Novel 3-benzoyl-2-piperazinylquinoxaline derivatives as potential antitumor agents

Article abstract of DOI:10.1002/jhet.5570430304

A series of new benzoylquinoxaline derivatives (7-26) was synthesized and evaluated for antitumor activity against a panel of 60 human cell lines at the NCI of Bethesda. Among the compounds which have passed the preliminary screening, compound 23 exhibite

Full text of DOI:10.1002/jhet.5570430304

May-Jun 2006
541
Novel 3-Benzoyl-2-piperazinylquinoxaline Derivatives as
Potential Antitumor Agents
a *
a
a
a
Sandra Piras Mario Loriga , Antonio Carta , Giuseppe Paglietti
b
b
M. Paola Costi , Stefania Ferrari
a
Dipartimento Farmaco Chimico Tossicologico, Università degli Studi di Sassari
via Muroni 23/a, 07100 Sassari -Italy
Dipartimento di Scienze Farmaceutiche, Università di Modena e Reggio Emilia,
via Campi 183, 41100, Modena-Italy
b
Received May 3, 2005
A series of new benzoylquinoxaline derivatives (7-26) was synthesized and evaluated for antitumor activ-
ity against a panel of 60 human cell lines at the NCI of Bethesda. Among the compounds which have passed
the preliminary screening, compound 23 exhibited the best profile and growth inhibition activity at 100 - 10
µM. The compounds were then tested towards a folate-dependent enzymes bio-library including
Thymidylate synthases enzymes and human Dihydrofolate reductase at 10 µM. The most of compounds
exhibited a moderate inhibitory activity towards all or some of the enzymes tested with detectable inhibition
constants (K ) values in the range of 0.6-70 µM. Compounds 21, 23, 24 showed K in the range of 10-38 µM
i
i
against both hDHFR and hTS.
J. Heterocyclic Chem., 43, 541 (2006).
Among all the folic acid derivatives that have been widely
modified only two drugs, methotrexate (MTX) and tomudex
(Figure 1), have emerged and are marketed as classical
antifolic agents in anticancer chemotherapy, while among
the non classical antifolates other two compounds, trime-
trexate (TMQ) and piritrexim (PTX) (Figure 2), remain of
interest as reference of antifolic activity but not in use as
anticancer drugs because of their host toxicity [1-4].
According to the above-cited modifications methotrex-
ate and tomudex are closely related to folic acid and main-
tain the glutamate moiety. In contrast trimetrexate and pir-
itrexim contain a more lipophilic side chain reminiscent of
well-known DHFR inhibitors trimethoprim (TMP) and
pyrimethamine used as antimicrobial and antiprotozoal
drugs.
quinoxaline derivatives referring to these classes on the
ground that quinoxaline ring may act as bioisoster of pteri-
dine or quinazoline ring.
From the biological screening at NCI several com-
pounds were endowed with anticancer activity between
100 and 10 µM concentration [5-17] associated sometime
with antifolic activity [11,15].
It was expected that the observed anticancer activity was
due to the inhibition of key enzymes involved in DNA syn-
thesis with folate-dependent activity. Among them
Dihydrofolate reductase (DHFR) and Thymidylate syn-
thase (TS), as part of the thymidylate synthase cycle. Most
of the compounds were tested in free cells assays to iden-
tify the enzyme inhibition profile and some of them
resulted in low micromolar inhibitors of DHFR [11,15].
These results prompted us to produce novel compounds
with the aim to increase the DHFR and/or TS inhibitory
activity and thus the anticancer action.
As examples of modifications reported in the series of
classical and non classical antifolate type compounds,
Paglietti et al. have described more than three hundred

542
S. Piras, M. Loriga, A. Carta, G. Paglietti, M. P. Costi, S. Ferrari
Vol. 43
Figure 1. Folic acid and folate analogs with anticancer activity.
Figure 2. Folate analogs with antibacterial and antiparasitic activity.
In this note we have undertaken the preparation of com-
Diaminobenzene (1) and phenylpyruvic acid (2a), sec-
ondary cyclic amine (6a-e) were all commercially avail-
able. The acids 2b-d were known and have been prepared
according to literature [19,20,21]. Ring closure to quinox-
alinones (3a-d) was obtained in good yields carrying out
the condensation in ethanol at 90°C; compound 3a was
identical with that previously described by Romanenko et
al. [22] while compound 3b was reported by Pailer et al.
[23]. The methylene bridge of 3a-d underwent oxidation
with chromic anhydride in acetic acid to 3-benzoylquinox-
alinones (4a-d) in good yields. Compound 4a was previ-
ously reported by Romanenko et al. [22], while compound
4b was reported by Dahn and Nussbaum [24]. 3-Benzoyl
quinoxalinones (4a-d) were converted into 2-chloro-3-
benzoylquinoxaline derivatives (5a-d) by heating with an
pounds 7-26 (Figure 3; Scheme 1) in order to evaluate the
influence of the substituents, which differ from those usu-
ally employed in the previous papers [5-17]. Quinoxaline
does not bear any substituent in benzene counterpart while
on the pyrazine ring in place of a phenyl group at position
3 we introduced a more flexible 3', 4'-disubstituted benzoyl
4
moiety. At position 2 a N -substituted piperazine repre-
sents a novelty that in other cases led to interesting com-
pounds endowed with anticancer activity [18].
excess of POCl at 120 °C. Of these intermediates, com-
3
pound 5a was known and reported in the reference [22],
while compound 5b appeared in other paper [24] without
spectroscopic data. As we have extensively observed in
other papers [5-17] thermal nucleophilic displacement of
chlorine at position 2 or 3 of quinoxaline ring occurs easily
by the secondary cyclic amine (6a-e) to give the desidered
compounds 7-26 in fair to good yields (Table 1). Structure
elucidation of the proposed structures came from the
whole of both analytical and spectroscopical data (Tables 1
and 2).
Figure 3. Compounds 7-26, synthesized in the present work.
Additionally, it is well known that many folate-related
compounds can show broader or species-specific
inhibitory profiles [11,15], therefore, as a side screening
rapid assay we explored the general antifolic inhibitory
activity of the compounds against the folate-dependent
enzyme bio-library based on TS, including also DHFR
enzyme.
All the compounds were tested against a TS-based bio-
library composed of TS enzymes from different species
such as Enterococcus faecalis, Lactobacillus casei,
Escherichia coli, human Thymidylate synthases and
The preparation of compounds 7-26 was achieved
according to the sequence of reactions of Scheme 1. 1,2-
human dihydrofolate reductase (Table 3). The K values
ranged within two orders of magnitude, 0.6 µM and 79
i

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Novel 3-Benzoyl-2-piperazinylquinoxaline Derivatives as Potential Antitumor Agents
543
gram [25]. Only four of them (13, 17, 23, 24) passed the
preliminary three cell lines panel test and the results of
their activity over 60 human tumor cell-lines are derived
from dose-response curves and are presented in two differ-
ent Tables (4, 5).
µM. Compounds 7, 8, 11, 14, 23 showed K values ranging
i
between 7 and 46 µM towards EfTS (Table 3). The most
interesting is compound 8 that is inactive at 10 µM, against
the human enzymes, thus showing a specificity profile.
Considering EcTS affinity profile, compounds 7, 11-14
and 19, showed some inhibitory activity in the range 20-74
µM. 10 compounds out of 17 showed some inhibitory
activity against hDHFR, where compound 7 was the most
In Table 4 the response parameters (-log GI ), (-log
50
TGI) and (-log LC ) refer to the concentration of the
50
agent in the assay that produced 50% growth inhibition
(GI), total growth inhibition (TGI) and 50% cytotoxicity
(LC), respectively, and are expressed as mean graph mid-
points.
In Table 5, we reported the activities of those com-
pounds, which showed mean growth inhibition on 8 panel
cell lines at µM concentration. From the data of Tables 4
and 5 it is evident that the most active was compound 23
active with K value of 5 µM. The synthesized compounds
i
did not inhibit very well hTS i.e. only 5 out of 17 showed
some inhibitory activity and well above 20 µM. Due to sol-
ubility problems, compounds 10, 25 and 26 couldn't be
tested at 10 µM. In general we can consider that these
compounds didn't show high affinity towards pathogenic
enzyme TS, thus excluding LcTS as model enzyme, being
compound 7 the most active one with a K of 5µM against
with GI =15.1 µM and was selective against the colon
i
50
hDHFR.
panel cell line (6.9 µM) and significantly active at 10 µM
Compounds 7-26 of Scheme 1 were submitted for in
vitro anticancer evaluation at National Cancer Institute
(Bethesda-USA) according to a well known screening pro-
over the most cell lines. Unfortunately, results show that
this compound is also the most cytotoxic with LC =72.5
50
µM. Compound 13 was less active than 23 but exhibited

544
S. Piras, M. Loriga, A. Carta, G. Paglietti, M. P. Costi, S. Ferrari
Vol. 43
almost the same activity on Leukemia, melanoma, renal
cancer cell lines. Compound 24 exhibited growth inhibi-
tion only on breast cancer cell lines. Comparing the tumor
growth inhibition and the enzyme activity inhibitory pro-
file for the four compounds evaluated in vitro, 23 and 24
showed the best enzyme inhibition profile against human
enzymes, hTS and hDHFR. Moreover, compound 23
exhibited significant antifolate activity against bacterial
EfTS, LcTS. Compound 13 showed a moderate enzyme
cancer activity but was inactive against all the enzymes,
thus it is not clear which inhibition mechanism is expected
in this case.
In summary a series of new benzoylquinoxaline deriva-
tives (7-26), structurally related to the nonclassical antifo-
lates trimetrexate and piritrexim, in which the 5,8-dideaza-
or 5-deaza-pteridine moiety was replaced by a quinoxaline
ring, was synthesized. Evaluation of the data from both
enzymatic and anticancer screening allow us to conclude
that the observed anticancer activity can be due to an enzy-
matic inhibitory effect. In particular compounds 23 and 24
inhibition activity towards hTS (Ki of 42 µM) and a K of
i
0.60 µM against LcTS. Compound 17 showed some anti-

May-Jun 2006
Novel 3-Benzoyl-2-piperazinylquinoxaline Derivatives as Potential Antitumor Agents
545

546
S. Piras, M. Loriga, A. Carta, G. Paglietti, M. P. Costi, S. Ferrari
Vol. 43
Table 3
qualitative and were recorded in nm in ethanol solution with a
Perkin-Elmer Lambda 5 spectrophotomer. IR spectra (Nujol
Ki Values at 10µM Concentration of Compounds 7-26
1
mulls) were recorded with Perkin- Elmer 781 instrument.
H
Compd
EfTS
LcTS
EcTS
hDHFR hTS
NMR spectra were recorded at 200 MHz with a Varian XL-200
instrument using TMS as internal standard. Elemental analyses
were performed at Laboratorio di Microanalisi, Dipartimento di
Chimica, University of Sassari. The analytical results for C, H,
and N were within 0,4% of the theoretical values.
7
8
9
12
15
33
37
70
33
1.6
74
5
>190
>190
>190
>190
29
>190
>190
59
20
32
>190
>190
29
>190
46
>190
>190
7
>190
>190
>190
>190
>190
>190
>190
>190
8
11
12
13
14
15
16
17
18
19
20
21
22
23
24
16
General Procedure for Preparation of the 3-(3,4-R-
benzyl)quinoxalin-2-ones 3a-d.
0.6
14
>190
18
>190
12
>190
79
38
42
32
>190
>190
>190
>190
>190
>190
>190
27
A mixture of equimolar amounts (9.24 mmol) of 1,2-
diaminobenzene (1) and the appropriate phenylpiruvic acid (2a-
d) in ethanol (38 ml) was refluxed for 2 h. After cooling at 4 °C
the crude product formed was collected to give the pure sub-
stances after recrystallization from ethanol.
Compound 3-benzylquinoxalin-2-one (3a) was obtained as
described [22], in 64% yield, mp 197-199 °C (lit.[22]) 194-
197°C).
>190
>190
>190
>190
>190
>190
53
>190
10
>190
>190
>190
>190
>190
62
>190
>190
>190
>190
>190
>190
38
>190
10
>190
28
>190
38
20
Compound 3-(4-methoxybenzyl)quinoxalin-2-one (3b).
This compound was obtained in 61% yield, mp 198-199 °C
(lit. [22] mp 198-199°C). Its H-NMR is now described for the
Table 4
-logGI , -logTGI, -logLC mean graph midpoints (MG-MID)
1
a
50
50
first time :(CDCl ) δ: 12.65 (s, 1H, NH), 7.82 (dd, 1H, H8, J=8.2
3
of in vitro inhibitory activity test for compounds 13, 17, 23, 24
and 2.8), 7.58-7.20 (m, 3H, H-5,6,7), 7.40 (d, 2H, H-2',6', J=8.6),
b
against human tumor cell lines .
6.83(d, 2H, H-3',5', J=8.6), 4.22 (s, 2H, CH ), 3.75 (s, 3H,
2
OCH ).
3
Compd
-logGI =µM
-logTGI
-logLC =µM
50
50
3-(4-chlorobenzyl)quinoxalin-2-one (3c).
13
17
23
24
4.48 = 33.1
4.35 = 44.7
4.82 = 15.1
4.01 = 97.7
4.06
4.02
4.37
4.00
4.00 = 100
4.00 = 100
4.14 = 72.5
4.00 = 100
This compound was obtained in 66 % yield, mp 226-227 °C.
1
IR (nujol): 1630, 1580 cm- . UV (EtOH): 332, 282, 221, 202 nm.
1
H-NMR (CDCl /DMSO-d ) δ: 12.01 (s, 1H, NH), 7.75 (d, 1H,
3
6
H-8, J=8.2), 7.43-7.35 (m, 3H, arom), 7.32-7.20 (m, 4H, arom),
a
MG-MID, mean graph midpoints; the average sensitivity of all cell
4.20 (s, 2H, CH ).
2
b
lines towards the test agent; from NCI.
Anal. Calcd. for C H ClN O (270.72) C, 66.55; H, 4.10; N,
15 11
2
10.35. Found: C, 66.60; H, 4.20; N, 10.44.
Table 5
3-(3,4-dimethoxybenzyl)quinoxalin-2-one (3d).
This compound was obtained in 70% yield, mp193-197 °C. IR
Mean growth-inhibition (GI ) values in µM of
50
compounds 13, 17, 23, and 24.
1
(nujol) : 3170, 1640, 1620, 1590 cm- . UV (EtOH) : 332, 281,
Panel/Cell Line
13
17
23
24
1
228, 204 nm. H-NMR (CDCl /DMSO-d ) δ: 12.18 (s, 1H, NH),
3
6
GI ( µM)
50
7.85 (d, 1H, H-8, J=7.8), 7.60-7.30 (m, 3H, arom), 7.28-7.09 (m,
Leukemia
26.0
29.0
34.0
39.0
24.0
69.1
24.0
87.0
35.0
40.7
44.0
40.7
64.5
30.2
72.4
40.0
72.4
44.0
11.2
15.1
6.9
10.9
24.0
16.9
20.9
31.2
17.8
>100
>100
>100
>100
>100
>100
>100
>100
39.0
2H, arom), 6.81 (m, 1H, arom), 4.23 (s, 2H, CH ), 3,87 (s, 3H,
Non small Cell Lung Cancer
Colon Cancer
CNS Cancer
2
OCH ), 3.83 (s, 3H, OCH ).
3
3
Anal. Calcd. for C
H N O (296.32) C, 68.91; H, 5.44; N,
17 16 2 3
Melanoma
9.45. Found: C, 69.15; H, 5.40; N, 9, 27.
Ovarian Cancer
Renal Cancer
Prostate Cancer
Breast Cancer
General procedure for preparation of 3-(3,4-R-benzoyl) quinox-
alin-2-ones (4 a-d)
To a mixture of the suitable 3-benzylquinoxalin-2-ones (3a-d)
(4.00 mmol) in glacial acetic acid (30 ml), a 10% aqueous solu-
tion of chromic anhydride (5.3 ml) was added and then heated
under stirring at 50 °C for 2 h. In the end water (22 ml) was added
and the resulting mixture cooled at –20 °C overnight. The result-
ing precipitate was collected by filtration and washed with water
to give white-yellow products, which displayed a single spot on
tlc. Purification was accomplished on recrystallization from
ethanol.
showed the best enzyme inhibition profile against human
enzymes, hTS and hDHFR with a K in the range of 10-38
i
µM.
EXPERIMENTAL
Compound 3-benzoylquinoxalin-2-one (4a) was obtained as
described [22] in 68% yield: mp 258-260°C (lit [22] m.p.255-258
°C).
Melting Points are uncorrected and were recorded on a Köfler
or an electrothermal melting point apparatus. UV spectra are

May-Jun 2006
Novel 3-Benzoyl-2-piperazinylquinoxaline Derivatives as Potential Antitumor Agents
547
Compound 3-(4-methoxybenzoyl)quinoxalin-2-one (4b)
Anal. Calcd. for C H ClN O (328.75) C, 62.11; H, 3.99; N,
17 13 2 3
8.52. Found: C, 61.89; H, 4.24; N, 8.42.
This compound was obtained as described [24] in 73% yield;
mp 244-246°C (lit [24] mp 244-246 °C). IR (nujol): 1680, 1650,
1610 cm . UV (EtOH): 295, 296, 203 nm. H-NMR
2
General Procedure for Preparation of the 2-(4-R -piperazinyl)-3-
-1
1
1
(3-R, 4-R -benzoyl)quinoxalines (7-26).
(CDCl /DMSO-d ) δ: 12.65 (s, 1H, NH), 7.98 (d, 2H, H-8,
3
6
A mixture of one mole equivalent of chloroquinoxaline (8.4
mmol) (5a-d) and 3 mole equivalent (25.2 mmol) of the appro-
priate substituted piperazine (6a-e) was stirred under heating at
100 °C for 2.5 h. In all cases crude gummy products were formed
and purified by recrystallization from ethanol (8, 9, 19, 24), or
flash chromatography over silica gel eluting with chloroform
(14); a mixture of chloroform/methanol in 98:2 ratio (7, 12, 13),
in 95:5 ratio (17, 22, 23); a mixture petrol-ether/ethyl acetate in
85:15 ratio (15, 16), in 8:2 ratio (11, 20, 21), in 7:3 ratio (10, 25,
26); ethyl acetate (18).
J=8.8), 7.55 (d, 1H, H-5, J=8.6), 7.42-7.24 (m, 2H, H-6,7), 6.96
(d, 2H, H-3',5', J=8.6), 3.90 (s, 3H, OCH ).
3
3-(4-chlorobenzoyl)quinoxalin-2-one (4c).
This compound was obtained in 73% yield, mp: 236-238 °C,
-1
IR (nujol): 3180, 1680, 1630, 1590 cm . UV (EtOH): 258, 228,
1
204 nm. H-NMR (CDCl /DMSO-d ) δ: 7.97 (d, 2H, H-2',6',
3
6
J=8.2), 7.82 (d, 1H, arom., J=8.4), 7.70-7.25 (m, 3H, arom), 7.50
(d, 2H, H-3',5', J=8.2).
Anal. Calcd. for C H ClN O (284.71) C, 63.28; H, 3.19; N,
15
9
2 2
Yields, mp values, analytical data are reported in Table 1 while
spectroscopic data are reported in Table 2.
9.84. Found: C, 63.07; H, 3.54; N, 10.01.
3-(3,4-dimethoxybenzoyl)quinoxalin-2-one (4d).
This compound was obtained in 59% yield, mp: 237-240 °C,
REFERENCES
-1
IR (nujol): 3180, 1660, 1590 cm . UV (EtOH): 285, 229, 204
1
nm. H-NMR (CDCl ) δ: 12.18 (s, 1H, NH), 7.91 (d, 1H, H-8,
3
*
To whom correspondence should be addressed; e-mail
J=8.0), 7.74 (s, 1H, H-2'), 7.56-7.26 (m, 4H, arom), 6.89 (d, 1H,
address:piras@uniss.it
arom, J=8.2), 3.98 (s, 3H, OCH ), 3.96 (s, 3H, OCH ).
3
3
[1] R. L. Kisliuk, The Biochemistry of Folates. Folate
Antagonists as Therapeutic Agents; F. M. Sirotnak, J. J. Burchall, W.
D. Ensminger, and J. A. Montgomery, Eds; Academic Press, New
York, pp 1-68 (1984).
Anal. Calcd. for C
H N O (310.31) C, 65.80; H, 4.55; N,
17 14 2 4
9.03. Found: C, 65,62; H, 4.80; N, 8.96.
General Procedure for Preparation of the 2-Chloro-3-(3,4-R-ben-
[2] E. M. Barman, and L. M. Werbel, J. Med. Chem., 34, 479
(1991).
[3] C. J Allegra, J. A. Kovacs, J. C. Drake, B. A. Chabner, and
H. Masur,. J. Clin. Invest., 79, 478 (1987).
[4] J. A. Kovacs, C. J. Allegra, J. C. Swan, J. E. Parillo, B. A.
Chabner, and H. Masur, Antimicrob. Agents Chemother., 32, 430
(1988).
zoyl) quinoxaline (5a-d).
A mixture of 4 a-d (0.27 g, 9.15 mmol) and an excess of
POCl (2.3 ml, 24.70 mmol) was stirred under heating at 120 °C
3
for 3 h. On cooling, the mixture was taken up with ice and the
obtained solids were collected by filtration and washed with
water to give the crude brown products, which were recrystal-
lized from ethanol.
[5] M. Loriga, M. Fiore, P. Sanna, and G. Paglietti, Farmaco,
2-Chloro-3-benzoylquinoxaline (5a) was obtained as
described [22] in 59% yield; mp 140-141°C, (lit. [22] mp 138-
50, 289 (1995).
[6] M. Loriga, M. Fiore, P. Sanna, and G. Paglietti, Farmaco,
51, 559 (1996).
1
141°C) H-NMR (CDCl ) δ: 8.18-8.10 (m, 2H, arom), 7.95-7.82
3
[7] M. Loriga, S. Piras, P. Sanna, and G. Paglietti, Farmaco,
(m, 3H, arom), 7.72-7.45 (m, 4H, arom).
52, 157 (1997).
2-Chloro-3-(4-methoxybenzoyl)quinoxaline (5b).
[8] M. Loriga, P. Moro, P. Sanna, and G. Paglietti, Farmaco,
52, 531 (1997).
[9] G. Vitale, P. Corona, M. Loriga, and G. Paglietti,
Farmaco, 53, 139 (1998).
[10] P. Corona, G. Vitale, M. Loriga, and G. Paglietti,
Farmaco, 53, 150 (1998).
[11] P. Corona, G. Vitale, M. Loriga, and G. Paglietti, M. P.
Costi, Farmaco, 53, 480 (1998).
This compound was obtained as described [24] in 70% yield;
mp 120-121 °C (lit. [24] mp 114-115 °C) IR (nujol): 1680, 1620,
-1
1600 cm . UV (EtOH): 403, 352, 339, 291, 280, 248, 228 nm.
1
H-NMR (CDCl -DMSO-d ) δ: 8.22 (d, 2H, H-2',6', J=8.2), 7.80
3
6
(d, 1H, H-8, J=8.6), 7.72-7.37 (m, 3H, arom), 7.15 (d, 2H, H-
3',5', J=8.2), 4.00 (s, 3H, OCH ).
3
2-Chloro-3-(4-chlorobenzoyl)quinoxaline (5c).
[12] G. Vitale, P. Corona, M. Loriga, and G. Paglietti,
Farmaco, 53, 594 (1998).
[13] P. Corona, G. Vitale, M. Loriga, and G. Paglietti,
Farmaco, 55, 77 (2000).
[14] S. Piras, M. Loriga, and G. Paglietti, Farmaco, 57, 1
(2002).
[15] M. Loriga, S. Piras, G. Paglietti, M. P. Costi, and A,
Venturelli, Farmaco, 58, 51 (2003).
This compound was obtained in 73% yield, mp: 143-146 °C,
-1
IR (nujol): 1680, 1640, 1580 cm . UV (EtOH): 324, 243, 204
1
nm. H-NMR (CDCl ) δ: 8.20-8.10 (m, 2H, arom), 7.84-7.86 (m,
3
4H, arom), 7.52-7.47 (m, 2H, arom).
Anal. Calcd. for C H Cl N O (303.14) C,59.43; H, 2.66; N,
15
8
2 2
9.24. Found : C,59.40; H, 2.70; N, 9.19.
[16] S. Alleca, P. Corona, M. Loriga, G. Paglietti, R. Loddo, V.
Mascia, B. Busonera, and P. La Colla, Farmaco, 58, 639 (2003).
[17] S. Piras, M. Loriga, and G. Paglietti, Farmaco, 59, 185
(2004).
[18] E. Kumazawa, K. Hirotani, S. C. Burford, K. Kawagoe, T.
Miwa, I. Mitsui, and A. Ejima, Chem. Pharm. Bull., 45, 1471 (1997).
[19] J. E. Audia, D. A. Evrard, G. R. Murdoch, J. J. Droste, J.
2-Chloro-3-(3,4-dimethoxybenzoyl)quinoxaline (5d).
This compound was obtained in 54 % yield, mp: 200-203 °C,
-1
IR (nujol): 1680, 1630, 1610 cm . UV (EtOH): 375, 276, 221,
1
202 nm. H-NMR (CDCl ) δ: 8.16 (d, 1H, J=8.4, H-8), 8.84 (d,
3
1H, H-5, J=7.8), 7.68-7.53 (m, 3H, arom), 7.48-7.18 (m, 2H,
arom), 4.10 (s, 3H, OCH ), 4.04 (s, 3H, OCH ).
3
3

548
S. Piras, M. Loriga, A. Carta, G. Paglietti, M. P. Costi, S. Ferrari
Vol. 43
S. Nissen, K. W. Schenck, P. Fludzinsk, V. L. Lucaites, D. L. Nelson,
and M. L. Cohen, J. Med. Chem., 39, 2773 (1996).
[20] G. Simchen, and G. Siegl, Synthesis, 945 (1989).
[21] J. B. Niedrl, and A. Ziering. J. Am. Chem. Soc., 64, 885
(1942).
Heterocycl. Comp., 138 (1973).
[23] Pailer et al. Monatsh. Chem., 93, 1005, (1962).
[24] H. Danh, and J. Nussbaum, Helv. Chim. Acta, 52, 1661,
(1969).
[25] M. R. Boyd, Principles & Practice of Oncology, Vol 3,
n°10, (1989).
[22] V. D. Romanenko, and S. I. Burmistrow, Chem.