Synthesis, X-ray structure, and pharmacological activity of some 6,6-disubstituted chromeno[4,3-b]- and chromeno-[3,4-c]-quinolines

Article abstract of DOI:10.1002/ardp.200700089

Some chromeno[4,3-b]quinolines 4a-i were obtained from β-chloro carboxyaldehydes 3a-c with different aniline derivatives namely, aniline, 4-fluoroaniline, and 2-aminophenol. Surprisingly, 3a-c reacted with 2-aminothiophenol and afforded the chromeno[3,4-c

Full text of DOI:10.1002/ardp.200700089

396
Arch. Pharm. Chem. Life Sci. 2007, 340, 396–403
Full Paper
Synthesis, X-ray Structure, and Pharmacological Activity of
Some 6,6-Disubstituted Chromeno[4,3-b]- and Chromeno-
[3,4-c]-quinolines
Mohamed I. Hegab1, Abdel-Samee M. Abdel-Fattah2, Nabil M. Yousef1, Hany F. Nour1,
A. M. Mostafa3, and Mohey Ellithey4
1 Photochemistry Department, National Research Centre, Cairo, Egypt
2
Department of Chemistry, Cairo University, Cairo, Egypt
3 Solid State Department, National Research Centre, Cairo, Egypt
4 Pharmacology Department, National Research Centre, Cairo, Egypt
Some chromeno[4,3-b]quinolines 4a–i were obtained from b-chloro carboxyaldehydes 3a–c with
different aniline derivatives namely, aniline, 4-fluoroaniline, and 2-aminophenol. Surprisingly,
3a–c reacted with 2-aminothiophenol and afforded the chromeno[3,4-c]quinoline derivatives
5a–c. Single-crystal X-ray diffraction studies of 4e and 5b provided good support for the estab-
lished structure. Compounds 4b and 5b showed significant anti-inflammatory and ulcerogenic
score activities compared to that of indomethacin.
Keywords: Anti-inflammatory / b-Chloro carboxyaldehyde / Chromeno[4,3-b]quinoline / Chromeno[3,4-c]quinoline / X-
ray structure determination /
Received: February 28, 2007; accepted: May 4, 2007
DOI 10.1002/ardp.200700089
Supporting Information for this article:
Crystallographic data for the structures of compounds 4e and 5b have been deposited at the CCDC as supple-
mentary data, deposition no. CCDC No. 618025 and CCDC No. 618026 copies of the data can be obtained, free
of charges on application to CCDC-12 Union Road, Cambridge CB2 1EZ, UK. E-mail: deposit@ccdc.cam.ac.uk.
boxyaldehyde with fluoroaniline [7]. Acridine derivatives
Introduction
exhibit antitumor [8, 9], fungicidal [10, 11], antiparasitic
[12], antimicrobial [13, 14], anti-inflammatory, and anal-
gesic activities [15–17]. Some of the acridine derivatives
also possess kinase inhibition properties [18]. Some qui-
noline derivatives showed strong activity, as HIV-inte-
grase inhibitors [19–21] and also possessed interesting
antifungal and herbicidal activity [22]. Moreover, benzo-
pyran-4-ones constitute an important class of naturally
occurring substances [23–25] and draw the attention of
many researchers due to their well known properties as
anti-tuberculosis [26] agents. Therefore, it seemed very
interesting to investigate the chemistry of some hin-
dered b-chloro carboxyaldehydes towards some aniline
derivatives, namely aniline, 4-fluoroaniline, 2-aminophe-
nol, and 2-aminothiophenol and to evaluate the pharma-
cological activity of some new products as anti-inflamma-
tory and ulcerogenic score activities.
The Vilsmeier–Haack reaction of active methylene com-
pounds mainly lead to the formation of b-halo carboxyal-
dehyde which constitute a class of compounds that have
served as useful intermediates towards construction of
different heterocyclic compounds [1]. Accordingly, some
of b-chloro carboxyaldehydes were reacted with phenyl-
hydrazine and 2-mercapto acetic acid and its ethyl ester
to give the corresponding pyrazolo and thieno deriv-
atives [2–6]. Some fluorobenzo[c]acridine derivatives
were synthesized from the corresponding b-chloro car-
Correspondence: Mohamed I. Hegab, Photochemistry Department, Na-
tional Research Centre, El-Behoos St., Dokki, Cairo 12622, Egypt.
E-mail: mihegab65@yahoo.com
Fax: +20 20337-0931
i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2007, 340, 396–403
Chromeno[4,3-b]- and Chromeno[3,4-c]Quinolines
397
Table 1. Physicochemical data of the new compounds.
Compd. Mp.
Yield
(%)
Mol. formula
Mol. Wt.
(8C)
2c
3c
4a
4b
4c
4d
4e
4f
4g
4h
4i
5a
5b
5c
7
Colorless oil
Yellow oil
40
55
30
19
57
38
19
18
22
14
14
13
55
43
71
C12H13ClO 208.67
C13H13ClO2 236.68
C18H15NO 261.33
C21H19NO 301.39
C19H17NO 275.35
C18H14FNO 279.32
C21H18FNO 319.38
C19H16FNO 293.34
C18H15NO2 277.33
C21H19NO2 317.36
C19H17NO2 291.35
C18H15NO 261.33
C21H19NO 301.39
C19H17NO 275.35
Yellow/104–106
Yellow/139–140
Yellow /129–130
Yellow/130–131
Yellow/179–180
Yellow/158–159
Yellow/57–58
Yellow/114–115
Yellow/145–146
Yellow/120–121
Yellow/192–193
Brown oil
Scheme 1. Synthesis route of compounds 1–3.
Results and discussion
Chemistry
Herein, we report the reaction of 4-chloro-2,2-disubsti-
tuted chromene-3-carboxyaldehyde with aniline, 4-fluo-
roaniline, 2-aminophenol, and 2-aminothiophenol to get
some new chromenoquinoline derivatives. Chromanone
derivatives 1a–c were reacted with Vilsmeier reagent to
afford the corresponding chloro derivatives 2a–c along
with b-chloro carboxyaldehyde derivatives 3a–c
(Scheme 1; [6]). R,S-4-Chloro-2-ethyl-2-methy(2H)chro-
mene 2c and R,S-4-Chloro-2-ethyl-2-methyl(2H)chromene-
3-carboxyaldehyde 3c have not been described before and
they are established by physical and spectral data
(Tables 1, 2).
Yellow/226–227
C21H20ClNOS 369.88
Ray et al. have reported the reaction of 1-chloro-3,4-
dihydro-2-naphthaldehyde with 2- and 4-fluoroaniline in
ethanolic HCl (catalytic) to get the corresponding aryli-
mine hydrochlorides [7] which were heated at 200-2508C
to give 9-fluoro- and 11-fluoro-3,4-dihydrobenzo[c]acri-
dine, respectively. Therefore, 4-chloro-2,2-disubstitu-
ted(2H)chromene-3-carboxyaldehydes 3a-c, reacted with
aniline in acetic acid under reflux for 3 h, afforded the
corresponding products (6H)chromeno[4,3-b]quinolines
4a–c rather than (6H)chromeno[3,4-c]quinolines 5a–c
(Scheme 1).
The chemical structures of compounds 4a–c were
established by physical and spectral data as well as ele-
mental analyses (Tables 1, 2). The mass spectrum of 4a
shows the prominent ion peak M+ at m/z 261 (20%).
Accordingly, 4-chloro-2,2-disubstituted(2H)chromene-3-
carboxyaldehydes 3a–c reacted with 4-fluoroaniline in
acetic acid under reflux for 3 h and afforded the corre-
sponding products 9-fluoro(6H)chromeno[4,3-b]quino-
lines 4d–f rather than 11-fluoro(6H)chromeno[3,4-c]qui-
nolines 5d-f (Scheme 1). The spectral data (IR, 1H- and 13C-
NMR, and MS) as well as elemental analyses established
the structures of 4d–f. The13C-NMR of 4e is in accordance
with that of 9-fluoro- and 11-fluoro-3,4-dihydrobenz[c]a-
cridine [7] (Table 2). The mass spectrum of 4e, for exam-
Figure 1. Molecular structure of compound 4e; ellipsoids of
thermal vibration are shown with 50% probability.
ple, shows the prominent ion peak at m/z 319 M+ (34%).
Moreover, the single crystal X-ray of 4e gives a good evi-
dence of the formation of the regioisomers 4a–i rather
than 5a–i. The single crystal X-ray determination of 4e is
shown in Fig. 1.
On the other hand, 4-chloro-2,2-disubstituted(2H)chro-
mene-3-carboxyaldehydes 3a–c, reacted with 2-amino-
phenol, afforded the corresponding products 11-hydroxy
(6H)chromeno[4,3-b]quinolines 4g–i (Scheme 1). The
structures of 4g–i were established by spectral data
i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

398
M. I. Hegab et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 396–403
Table 2. IR, 1H-, 13C-NMR, and mass spectra for the new compounds.
Compd.
2c
IR (cm– 1
)
1H- and13C-NMR (d ppm)
MS m/z (%)
2972, 2929,1631, 1605,
1480, 1453, 1249, 752
1.02 (t, J = 7.3 Hz, 3H, CH3CH2), 1.44 (s, 3H, CH3), 1.78
(q, J = 7.3 Hz, 2H, CH3CH2), 5.75 (s, 1H, 3-H), 6.84 (d, J =
8.2 Hz, 1H, ArH), 6.91-6.99 (m, 1H, ArH), 7.18–7.29
(m, 1H, ArH), 7.47 (dd, J = 7.4 Hz, 1.2 Hz, 1H, ArH).
3c
4a
2970, 2932, 1673, 1600, 0.92 (t, J = 7.4 Hz, 3H, CH3CH2), 1.60 (s, 3H, CH3),
1559, 1454, 1293, 756
1.70–1.88 (m, 1H, CH3CHaHb), 2.23-2.41 (m, 1H,
CH3CHaHb), 6.85 (d, J = 8.2 Hz, 1H, ArH), 6.97–7.04
(m, 1H, ArH), 7.21–7.42 (m, 1H, ArH), 7.70 (d, J =
7.8 Hz, 1H, ArH), 10.29 (s, 1H, CHO).
2959, 2925, 1728, 1602, 1.78 (s, 6H, 2 CH3), 6.99 (d, J = 8.1 Hz, 1H, ArH),
261 (M, 20), 245 (M – CH3, 100), 230 (2),
217 (16), 149 (8), 123 (10), 109 (10).
1459, 1263
7.14–7.17 (m, 1H, ArH), 7.35–7.38 (m, 1H, ArH),
7.49–7.51 (m, 1H, ArH), 7.67–7.80 (m, 1H, ArH), 7.92
(s, 1H, ArH), 8.13 (d, J = 8.4 Hz, 1H, ArH), 8.50–8.53
(m, 1H, ArH), 7.78 (d, J = 8.1 Hz, 1H, ArH).
4b
4c
2928, 2855, 1602, 1488, 1.19–2.26 (m, 10H, 5 CH2), 6.96–7.10 (m, 2H, ArH),
301 (M, 26), 300 (M –H, 31), 272 (11),
1457, 1262
7.26–7.44 (m, 2H, ArH), 7.57–7.72 (m, 2H, ArH), 7.86 257 (100), 245 (14), 216 (17), 188 (5).
(s, 1H, ArH), 8.05 (d, J = 8.6 Hz, 1H, ArH), 8.39–8.44
(m, 1H, ArH).
2969, 2937, 1602, 1490, 0.84–0.91 (m, 3H, CH3CH2), 1.68 (s, 3H, CH3), 1.75–
275 (M, 10), 260 (M – CH3, 6), 246 (M –
C2H5, 100), 217 (13), 123 (8).
1457, 1241
1.89 (m, 1H, CHaHbCH3), 1.96-2.14 (m, 1H,
CHaHbCH3), 6.90 (d, J = 8.0 Hz, 1H, ArH), 7.00–7.07
(m, 1H, ArH), 7.17–7.44 (m, 2H, ArH), 7.57–7.78
(m, 2H, ArH), 8.04 (d, J = 8.4 Hz, 1H, ArH), 8.41 (d, J =
7.6 Hz, 1H, ArH), 7.78 (s, 1H, ArH).
4d
4e
2963, 1446, 1261
1.77 (s, 6H, 2 CH3), 6.99 (d, J = 8.1 Hz, 1H, ArH), 7.14 279 (M, 23), 264 (M – CH3, 100), 235 (12),
(t, J = 7.5 Hz, 1H, ArH), 7.35–7.38 (m, 1H, ArH), 7.48– 149 (2).
7.51 (m, 1H, ArH), 7.67–7.76 (m, 1H, ArH), 7.86 (s, 1H,
ArH), 8.09–8.14 (m, 1H, ArH), 7.47 (d, J = 7.8 Hz, 1H,
ArH).
2928, 2858, 1608, 1494, 1.18–1.90 (m, 8H, 4 CH2), 2.21 (d, J = 14.0 Hz, 2H,
1457, 1298, 1262
319 (M, 34), 275 (M – C3H8, 100), 262
(13), 234 (11).
CH2), 6.95–7.09 (m, 2H, ArH), 7.18 (s, 1H, ArH),
7.25–7.42 (m, 2H, ArH), 7.80 (s, 1H, ArH), 7.99–8.06
(m, 1H, ArH), 8.36 (dd, J = 7.8, 1.8 Hz, 1H, ArH)/ 21.41,
25.28, 35.17, 78.43, 110.68 (d, JC-F = 21.75 Hz), 117.87,
119.46 (d, JC-F = 25.50 Hz), 121.95, 123.04, 125.26,
128.38 (d, JC-F = 10.50 Hz), 129.01, 131.59 (d, JC-F
=
9.00 Hz), 131.68, 134.80, 144.60, 147.76, 154.71,
160.23 (d, JC-F = 246.00 Hz).
4f
3047, 2971, 2925, 2876, 0.85-0.90 (m, 3H, CH3CH2), 1.70 (s, 3H, CH3), 1.76–
293 (M, 23), 264 (M – C2H5, 100), 235
(11), 132 (7).
1601, 1498,1460, 1215
1.89 (m, 1H, CHaHbCH3), 2.01–2.11 (m, 1H,
CHaHbCH3), 7.00 (d, J = 8.1 Hz, 1H, ArH), 7.12 (t, J =
7.4 Hz, 1H, ArH), 7.38–7.43 (m, 1H, ArH), 7.63–7.78
(m, 2H, ArH), 8.09 (d, J = 8.1 Hz, 1H, ArH), 8.30–8.34
(m, 2H, ArH).
4g
4h
3745, 2963, 2923, 1492, 1.78 (s, 6H, 2 CH3), 7.00 (d, J = 8.1 Hz, 1H, ArH),
1460, 1252
277 (M, 37), 262 (M – CH3, 100), 233 (7),
7.14–7.18 (m, 2H, ArH), 7.30 (d, J = 8.4 Hz, 1H, ArH), 117 (9).
7.36–7.40 (m, 2H, ArH), 7.93 (s, 1H, ArH), 8.2 (bs, 1H,
OH exchangeable with D2O), 8.43 (d, J = 7.8 Hz, 1H,
ArH).
3445, 2924, 2854, 2364, 0.89-1.81 (m, 10H, 5 CH2), 6.99–7.05 (m, 1H, ArH),
1629, 1543, 1485, 1454, 7.12–7.18 (m, 1H, ArH), 7.38–7.47 (m, 3H, ArH),
273 (M – C3H8, 70), 154 (56), 96 (40), 55
(100).
1254
7.60–7.63 (m, 1H, ArH), 7.72–7.76 (m, 1H, ArH),
8.04 (dd, J = 7.8, 1.2 Hz, 1H, ArH), 11.42 (bs, 1H, OH
exchangeable with D2O).
i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2007, 340, 396–403
Table 2. Continued
Chromeno[4,3-b]- and Chromeno[3,4-c]Quinolines
399
Compd.
4i
IR (cm– 1
)
1H- and13C-NMR (d ppm)
MS m/z (%)
3368, 2971, 2925, 2876, 0.86 (t, J = 7.4 Hz, 3H, CH3CH2), 1.70 (s, 3H, CH3),
1602, 1491,1463
291 (M, 21), 262 (M – C2H5, 100), 233 (8),
204 (5), 131 (4).
1.82–1.84 (m, 1H, CHaHbCH3), 2.06–2.15 (m, 1H,
CHaHbCH3), 6.96 (d, J = 8.5 Hz, 1H, ArH), 7.01–7.15
(m, 2H, ArH), 7.37–7.39 (m, 3H, ArH), 8.20 (s, 1H, ArH),
8.73 (d, J = 8.1 Hz, 1H, ArH), 9.63 (bs, 1H, OH, ex-
changeable with D2O).
5a
2924, 1561, 1454, 1252
1.73 (s, 6H, 2 CH3), 7.11–7.19 (m, 2H, ArH), 7.36–
7.42 (m, 1H, ArH), 7.57–7.62 (m, 1H, ArH), 7.69–
7.75 (m, 1H, ArH), 8.04 (dd, J = 7.8 Hz, 1.5 Hz, 1H,
ArH), 8.13–8.16 (m, 1H, ArH), 8.53–8.56 (m, 1H, ArH),
8.33 (s, 1H, CH=N).
261 (M, 14), 246 (M –CH3, 100), 217(7),
189 (5).
5b
5c
2930, 2854, 1558, 1501, 1.62–1.99 (m, 10H, 5 CH2), 7.20–7.25 (m, 2H, ArH),
301 (M, 30), 300 (M –H, 4), 272 (10), 258
1444, 1245
7.43-7.46 (m, 1H, ArH), 7.68—7.71 (m, 1H, ArH), 7.78 (100), 245 (14), 216 (6), 189 (10).
(dd, J = 8.4, 1.5 Hz, 1H, ArH), 8.05–8.08 (m, 2H, ArH),
8.51 (d, J = 8.7 Hz, 1H, ArH), 8.97 (s, 1H, CH=N).
2971, 2930, 1604, 1483, 0.83–0.88 (m, 3H, CH3CH2), 1.66 (s, 3H, CH3), 1.80–
275 (M, 6), 246 (M – C2H5, 100), 217 (6),
123 (4).
1454, 1253
1.88 (m, 1H, CHaHbCH3), 1.97–2.03 (m, 1H,
CHaHbCH3), 7.11–7.22 (m, 2H, ArH), 7.40–7.46 (m,
1H, ArH), 7.67 (t, J = 7.8 Hz, 1H, ArH), 7.75–7.80 (m,
1H, ArH), 8.04–8.09 (m, 2H, ArH), 8.51 (d, J = 8.4 Hz,
1H, ArH), 8.89 (s, 1H, CH=N).
7
2925, 2644, 1591, 1548, 1.61–1.85 (m, 8H, 4 CH2), 2.50 (d, J = 12.0 Hz, 2H,
369 (M, 56), 333 (M – HCl, 85), 299 (56),
276 (42), 258 (100), 136 (57), 109 (30), 91
(18).
1442, 1286, 756
CH2), 4.71 (s, 1H, SH, exchangeable with D2O),
6.92–7.32 (m, 6H, ArH), 7.60–7.65 (m, 2H, ArH),
8.82 (s, 1H, CH=N).
(Table 2). The IR spectrum of 4g shows OH at v 3745 cm– 1
.
The1H-NMR spectrum of 4g shows OH at d 8.2 as a singlet,
which is exchangeable with D2O. The mass spectrum of
4g shows the prominent ion peak M+ at m/z 277 (37%).
Simay and Takꢀcs have reported the synthesis of the
fused heterocycles pyrazolo[49,39:5,6]pyrido[2,3-b][1,5]ben-
zothiazepine and pyrazolo[49,39:5,6]pyrido[2,3-b][1,5]ben-
zoxazepine [27]. In the present work, surprisingly, 4-
chloro-2,2-disubstituted(2H)chromene-3-carboxyalde-
hydes 3a–c reacted with 2-aminothiophenol in acetic
acid under reflux for 3 h and afforded (6H)chromeno[3,4-
c]quinolines 5a–c through the corresponding 1,4-thiaze-
pine 6 after extrusion of sulfur (Scheme 1). The structures
of 5a–c were established by physical and spectral data
1
(IR, H-NMR, and MS) (Tables 1, 2) as well as elemental
analyses. So, the IR spectrum of 5b shows HC=N at v
1558 cm– 1, its 1H-NMR shows CH=N at d 8.97 as a singlet.
The mass spectrum of 5b shows the prominent ion peak
M+ at m/z 301 (30%). Moreover, the single crystal X-ray
determination of 5b gives a good evidence for the prod-
ucts (Fig. 2).
4-Chlorospiro(2H)chromene(2,19)cyclohexane-3-carbox-
yaldehydes 3b reacted with 2-aminothiophenol in etha-
nol under reflux for 30 min to give 4-chloro-3-(2-thiolphe-
nyl)iminomethylene spiro(2H)chromene(2,19)cyclohex-
Figure 2. Molecular structure of compound 5b; ellipsoids of ther-
mal vibration are shown with 50% probability.
i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

400
M. I. Hegab et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 396–403
Table 3. Anti-inflammatory activity for derivatives 4a–c, 4f, 4i,
5a,b, and 5c.
Compound
Anti-inflammatory activity (5mg/kg, p.o)
(inhibition l S.E.M)
Ulcerogenic score
1 h
Indomethacin 43 l 5
2 h
3 h
56 l 6
27 l 2
35 l 2
31 l 5
25 l 6
21 l 4
40 l 2
51 l 1
49 l 3
62 l 5
33 l 2
40 l 1
35 l 4
31 l 5
25 l 5
45 l 3
56 l 2
54 l 2
4a
4b
4c
4f
17 l 1
24 l 2
21 l 5
15 l 6
13 l 5
31 l 2
42 l 2
38 l 3
4i
5a
5b
5c
Significant difference at p a 0.05.
Anti-inflammatory activity
The anti-inflammatory activities of the tested com-
pounds were evaluated by carrageenan-induced paw
edema by the method of Hernandez–Perez et al. [36]. The
compounds were tested at 5mg/kg oral dose and were
compared with indomethacin as reference drug. The
results are listed in Table 3. The histogram (Fig. 1)
showed the percent inhibition of edema induced by the
reference drug and tested compounds, respectively.
Results showed that three compounds, 4b, 5b, and 5c of
the tested compounds showed significant (p a 0.05) inhib-
ition against carrageenan-induced edema in rats.
The anti-inflammatory activities of the tested com-
pounds ranged from 25–55%, whereas the standard
drug, indomethacin showed an activity of 62% after 3 h.
The anti-inflammatory activity of chromenoquinoline
derivatives 4a–c, 4f, 4i, 5a,b, and 5c revealed that 6-ethyl-
Scheme 2. Synthesis route of compounds 4 and 5.
6-methyl-11-hydroxy(6H)chromeno[4,3-b]quinoline
4i
was found to be of lower activity (25%) than the other
ane 7, which was treated with ethanolic sodium ethoxide tested compounds (28–55%). The regioisomer chro-
to obtain 5b (Scheme 1). The structure of 7 was estab- meno[4,3-b]quinolines 4a–c have lower activity (33–40%)
lished by physical and spectral data (Tables 1, 2) as well than the other regioisomer chromeno[3,4-c]quinolines
as elemental analyses. The IR spectrum of 7 shows (SH) at 5a–c (45–56%). On the other hand, derivatives 5c and 5b
v 2644 cm– 1 and (C=N) at 1591 cm– 1. 1H-NMR spectrum of showed maximum inhibition of inflammation 54 and
7 shows SH at d 4.71 (exchangeable with D2O), CH=N at 56%, respectively. The inhibition (in %) of carrageenan-
d 8.82. Its MS shows the prominent ion peak at 369 induced edema by indomethacin and the test com-
(M+, 56). The formation of 6,6-disubstituted chro- pounds is shown in Fig. 3 for 4a–c, 4f and 4i and in Fig. 4
meno[4,3-b]quinolines 4a–i can be explained via the fol- for 5a–c.
lowing Scheme 2.
Ulcerogenic activity
Pharmacological screening
The tested compounds 4a–c, 4f, 4i, 5a,b and 5c were
Eight representative compounds 4a–c, 4f, 4i, 5a–c were screened for their ulcerogenic activity at dose level 10,
studied with respect to anti-inflammatory and ulcero- 50, 100 mg/kg (Table 4; [37]). The tested compounds 5b
genic activities.
and 5c have no ulcerogenic toxicity, while 4a–c, 4f, and
i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2007, 340, 396–403
Chromeno[4,3-b]- and Chromeno[3,4-c]Quinolines
401
5b and 5c was found to be 150 mg/kg and 165 mg/kg
(i.p.), respectively, while LD50 of indomethacin is 50 mg/
kg (i.p.).
Experimental
Melting points were determined on open glass capillaries using
Electrothermal IA 9000 SERIES digital melting point apparatus
(Electrothermal, Essex, U.K.) and are uncorrected. Microanalyses
were performed with all final compounds on Elementar-Vario
EL, Microanalytical Unit, Central Services Laboratory, National
Research Centre, Cairo, Egypt and were found within l 0.3% of
the theoretical values. The NMR spectra were recorded on a Var-
ian Mercury VX-300 NMR spectrometer (Varian, Palo Alto, CA,
USA). 1H-NMR spectra were run at 300 MHz and 13C-NMR spectra
were run at 75.46 MHz in CDCl3 as solvent. Chemical shifts are
quoted in d and were related to that of the solvents (Micro-ana-
lytical Center of Cairo University, Cairo). Splitting patterns were
given as follow: s: singlet; d: doublet; t: triplet; m: multiplet.
Mass spectra were recorded on Shimadzu GCMS-QP 1000EX (EI,
70 eV; Shimadzu, Tokyo, Japan), (Micro-analytical Center of
Cairo University, Cairo). IR spectra were obtained with Brucker-
Vector 22 (Bruker Bioscience, Billerica, MA, USA) for neat sam-
ples (for liquids) or KBr wafers (for solid) (Micro-analytical Center
of Cairo University, Cairo). Compounds 1a, c [28], 1b [29], 2a [30],
2b [31], 3a, b [6] were prepared according to the literature.
Figure 3. Inhibition (%) of carrageenan-induced edema by indo-
methacin (Ind.) and test compounds 4a–c, 4f and 4i.
Figure 4. Inhibition (%) of carrageenan-induced edema by indo-
methacin (Ind.) and test compounds 5a–c.
Chemistry
Table 4. Gastric ulceration in ratsa).
Reaction of ketones 1c with Vilsmeier reagent
In a three-necked flask, was placed dimethylformamide (2.8 g,
37 mmol) and methylene chloride (20 mL). After cooling in an
ice bath to 0–58C, phosphorus oxychloride (2.7 g, 30 mmol) was
added dropwise. Addition was regulated to maintain the temper-
ature of the mixture below 208C. After the addition of phospho-
rus oxychloride was completed, the reaction was continued at
room temperature for 2 h. Following this period, the mixture
was cooled again in an ice bath and a solution of ketone 1c
(3.5 g, 18 mmol) in methylene chloride (30 mL) was added drop-
wise to the mixture while maintaining the temperature of the
reaction below 208C with external cooling. After this addition
was completed, the reaction was continued at room tempera-
ture for 24 h and then poured over crushed ice; solid sodium
bicarbonate was added until the formation of carbon dioxide
ceased. After the mixture had been stirred at room temperature
for 2 h, the aqueous layer was extracted with methylene chlor-
ide. The aqueous portion was extracted twice with 80 mL of
methylene chloride. The combined methylene chloride extracts
were washed twice with water (50 mL), dried with sodium sul-
fate, and evaporated under reduced pressure. Chromatography
of the residue over silica gel (Merck 60, particle size 0.06–0.20
mm, Merck, Darmstadt, Germany), petroleum ether 60–808C
was used as an eluent to afford 2c and 3c.
Compound
Dose (mg/kg)
10
50
100
Indomethacin
3/6 (1.4 l 0.18)b) 5/6 (1.9 l 0.15)b) 6/6 (2.1 l 0.17)b)
4a
4b
4c
4f
0/6 (0.00)
0/6 (0.00)
0/6 (0.00)
0/6 (0.00)
0/6 (0.00)
0/6 (0.00)
0/6 (0.00)
0/6 (0.00)
0/6 (0.00)
0/6 (0.00)
0/6 (0.00)
0/6 (0.00)
0/6 (0.00)
0/6 (0.00)
0/6 (0.00)
0/6 (0.00)
2/6 (1.2 l 0.08)b)
2/6 (1.1 l 0.07)b)
2/6 (1.1 l 0.07)b)
3/6 (1.65 l 0.09)b)
3/6 (1.75 l 0.10)b)
1/6 (0.75 l 0.06)b)
0/6 (0.00)
4i
5a
5b
5c
0/6 (0.00)
a)
Number of rats with lesions more than 0 mm in length per
total number of rats. The number in parenthese is the mean
ulcer index [mm] with S.E.M.
b)
Significant difference at p a 0.05.
4i showed mild ulceration at a dose of 100 mg/kg. Com-
pound 5a showed lower ulcerogenic activity at 100 mg/
kg (0.75 l 0.06), compared with indomethacine which
showed ulcerogenic activity from (1.35 l 0.18 to
2.1 l 0.17).
Reaction of b-chloro carboxyaldehyde 3a, b, c with
aniline, fluoroaniline and 2-aminophenol
Acute toxicity (LD50)
LD50 of the most active compounds 5b and 5c was deter-
mined using a graphical method [38]. LD50 of compounds
An appropriate aniline derivatives (1.04 mmol) was poured into
a solution of the b-chloro carboxyaldehyde 3a, 3b, or 3c
(1.04 mmol) in acetic acid (15 mL). The reaction mixture was
i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

402
M. I. Hegab et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 396–403
refluxed for 3 h and then evaporated under reduced pressure.
The residue was dissolved in dichloromethane and the resulting
solution was washed with 5% aqueous NaHCO3 and water, dried
over Na2SO4, and evaporated to dryness. Chromatography of the
residue over silica gel (Merck 60, particle size 0.06–0.20 mm;
Merck), petroleum ether 60–808C : diethyl ether (40 : 1) was
used as an eluent to afford the corresponding products 4a–i.
Pharmacology
Materials and methods
Materials: Indomethacin was purchased from Nile Co. (Nile Co.,
Cairo, Egypt). Carrageenan, used to induce edema, was pur-
chased from Sigma Chemicals Co., St. Louis, MO, USA. Plethys-
mometer 7150, (Ugo Basile, Italy) was used to measure the vol-
ume of paw edema.
Animals: Both mice and rats used were Wister albino of either
sex, produced from National Research Centre, Giza, Egypt; they
were housed under suitable laboratory conditions through the
period of investigation. Animals were fed standard pellet chow
(El-Nasr Chemical Company, Cairo, Egypt) and allowed free
access to water. The data for activity and toxicity were evaluated
statistically using Student's t-test. A level of p a 0.05 was adopted
for the test of significance.
Reaction of b-chloro carboxyaldehyde 3a, b, c with
2-aminothiophenol in acetic acid
2-Aminothiophenol (0.80 g, 2.7 mmol) was poured into a solu-
tion of the b-chloro carboxyaldehyde 3a, 3b, or 3c (2.7 mmol) in
acetic acid (15 mL). The reaction mixture was refluxed for 3 h
and then evaporated under reduced pressure. The residue was
dissolved in dichloromethane and the resulting solution was
washed with 5% aqueous NaHCO3 and water, dried over Na2SO4,
and evaporated to dryness. Chromatography of the residue over
silica gel (Merck 60, particle size 0.06–0.20 mm), petroleum
ether 60–808C : diethyl ether (40 : 1) was used as an eluent to
afford the corresponding products 5a–c.
Anti-inflammatory activity
Anti-inflammatory activity of the compounds under investiga-
tion was studied in rats using carrageenan. A suspension of the
tested compounds and reference drug indomethacin in carboxy
methylcellulose (CMC) solution (0.5% w/v in water) was adminis-
trated orally to rats in one dose (5 mg/kg). Control animals were
treated similarly with CMC (0.5% w/v in water).
After 30 min, 0.1 mL of freshly prepared 1% carrageenan solu-
tion in normal saline was injected into the subplantar region of
the right hind paw according to the method of Hernandez–
Perez et al. [36]. The right paw volume was measured by Plethys-
mometer 7150, directly before and at 1, 2, 3 h intervals after
administration of the tested compounds. The anti-inflammatory
activity of the tested compounds and reference drug was deter-
mined with the following formula [39]:
Reaction of b-chloro carboxyaldehyde 3b with
2-aminothiophenol in ethanol
2-Aminothiophenol (0.19 g, 1.58 mmol) was poured into a solu-
tion of b-chloro carboxyaldehyde 3b (0.41 g, 1.56 mmol) in etha-
nol (15 mL). The reaction mixture was refluxed for 30 min. The
formed solid was filtered off hot to afford a pure 4-chloro-3-(2-thi-
olphenyl)iminomethylene spiro(2H)chromene(2,19)-cyclohexane
7.
Reaction of compound 7 with ethanolic sodium ethoxide
To an ethanolic sodium ethoxide solution prepared from
sodium (0.02 g, 1 mmol) and absolute ethanol (15 mL) 7 (0.36 g,
1 mmol) was added. The mixture was refluxed for 5 h, and then
unreacted compound 7 was filtered off. The filtrate was evapo-
rated under reduced pressure and the residue was purified by
column chromatography (silica gel 0.06–0.2 particle size, CHCl3
as an eluent) to afford 0.28 g (93%) 5b.
% Anti-inflammatory activity = (Vc – Vt/Vc)6100
Where Vc represents the mean increase in paw volume in the
control group of rats. Vt represents the mean increase in paw
volume in rats treated with tested compounds and data are
expressed as mean l S.E.M., the students t-test was applied to
determine the significance of the difference between the control
group and rats treated with the test compounds.
X-Ray data collection
A suitable crystal of compounds 4e and 5b was selected and
mounted with epoxy on the tip of a fine glass fiber. All X-ray crys-
tallographic measurements were made at 298 K on an Enraf-
Nonius 590 Kappa CCD single crystal diffractometer equipped
with graphite monochromatized Mo-Ka radiation (k = 0.71073 ꢁ)
operating in u-x scan mode; the crystal to detector distance was
40 mm. Further details are summarized in Table 1. The cell
refinement and data reduction were carried out using Denzo
and Scalepak programs [32], the structures were solved by the
direct method using the SIR92 program [33] and anisotropic dis-
placement parameters were applied to non-hydrogen atoms in
full-matrix least-squares refinement based on F2 using the
maXus package [34]. Then, the hydrogen atoms bonded to the
carbon were included using the riding model. The final cycle of
the full-matrix least-squares refinement was based on 1960
observed reflections with I A 3s (I) and 433 variable parameter
for the compound 4e and 1629 reflections with I A 3s (I) and 208
variable parameter for the compound 5b The molecular
graphics were prepared using the ORTEP program [35].
Ulcerogenic activity [37]
Albino rats have been divided into different groups containing
six animals in each group. Ulcerogenic activity was evaluated
after p.o. administration of the tested compounds or indometha-
cin at doses of 10, 50, and 100 mg/kg, control rats received the
vehicle p.o (suspension of 0.5% w/v CMC). Food but not water was
removed 24 h before administration of the tested compounds.
After 6 h, the rats were scarified and the stomach was removed,
and opened along the greater curvature, washed with distilled
water and cleaned gently by dipping into saline. The mucosed
damage for each stomach was examined using a stereoscopic
microscope, the mucosal damage was compared with indome-
thacin. The mean score of each treated group was regarded as
severity index of gastric mucosal damage. Data are expresses as
mean l S.E.M., the Students t-test was applied to determine the
significance of the difference between the standard group and
rats treated with the tested compounds.
i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2007, 340, 396–403
Chromeno[4,3-b]- and Chromeno[3,4-c]Quinolines
403
[20] F. Zouhiri, M. Danet, C. Bꢂnard, M. Normand-Bayle, et al.,
Tetrahedron Lett. 2005, 46, 2201–2205.
Acute toxicity (LD50) [38]
The median lethal doses (LD50) of the most active compounds 5c
and 5b were determined in mice. Groups of male adult albino
mice, each consisting of six animals, were injected i.p. with
graded doses of each of the test compounds. The percentage of
mortality in each group of animals was determined 24 h after
injection. Computation of LD50 was processed by a graphical
method.
[21] Y. Pommier, A. A. Johnson, C. Marchand, Nat. Rev. Drug.
Discov. 2005, 4, 236–248.
[22] R. Musiol, J. Jampilek, K. Kralova, B. Podeszwa, et al., 9th
International Electronic Conference on Synthetic
Organic Chemistry (ECSOC-9), 1–30 November 2005,
http//www.usc.es/congresos/ecsoc/9/ecsoc9.HTM & http//
www.mdpi.net/ecsoc/.
[23] M. A. Pomce, J. M. Scervino, R. Erra-Balsells, J. A.
Occampo, A. M. Godeas, Phytochemistry 2004, 65, 3131–
3134.
References
[1] B. C. Sekhar, S. R. Ramadas, D. V. Ramana, Heterocycles
2000, 53, 941–977.
[24] F. Cottiglia, B. Dhanapal, O. Sticher, J. Heilmann, J. Nat.
Prod. 2004, 67, 537–541.
[2] T. Aubert, M. Farnier, I. Meunier, R. Guilard, J. Chem. Soc.
Perkin Trans. I 1989, 2095–2098.
[25] J. Mutanyatta, B. Matapa, D. D. Shushu, B. M. Abegaz, Phy-
tochemistry 2003, 62, 797–804.
[3] M. I. El-Deen, Chin. J. Chem. 1999, 17, 391–397.
[26] Y. Lin, Y. Zhou, M. T. Flavin, L. Zhou, et al., Bioorg. Med.
Chem. 2002, 10, 2795–2802.
[4] M. I. El-Deen, I. K. H. Abd El–Fattah, A. El–Gohary, Phos-
phorus Sulfur Silicon Relat. Elem. 2003, 178, 1463–1476.
[5] B. K. Clarke, D. N. Gregory, R. M. Scrowston, J. Chem. Soc.
Perkin Trans. I 1973, 2956–2960.
[27] A. Simay, K. Takꢀcs, J. Heterocyclic Chem. 1982, 19, 809–
811.
[6] M. I. Hegab, M. M. Abdulla, Arch. Pharm. Chem. Life Sci.
2006, 339, 41–47.
[28] F. A. G. El-Essawy, S. M. Yassin, I. A. El–Sakka, A. F. Khat-
tab, et al., J. Org. Chem. 1998, 63, 9840–9845.
[7] D. Pan, G. K. Kar, J. K. Ray, J. M. Lin, et al., J. Chem. Soc.
Perkin Trans. I 2001, 2470–2475.
[29] H. J. Kabbe, Synthesis 1978, 886–887.
[30] A. Alberola, B. Calvo, A. G. Ortega, R. Pedrosa, J. Chem. Soc.
Perkin Trans. I 1992, 3075–3080.
[8] T. Sugaya, Y. Mimura, Y. Shida, Y. Osawa, et al., J. Med.
Chem. 1994, 37, 1028–1032.
[31] T. Eszenyi, T. Tꢃmꢀr, P. Sebꢄk, Tetrahedron Lett. 1991, 32,
[9] M. S. Sham, B. Gurudas, K. J. Rafid, S. Rakesh, et al., Cent.
Eur. J. Chem. 2004, 2, 1–15.
827–828.
[32] Z. Otwinowski, W. Minor in Processing of X-ray Diffraction
Data Collected in Oscilation Mode, Methods in Enzymology,
Vol. 276: Macromolecular Crystallography Part A, (Eds.:
C.W. Carter, Jr. & R. M. Sweet), Academic Press, New
York, 1997.
[10] V. K. Misra, S. C. Bahel, J. Ind. Chem. Soc. 1984, 61, 916–
918.
[11] A. Srivastava, R. B. Pathak, S. C. Bahel, J. Ind. Chem. Soc.
1985, 62, 486–487.
[12] L. Nagadi, N. G. Bisri, A. Mahmoud, A. M. Galy, et al., Arz.
Forsch. 1993, 43, 480–483.
[33] A. Altomare, M. C. Burla, M. Camalli, G. L. Cascarano, et
al., J. Appl. Cryst. 1999, 32, 115–119.
[13] I. S. Shulga, A. K. Sukhomlinov, A. I. Goncharov, E. M.
Dikaya, Farm. Zh. (Kiev) 1974, 29, 27–29. Chem. Abstr.
1974, 81, 105236s.
[34] S. Mackay, C. J. Gilmore, C. Edwards, N. Stewart, K.
Shankland, maXus Computer Program for the Solution and
Refinement of Crystal Structures Bruker Nonius, The Neth-
erlands, MacScience, Japan & The University of Glasgow,
1999.
[14] N. A. Gaiukevich, G. S. Bashura, I. M. Pestsev, O. A. Pime-
nov, A. I. Pyatkop, Farm. Zh. (Kiev) 1973, 28, 50–54.
[15] S. G. Isaev, I. S. Shulga, A. V. Kaliman, N. E. Sheveleva, L.
F. Silaeva, Farm. Zh. (Kiev) 1988, 2, 68–69. Chem. Abstr.
1988, 109, 31552e.
[35] C. K. Johnson, ORTEP-II. A Fortran Thermal-Ellipsoid Plot Pro-
gram. Report ORNL-5138 Oak Ridge National Laboratory,
Oak Ridge, Tennessee, USA, 1976.
[16] I. B. Taraporewala, J. M. Kauffman, J. Pharm. Sci. 1990, 79,
[36] M. Hernandez-Perez, R. M. Rabanal, M. C. de la Torre, B.
173–178.
Rodriguez, Planta Med. 1995, 61, 505–509.
[17] A. N. Gaidukevich, G. P. Kazakov, A. A. Kravchenko, L. A.
Porokhnyak, V. V. Dinchuk, Khim. Farm. Zh. 1987, 21,
1067–1070; Chem. Abstr. 1988, 108, 68486s.
[37] H. Ikuta, H. Shirota, S. Kobayashi, Y. Yamagishi, et al., J.
Med. Chem. 1987, 30, 1995–1998.
[38] F. Sztaricskai, I. E. Takaccs, F. Pusztai, G. Szabo, I. Cssipo,
[18] S. M. Sondhi, G. Bhattacharjee, R. K. Jameel, R. Shukla, et
al., Cent. Europ. J. Chem. 2004, 2, 1–15.
Arch. Pharm. Med. Chem. 1999, 332, 321–326.
[19] K. H. Mekouar, J. F. Mouscadet, D. Desmaele, F. Subra, et
al., J. Med. Chem. 1998, 41, 2846–2857.
[39] H. Nojima, H. Tsuneki, I. Kimura, M. Kimura, Br. J. Phar-
macol. 1995, 116, 1680–1684.
i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com