) in acetone (20 mL) was refluxed for 1 h. The
solvent was removed and the residue was purified by column
chromatography (ethyl acetate/petroleum ¼ 1:1, v/v) to give prod-
uct 19 as a white solid (1.20 g, 92%). mp: 212–2148C; MS (EI) 323.3.
1H NMR (300 MHz, DMSO-d6): d ¼ 5.09 (s, 2H), 7.74–7.77 (m, 2H),
7.88–7.91 (m, 2H), 8.06 (s, 2H), 8.34 (s, 1H), 9.04 (s, 1H).
General procedure for the synthesis of the compounds 20
A mixture of 19 (1 mmol) and aniline (1 mmol) in isopropanol
(2 mL) was refluxed for 3 h. After allowing the reaction mixture
to cool to room temperature, the precipitate was collected,
washed with isopropanol and dried to provide the products 20.
2-((4-(3-Chloro-4-(3-fluorobenzyloxy)phenylamino)-
Experimental
quinazolin-6-yl)methyl)isoindoline-1,3-dione (20a)
Yield 77%; mp: 259–2628C; MS (EI) 538.4. 1H NMR (300 MHz,
DMSO-d6): d ¼ 5.01 (s, 2H), 5.30 (s, 2H), 7.17–7.22 (m, 1H),
7.30–7.35 (m, 3H), 7.44–7.57 (m, 2H), 7.82 (d, J ¼ 5.7 Hz, 1H),
7.87–7.97 (m, 5H), 8.07–8.10 (d, J ¼ 8.7 Hz, 1H), 8.64 (s, 1H), 8.90
(s, 1H), 11.49 (br, 1H).
Chemistry
All reagents and solvents were from commercial sources. Melting
points were determined on an X4 microscope. 1H NMR and
13C NMR spectra were recorded on JEOL AL 300 (300 MHz) and
Bruker AVANCEIII 400 (400 MHz) instruments. Elemental
analyses were performed on a Vario EL III (Germany) instrument.
High resolution mass spectra were recorded on a Bruker Apex IV
FTMS mass spectrometer.
2-((4-(3-Chloro-4-fluorophenylamino)quinazolin-6-
yl)methyl)isoindoline-1,3-dione (20b)
Yield 81%; mp: 267–2688C; MS (EI) 432.4. 1H NMR (300 MHz,
DMSO-d6): d ¼ 4.98 (s, 2H), 7.45 (t, J ¼ 9.0 Hz, 1H), 7.74–7.95
(m, 7H), 8.13 (d, J ¼ 6.0 Hz, 1H), 8.44 (s, 1H), 8.61 (s, 1H), 9.98
(br, 1H).
6-Methylquinazolin-4-ol (16)
A mixture of 2-amino-5-methylbenzoic acid 15 (7.20 g, 48 mmol)
and formamide (7.6 mL) was refluxed for 4 h. After cooling the
solution to room temperature, water (30 mL) was added. The
precipitate formed was isolated, washed with water and dried to
provide the product 16 as a white solid (5.50 g, 77%). mp: 266–
2678C, lit. mp [29]: 260–2618C; MS (EI) 160.3. 1H NMR (300 MHz,
DMSO-d6): d ¼ 2.44 (s, 3H), 7.57 (d, J ¼ 8.4 Hz, 1H), 7.64
(dd, J ¼ 8.25 Hz, 1.2 Hz, 1H), 7.92 (d, J ¼ 0.9 Hz, 1H), 8.03
(s, 1H), 12.17 (br, 1H).
2-((4-(3-Bromophenylamino)quinazolin-6-yl)methyl)-
isoindoline-1,3-dione (20c)
Yield 92%; mp: 236–2378C; MS (EI) 460.4. 1H NMR (300 MHz,
DMSO-d6): d ¼ 45.02 (s, 2H), 7.43–7.56 (m, 2H), 7.68 (d, J ¼ 8.1 Hz,
1H), 7.87–7.98 (m, 6H), 8.10 (d, J ¼ 8.7 Hz, 1H), 8.70 (s, 1H), 8.96
(s, 1H), 11.57 (br, 1H).
4-Chloro-6-methylquinazoline (17)
General procedure for the synthesis of the compounds 21
To a solution of 20 in methanol (2 mL), a mixture of methyl-
amine (2 mL) and methanol (8 mL) was added and the resulting
mixture was stirred at room temperature overnight. The
solvent was removed and the residue was dissolved in 3 mol/L
HCl (5 mL). The precipitate formed was dissolved in water
and the mixture was extracted with EtOAc (2 ꢀ 15 mL). The
aqueous phase was neutralized to pH ¼ 10 with 10 mol/L
sodium hydroxide solution and extracted with EtOAc
(3 ꢀ 15 mL). The combined organic phase was washed with brine
(2 ꢀ 15 mL), dried over Na2SO4 and the solvent was removed
to give the products 21, which were used directly without
purification.
A solution of 16 (3.12 g, 21 mmol), SOCl2 (52 mL) in DMF (1 mL)
was refluxed for 6 h. Excess SOCl2 was removed under reduced
pressure and the residue was purified by column chromatog-
raphy (ethyl acetate/petroleum ¼ 1:3, v/v) to give the product 17
as a yellow solid (1.36 g, 36%). mp: 107–1088C, lit. mp [30]: 105–
1068C; MS (EI) 178.1. 1H NMR (300 MHz, DMSO-d6): d ¼ 2.62
(s, 3H), 7.81 (dd, J ¼ 8.5 Hz, 1.5 Hz, 1H), 7.98 (d, J ¼ 8.7 Hz,
1H), 8.04 (s, 1H), 8.99 (s, 1H).
6-(Bromomethyl)-4-chloroquinazoline (18)
A mixture of 17 (0.89 g, 5 mmol), N-bromosuccinimide (NBS)
(0.89 g, 5 mmol) and a catalytic amount of benzoyl peroxide in
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X. Zhang et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 44–52
7.12–7.78 (m, 3H), 8.03 (s, 1H), 8.45 (s, 1H), 8.58 (s, 1H), 9.84
(br, 1H), 10.59 (br, 1H). Anal. calcd. for C27H24ClFN4O3S2:
C, 56.78; H, 4.24; N, 9.81. Found: C, 56.85; H, 4.255; N, 9.757.
General procedure for the synthesis of the compounds
14a–14f
A mixture of 21 (1 mmol), Et3N (2 mmol) and DMF (2 mL) was
stirred for 15 min and CS2 (4 mmol) was added dropwise. After
stirring for 0.5 h, halohydrocarbon was added. The agitation was
continued until TLC showed that the reaction was completed,
then 15 mL water was added to the mixture. The mixture was
extracted with EtOAc (3 ꢀ 15 mL). The combined organic layer
was washed with water (2 ꢀ 15 mL), dried over anhydrous Na2SO4
and concentrated in vacuum. The crude residue was purified by
column chromatography (ethyl acetate/petroleum ¼ 3:2, v/v) to
afford the products 14a–14f.
2-(Benzylsulfonyl)ethyl(4-(3-chloro-4-(3-
fluorobenzyloxy)phenylamino)quinazolin-6-yl)-
methylcarbamodithioate (14f)
Yield 24%; mp: 168–1708C; 1H NMR (400 MHz, DMSO-d6):
d ¼ 3.40–3.44 (m, 2H), 3.57–3.61 (dt, J ¼ 8.4, 2.4 Hz, 2H), 4.57
(s, 2H), 5.00–5.01 (d, J ¼ 5.2 Hz, 2H), 5.26 (s, 2H), 7.16–7.21
(m, 1H), 7.29–7.35 (m, 3H), 7.38–7.50 (m, 6H), 7.73 (dd, J ¼ 8.8,
2.8 Hz, 1H), 7.78 (s, 1H), 8.02 (d, J ¼ 2.8 Hz, 1H), 8.46 (s, 1H), 8.59
(s, 1H), 9.85 (br, 1H), 10.70 (br, 1H). Anal. calcd. for C32H28ClFN4O3S3:
C, 57.60; H, 4.23; N, 8.40. Found: C, 57.15; H, 4.23; N, 8.38.
2-(1,3-Dioxolan-2-yl)ethyl(4-(3-chloro-4-(3-
fluorobenzyloxy)phenylamino)quinazolin-6-yl)methyl-
Ethyl 2-cyano-3-(3-methoxy-4-methylphenylamino)-
acrylate (23)
carbamodithioate (14a)
Yield 35%; mp: 158–1608C; 1H NMR (300 MHz, DMSO-d6):
d ¼ 1.95–2.04 (m, 2H), 3.31 (t, J ¼ 7.5 Hz, 2H), 3.80–3.97
(m, 4H), 4.92 (t, J ¼ 7.5 Hz, 1H), 5.05 (d, J ¼ 5.1 Hz, 2H), 5.31
(s, 2H), 7.20–7.39 (m, 4H), 7.48–7.56 (m, 1H), 7.77–7.82 (m, 3H),
8.07 (d, J ¼ 2.1 Hz, 1H), 8.50 (s, 1H), 8.63 (s, 1H), 9.88 (br, 1H),
10.57 (br, 1H). Anal. calcd. for C28H26ClFN4O3S2: C, 57.48; H, 4.48;
N, 9.58. Found: C, 57.32; H, 4.75; N, 9.43.
A solution of 3-methoxy-4-methyl aniline 22 (10.96 g, 80 mmol)
and ethyl(ethoxymethylene)cyanoacetate (13.54 g, 80 mmol) in
toluene (32 mL) was refluxed for 5 h. After allowing the solution
to cool to room temperature, the precipitate was isolated,
washed with ether (15 mL) and dried to afford the product 23
as a yellow solid (18.6 g, 94%). mp: 152–1568C, lit. mp [31]: 1248C;
MS (EI) 260.4. 1H NMR (300 MHz, CDCl3): d ¼ 1.37 (t, J ¼ 7.2 Hz,
3H), 2.19 (s, 3H), 3.85 (s, 3H), 4.26–4.33 (m, 1H), 6.51 (d, J ¼ 1.8 Hz,
1H), 6.60 (dd, J ¼ 7.8, 2.1 Hz, 1H), 7.12 (d, J ¼ 8.1 Hz, 1H), 7.83
(d, J ¼ 13.5 Hz, 1H), 10.72 (br, 1H).
2-(1,3-Dioxolan-2-yl)ethyl(4-(3-chloro-4-fluorophenylamino)-
quinazolin-6-yl)methylcarbamodithioate (14b)
Yield 40%; mp: 162ꢁ1638C; 1H NMR (300 MHz, DMSO-d6):
d ¼ 1.90–1.97 (m, 2H), 3.26 (t, J ¼ 7.5 Hz, 2H), 3.75–3.92
(m, 4H), 4.88 (t, J ¼ 7.5 Hz, 1H), 5.01 (d, J ¼ 5.4 Hz, 2H), 7.47
(t, J ¼ 9.0 Hz, 1H), 7.80 (s, 3H), 8.19–8.21 (m, 1H), 8.47 (s, 1H),
8.64 (s, 1H), 9.96 (br, 1H), 10.54 (br, 1H). Anal. calcd.
for C21H20ClFN4O2S2: C, 52.66; H, 7.21; N, 11.70. Found:
C, 52.51; H, 4.233; N, 11.36.
4-Hydroxy-7-methoxy-6-methylquinoline-3-carbonitrile (24)
A stirred mixture of 23 (5.00 g, 19 mmol) and Dowtherm A
(200 mL) was refluxed for 24 h. After cooling to room tempera-
ture, the mixture was diluted with cyclohexane (100 mL). The
precipitate was collected, washed with cyclohexane and dried
to give the product 24 as a black solid (2.14 g, 53%). mp: >3008C;
MS (EI) 214.3. 1H NMR (300 MHz, DMSO-d6): d ¼ 2.25 (s, 3H), 3.91
(s, 3H), 6.99 (s, 1H), 7.88 (s, 1H), 8.63 (s, 1H), 12.58 (br, 1H).
2-(1,3-Dioxolan-2-yl)ethyl(4-(3-bromophenylamino)-
quinazolin-6-yl)methylcarbamodithioate (14c)
Yield 36%; mp: 90–928C; 1H NMR (300 MHz, DMSO-d6): d ¼ 1.90–
1.99 (m, 2H), 3.26 (t, J ¼ 7.5 Hz, 2H), 3.75–3.92 (m, 4H), 4.88
(t, J ¼ 7.5 Hz, 1H), 5.02 (d, J ¼ 5.4 Hz, 2H), 7.30–7.40 (m, 2H), 7.80
(s, 2H), 7.93 (t, J ¼ 6.9 Hz, 1H), 8.23 (s, 1H), 8.51 (s, 1H), 8.67 (s, 1H),
9.92 (br, 1H), 10.54 (br, 1H). HRMS: calcd. for C21H21BrN4O2S2 þ H,
505.03621; found (ESI-FTMS, (MþH)þ), 505.03601.
4-Chloro-7-methoxy-6-methylquinoline-3-carbonitrile (25)
A mixture of 24 (0.39 g, 2 mmol), 2 mL of POCl3 and three drops of
DMF was refluxed for 2 h. The reaction mixture was poured into
ice water (30 mL) and neutralized to pH ¼ 10 with 10 mol/L
sodium hydroxide solution. The precipitate was collected and
purified by column chromatography (ethyl acetate/petrole-
um ¼ 1:1, v/v) to give product 25 as a yellow solid (0.37 g, 84%).
mp: 196–1978C; MS (EI) 232.3. 1H NMR (300 MHz, DMSO-d6):
d ¼ 2.42 (s, 3H), 4.04 (s, 3H), 7.53 (s, 1H), 8.08 (s, 1H), 9.06 (s, 1H).
2-Cyanoethyl(4-(3-chloro-4-(3-fluorobenzyloxy)-
phenylamino)quinazolin-6-yl)methylcarbamodithioate (14d)
Yield 45%; mp: 173–1778C; 1H NMR (300 MHz, DMSO-d6):
d ¼ 2.93 (t, J ¼ 6.3 Hz, 2H), 3.50 (t, J ¼ 6.9 Hz, 2H), 5.02
(s, 2H), 5.27 (s, 2H), 7.17–7.49 (m, 5H), 7.72–7.79 (m, 3H), 8.03
(s, 1H), 8.47 (s, 1H), 8.59 (s, 1H), 9.84 (br, 1H), 10.75 (br, 1H). HRMS:
calcd. for C26H21ClFN5OS2 þ H, 538.09328; found (ESI-FTMS,
(MþH)þ), 538.09230.
6-(Bromomethyl)-4-chloro-7-methoxyquinoline-3-
carbonitrile (26)
A mixture of 25 (0.37 g, 1.7 mmol), N-bromosuccinimide (NBS)
(0.36 g, 2 mmol) and a catalytic amount of benzoyl peroxide in
CCl4 (5 mL) was refluxed for 0.5 h. After cooling to room
temperature, the reaction mixture was filtered. The filtrate
was concentrated and the residue was purified by column
chromatography (ethyl acetate/petroleum ¼ 1:4, v/v) to give
product 26 as a white solid (0.43 g, 85%). mp: 178–1828C;
MS (EI) 312.2. 1H NMR (300 MHz, DMSO-d6): d ¼ 4.10 (s, 3H),
4.14 (s, 3H), 4.90 (s, 2H), 7.58 (s, 1H), 7.63 (s, 1H), 7.69 (s, 1H),
8.45 (s, 1H), 8.60 (s, 1H), 9.13 (s, 1H), 9.17 (s, 1H).
Methyl-3-((4-(3-chloro-4-(3-fluorobenzyloxy)-
phenylamino)quinazolin-6-yl)methylcarbamothioylthio)-
propanoate (14e)
Yield 38%; mp: 169–1718C; 1H NMR (300 MHz, DMSO-d6):
d ¼ 2.74 (t, J ¼ 6.3 Hz, 2H), 3.50 (t, J ¼ 6.9 Hz, 2H), 3.61
(s, 3H), 5.00 (d, J ¼ 4.5 Hz, 2H), 5.26 (s, 2H), 7.16–7.52 (m, 5H),
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Arch. Pharm. Chem. Life Sci. 2013, 346, 44–52
Dithiocarbamic Acid Esters as EGFR Inhibitors
51
anhydrous Na2SO4, and the solvent was evaporated. The crude
residue was purified by column chromatography (ethyl acetate/
petroleum ¼ 3:2, v/v) to afford the products 14g–14i.
4-Chloro-6-((1,3-dioxoisoindolin-2-yl)methyl)-7-
methoxyquinoline-3-carbonitrile (27)
A mixture of 26 (0.43 g, 1.38 mmol) and potassium phthalimide
(0.55 g, 3 mmol) in acetone (20 mL) was refluxed for 1 h. The
solvent was removed and the residue was purified by column
chromatography (ethyl acetate/petroleum ¼ 1:2, v/v) to give
product 27 as a white solid (0.23 g, 45%). mp: 240–2448C;
MS (EI) 377.3. 1H NMR (300 MHz, DMSO-d6): d ¼ 4.06 (s, 3H),
4.96 (s, 2H), 7.63 (s, 1H), 7.88–7.97 (m, 5H), 9.11 (s, 1H).
2-(1,3-Dioxolan-2-yl)ethyl(4-(3-chloro-4-(3-
fluorobenzyloxy)phenylamino)-3-cyano-7-methoxy-
quinolin-6-yl)methylcarbamodithioate (14g)
Yield 24%; mp: 174–1778C; 1H NMR (300 MHz, DMSO-d6):
d ¼ 1.86–1.93 (m, 2H), 3.20 (t, J ¼ 7.5 Hz, 2H), 3.72–3.89
(m, 4H), 3.97 (s, 3H), 4.83 (t, J ¼ 4.5 Hz, 3H), 5.25 (s, 2H), 7.17–
7.47 (m, 8H), 8.27 (s, 1H), 8.51 (s, 1H). HRMS: calcd. for
C31H28ClFN4O4S2 þ H, 639.12973; found (ESI-FTMS, (MþH)þ),
639.12921.
General procedure for the synthesis of the compounds 28
A solution of 27 (1 mmol) and aniline (1 mmol) in isopropanol
(2 mL) was refluxed for 3 h. After cooling the reaction mixture to
room temperature, the precipitate was collected, washed with
isopropanol and dried to provide the products 28.
2-(1,3-Dioxolan-2-yl)ethyl(4-(3-chloro-4-
fluorophenylamino)-3-cyano-7-methoxy-quinolin-6-yl)-
4-(3-Chloro-4-(3-fluorobenzyloxy)phenylamino)-6-((1,3-
dioxoisoindolin-2-yl)methyl)-7-methoxyquinoline-3-
methylcarbamodithioate (14h)
Yield 53%; mp: 190–1928C; 1H NMR (300 MHz, DMSO-d6):
d ¼ 1.88–1.90 (m, 2H), 3.21 (t, J ¼ 7.5 Hz, 2H), 3.77–3.99
(m, 9H), 4.86 (s, 3H), 7.25–7.47 (m, 4H), 8.21 (s, 1H), 8.61
(s, 1H), 9.78 (br, 1H), 10.19 (br, 1H). HRMS: calcd. for
C24H22ClFN4O3S2 þ H, 533.08786; found (ESI-FTMS, (MþH)þ),
533.08724.
carbonitrile (28a)
Yield 80%; mp: 278–2828C; MS (EI) 592.5. 1H NMR (300 MHz,
DMSO-d6): d ¼ 4.01 (s, 3H), 4.84 (s, 3H), 5.24 (s, 2H), 7.15–7.46
(m, 8H), 7.83–7.94 (m, 4H), 8.05 (s, 1H), 8.50 (s, 1H), 9.61 (br, 1H).
4-(3-Chloro-4-fluorophenylamino)-6-((1,3-dioxoisoindolin-
2-(1,3-Dioxolan-2-yl)ethyl(4-(3-bromophenylamino)-3-
cyano-7-methoxy-quinolin-6-yl)methylcarbamodithioate
2-yl)methyl)-7-methoxyquinoline-3-carbonitrile (28b)
Yield 83%; mp: >3008C; MS (EI) 486.4. 1H NMR (300 MHz,
DMSO-d6): d ¼ 4.05 (s, 3H), 4.85 (s, 2H), 7.37–7.47 (m, 3H), 7.64
(d, J ¼ 1.8 Hz, 1H), 7.90 (d, J ¼ 8.4 Hz, 4H), 8.15 (s, 1H), 8.83
(s, 1H), 10.44 (br, 1H).
(14i)
Yield 41%; mp: 155–1578C; 1H NMR (300 MHz, DMSO-d6):
d ¼ 1.88–1.99 (m, 2H), 3.21 (t, J ¼ 7.5 Hz, 2H), 3.74–4.05
(m, 7H), 4.85 (t, J ¼ 4.5 Hz, 3H), 7.16–7.41 (m, 5H), 8.22 (s, 1H),
8.66 (s, 1H), 9.80 (br, 1H), 10.19 (br, 1H). Anal. calcd.
for C24H23BrN4O3S2: C, 51.52; H, 4.14; N, 10.01. Found: C,
51.26; H, 4.15; N, 9.94.
4-(3-Bromophenylamino)-6-((1,3-dioxoisoindolin-2-
yl)methyl)-7-methoxyquinoline-3-carbonitrile (28c)
Yield 99%; mp: >3008C; MS (EI) 512.3. 1H NMR (300 MHz,
DMSO-d6): d ¼ 4.05 (s, 3H), 4.85 (s, 2H), 7.31–7.60 (m, 5H),
7.86–7.94 (m, 5H), 8.25 (s, 1H), 8.95 (s, 1H), 10.91 (br, 1H).
Biological assays
The antiproliferative activity of the target compounds was
determined by MTT assay on the following cell lines: MDA-
MB-468, SK-BR-3 and HCT116. All cells used in the research were
prepared at 3.5 ꢀ 103 cells/mL concentration and each 100 mL
cell suspension was seeded onto 96-well microtiter plates for
24 h (378C, 5% CO2). Then various appropriate dilutions of the
tested compounds were added and incubated for 72 h. For
the control group, an equivalent concentration of DMSO (final
concentration 0.5%) was added. MTT (3-[4,5-dimethylthiazol-
2yl]-diphenyl tetrazolium bromide) method was used to
measure the number of surviving cells and the OD value
was recorded at 492/620 nm. The IC50 values were calculated
using Prism Graphpad software for the triplicate experiment.
General procedure for the synthesis of the compounds 29
To a solution of 28 in methanol (2 mL), a mixture of methyl-
amine (2 mL) and methanol (8 mL) was added and the resulting
mixture was stirred at room temperature overnight. The
solvent was removed and the residue was dissolved in 3 mol/L
HCl (5 mL). The precipitate formed was dissolved by water and
extracted with EtOAc (2 ꢀ 15 mL), the aqueous phase was
neutralized to pH ¼ 10 with 10 mol/L sodium hydroxide
solution and extracted with EtOAc (3 ꢀ 15 mL). The combined
organic phase was washed with brine (2 ꢀ 15 mL), dried over
Na2SO4 and the solvent was removed to give the products 29,
which were used directly without purification.
General procedure for the synthesis of the compounds
14g–14i
A mixture of 29 (1 mmol), Et3N (2 mmol) and DMF (2 mL) was
stirred for 15 min and CS2 (4 mmol) was added dropwise. After
stirring for 0.5 h, the corresponding halohydrocarbon was added.
The agitation was continued until TLC showed that the reaction
was completed, then 15 mL water was added to the mixture. The
mixture was extracted with EtOAc (3 ꢀ 15 mL). The combined
organic layer was washed with water (2 ꢀ 15 mL), dried over
The authors thank the National Natural Science Foundation of
China (No. 21172011) and the State Key New Drug Development
Program (contract grant No. 2009ZX09103–131) for financial support.
The authors have declared no conflict of interest.
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52
X. Zhang et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 44–52
[14] S. L. Cao, Y. P. Feng, Y. Y. Jiang, S. Y. Liu, G. Y. Ding, R. T. Li,
Bioorg. Med. Chem. Lett. 2005, 15, 1915–1917.
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www.archpharm.com