Synthesis of 6- and 9-alkylaminomethyl furoflavones as gastroprotective agents

Article abstract of DOI:10.1016/j.ejmech.2007.01.019

The synthesis of 9- and 6-alkylaminomethyl furoflavones 5a, b, 9a-c, 13a, b, 15a-g and 18 from the naturally occurring chromones visnagin and khellin. Gastroprotective potency of these compounds in the ethanol damage model was determined. The results indicate that, through appropriate substitution, furoflavones can be obtained that are gastroprotective.

Full text of DOI:10.1016/j.ejmech.2007.01.019

European Journal of Medicinal Chemistry 42 (2007) 1117e1127
http://www.elsevier.com/locate/ejmech
Original article
Synthesis of 6- and 9-alkylaminomethyl furoflavones
as gastroprotective agents
*
Fatma A. Ragab, Ghaneya S. Hassan , Hanan A. Yossef, Hanna A. Hashem
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, El-Kasr El-Aini Street, Cairo 11562, Egypt
Received 13 July 2006; received in revised form 9 January 2007; accepted 12 January 2007
Available online 27 January 2007
Abstract
The synthesis of 9- and 6-alkylaminomethyl furoflavones 5a, b, 9aec, 13a, b, 15aeg and 18 from the naturally occurring chromones
visnagin and khellin. Gastroprotective potency of these compounds in the ethanol damage model was determined. The results indicate that,
through appropriate substitution, furoflavones can be obtained that are gastroprotective.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: Mannich bases; Furoflavones; Furobenzopyran-5-ones; Gastroprotective potency; Claisen reaction
1. Introduction
alkylaminomethyl groups were synthesized and evaluated for
their gastroprotective activity in order to expand structuree
activity relationship and study the effect of structural modu-
lation around the flavone nucleus on its gastroprotective
properties.
The development of safe and effective drug, capable of
preventing stomach damage induced by NSAIDs or other gas-
tric-damaging substances [1e3], represents an important goal
of medicinal research [4e6]. Flavonic compounds (2-phenyl-
4H-benzopyran-4-one derivatives) either natural or synthetic
exhibit various biological activities, for example gastroprotec-
tive, antioxidant, anti-inflammatory and antitumor activities
[7e13]. The simple unsubstituted flavone was found to be
potent gastroprotective agent in an ethanol-induced gastric
damage model in rats [14]. It is found that in the 4-benzopyr-
one moiety, substitution in the 5-position with a methoxy
group provided a high level of gastroprotection that was com-
parable to that of unsubstituted flavone. Additionally a number
of substituted 5-methoxy flavones have been prepared and re-
tained the gastroprotective properties [9]. On the other hand,
furoflavones are not tested for the gastroprotective activity.
Thus in the present study two series of alkoxylated (4-me-
thoxy) and one series of hydroxylated (4-hydroxy) furofla-
vones, substituted at different positions (6 and 9) with
2. Chemistry
Conversion of the natural furochromone 1a (visnagin) to
the required 9-alkylaminomethyl furoflavones 5a, b, 9aec,
11dee and 13a, b was accomplished as depicted in Schemes
1 and 2. Visnagin 1a and Khellin 1b undergo typical b-dike-
tone cleavage by alkali to afford the benzofuran derivatives
2a and 2b [15]. On subjecting 2a to Mannich reaction
using secondary amines and paraformaldehyde, the 7-alkyla-
minomethyl benzofuran derivatives 3aeb were formed and
substitution was previously proved to be in the benzenoid
ring and not at the acetyl group [16]. The b-diketones 4a,
b have been synthesized through Claisen condensation of
3a, b with ethyl nicotinate. Compounds 4a, b were converted
to the corresponding furoflavones 5a, b by acid catalyzed
cyclodehydration with sulphuric acid, Scheme 1. On the other
hand the furoflavones 11aee in which the aromatic residue is
phenyl or substituted phenyl have been synthesized through
* Corresponding author. Tel.: þ20 2215933/0101811962; fax: þ20
23628426.
E-mail address: ghanmoom@yahoo.com (G.S. Hassan).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.01.019

1118
F.A. Ragab et al. / European Journal of Medicinal Chemistry 42 (2007) 1117e1127
H CO
(2a) /
3
H3CO
O
O
H CO
3
2ry amine /
HCHO
COCH3
OH
COCH
OH
3
10% KOH
O
O
O
CH
3
R1
2
R1
CH R
2
1
2a, b
3a, b
1
1
1
1
1a R : H
2a R : H
Ethyl nicotinate /
Na metal
1b R : OCH3
2b R : OCH3
Ethyl nicotinate /
Na metal
H CO
O
O
3
H CO
O
2
O
3
N
O
OH
N
O
OH
1
R
1
CH R
2
6a R : H
6a, b
1
6b R : OCH3
4a, b
(6a) /
O
N
3a, 4a, 5a R2
3b, 4b, 5b R2
:
20% H SO
2
20% H SO
2
4
4
:
N
CH
3
N
H CO
O
O
3
H CO
3
O
O
O
O
N
7
2
CH R
2
N
5a, b
48% HBr
2
48% HBr
HO
9a R :
N
O
2
N
N
CH
9b R :
3
HO
O
O
2
O
O
9c R :
N
2ry amine /
HCHO
O
O
N
8
2
CH R
2
N
9a-c
Scheme 1.
condensation of 2a or 3a with the corresponding aromatic
aldehydes to afford the a,b-unsaturated ketone derivatives
10aee followed by oxidative cyclization with SeO2, Scheme
2. The 4-hydroxylated furoflavones 9aec and 13a, b were
obtained through demethylation of the 4-methoxy furoflavones
5a, b, 7 and 11aec, respectively, with 48% HBr followed
by application of Mannich reaction, Schemes 1 and 2. Com-
pounds 13a, b were obtained from 11a, b, respectively. Simi-
lar methodology from 2a to afford compound 8. The
furoflavone 8 was converted to 9aec by Mannich reaction.
Attempts to introduce the alkylaminomethyl group directly
into the 6-position of the furoflavones 7 and 11aec failed,
consequently the 6-alkylaminomethyl derivatives 15aeg
have been obtained by applying Mannich reaction to the acyl-
benzofuran 6a and 6b followed by cyclization to the
corresponding furoflavones 15aeg with sulphuric acid,
Scheme 3. On the other hand, the 6-alkylaminomethyl furofla-
vone 18 where the aromatic residue is phenyl was obtained by
controlled alkaline hydrolysis of 11a to give the b-diketone 16
[17] which was subjected to Mannich reaction to give 17
followed by cyclization with sulphuric acid, Scheme 4.
3. Pharmacology, results, discussion and conclusion
Fifteen representative examples of the synthesized com-
pounds are initially screened in the rat ethanol-induced damage
model, a well-established and convenient model for the eval-
uation of gastric protection [18,19]. Gastroprotection data are
listed in Tables 1e4.

F.A. Ragab et al. / European Journal of Medicinal Chemistry 42 (2007) 1117e1127
1119
H CO
3
O
H CO
3
COCH
OH
3
A
CHO /
Alkalie /
Ethanol
O
O
Ar
OH
1
1
R
R
1
2a R : H
1
10a-e
10a & 11a R : H, Ar: C H
1
6
5
O
3a R :
CH
N
2
1
10b & 11b R : H, Ar: p-CIC H
6
4
1
10c & 11c R : H, Ar: p-H COC H
3
6
4
1
SeO /
2
10d & 11d R :
O, Ar: C H
6
CH
N
5
2
Amyl alcohol
1
10e & 11e R :
O, Ar: p-CIC H
CH
N
6
4
2
H CO
O
3
HO
O
(11a,b) /
48% HBr
O
O
Ar
O
O
Ar
1
R
12a, b
11a-e
12a Ar: C H
6
5
12b Ar: p-CIC H
6
5
2ry amine /
HCHO
HO
O
O
2
, Ar: C H
O
13a R :
N
N
6
5
2
O
, Ar: p-CIC H
6 4
Ar
O
13b R :
2
CH R
2
13a, b
Scheme 2.
3.1. Statistics
15e showed less statistically significant difference compared
to the control group (33.2, 33.5, 34.8 and 36.0, respectively),
Table 2. Comparison of each tested compound with the control
and all other compounds showed that there was highly signif-
icant difference between 11c with 13b, 5a, 11d, 12a or 13a
while there was less statistical difference between 15g with
13b, Table 3. Regarding the preventive index (PI) of the tested
compounds, it ranged from 16 (13b) to 53% (11c) but it did
not attain statistical significance, Table 4.
Data were summarized as mean, standard deviation (SD)
and standard error (SE) and were compared using one-way
analysis of variance (ANOVA). Significant ANOVA was
followed by least significant difference (LSD) per-wise com-
parison test. P value <0.05 was considered statistically sig-
nificant. All calculations were made on SPSS statistical
software, Tables 1e4.
3.2. Results
3.3. Discussion
All the tested compounds exhibited gastroprotective
activity. As regards the ulcer number, compounds 15g and
11c showed the least number of ulcer number (18.8, 19.7,
respectively) and control (33.0). However, there is no statisti-
cally significant difference in the ulcer number among all the
studied compounds including the control (P ¼ 0.114), Table 1.
On the other hand, the mean ulcer index was highly signifi-
cantly different from the control group (P ¼ 0.045) in the
case of compounds 11c, 15g, 18, 5b and 15a (24.0, 28.2,
29.6, 29.7 and 31.0, respectively). While 11b, 12b, 11a and
In the benzopyrone portion of the furoflavone system,
the type of aromatic substitution at 7-position affected the
gastroprotective effect as shown in Tables 1e4. The p-methoxy-
phenyl derivative 11c was more active than the p-chlorophenyl
11b which was more active than the phenyl derivative 11a.
The presence of 9-alkylaminomethyl substituent in these
compounds decreased the activity of 11d, e, while the presence
of 6-alkylaminomethyl substituent increased the activity (com-
pound 18 showed more activity than 11a). When the aromatic
group in position 7 was pyridinyl, the activity was slightly

1120
F.A. Ragab et al. / European Journal of Medicinal Chemistry 42 (2007) 1117e1127
O
H CO
3
O
H CO
O
O
3
2ry amine /
HCHO
O
N
2
OH
CH R
2
O
N
OH
1
R
1
R
6
14a-g
20% H SO
2
4
1
6a R : H
1
2
14a & 15a R : H, R : -N(CH )
1
3 2
6b R : OCH
3
1
2
N
O
14b & 15b R : H, R :
1
2
N
14c & 15c R : H, R :
1
2
N
N
CH
O
14d & 15d R : H, R :
3
H CO
3
O
O
2
1
2
CH R
2
14e & 15e R : OCH , R :
N
3
2
14f & 15f R1: OCH , R :
N
3
O
1
2
N
14g & 15g R : OCH , R :
N
CH3
1
3
R
N
15a-g
Scheme 3.
decreased (compounds 5a, 15a) except in the case of 9-N-
methylpiperazinomethyl derivative 5b which showed promis-
ing gastroprotective activity. It was found that the presence of
methoxy group showed great effect on the activity. Substitution
at 4-position with methoxy group (compounds 11aee) enhanc-
ed the gastroprotective activity, in contrast to 4-hydroxy
derivatives 12a, b, 13a, b which showed markedly decrease
in activity. Substitution with another methoxy group 15g
produced a potent level of gastroprotection.
3.4. Conclusion
In summary, we found that the presence of methoxy group
(either in 4, 9 or 7-position as methoxyphenyl) and through the
H3CO
O
H3CO
O
O
Ethanolic KOH
O
O
70 oC
OH
O
11a
16
2ry amine /
HCHO
H3CO
O
O
O
N
O
H3CO
O
CH2
20% H2SO4
CH2R2
O
O
OH
18
17
R2:
N
O
Scheme 4.

F.A. Ragab et al. / European Journal of Medicinal Chemistry 42 (2007) 1117e1127
1121
Table 1
Effect of the studied compounds on ulcer number values (P ¼ 0.114)
Compound
Number
Mean
SD
SE
Minimum
Maximum
Control
5a
5b
6
5
6
6
6
6
6
5
6
6
6
6
6
6
6
5
33.0
25.0
23.7
23.7
25.5
19.7
27.8
26.0
25.5
22.2
26.5
28.5
21.2
24.0
18.8
21.8
6.7
2.7
1.9
2.5
3.3
2.3
1.7
3.6
2.1
4.5
1.9
4.1
3.0
3.3
1.4
3.2
2.0
25
19
17
10
19
14
18
20
13
17
19
21
13
19
8
41
30
34
33
33
27
41
32
43
30
43
39
34
28
27
29
4.2
6.1
8.0
5.7
4.2
8.7
4.6
10.9
4.7
10.0
7.3
8.0
3.5
7.8
4.4
11a
11b
11c
11d
11e
12a
12b
13a
13b
15a
15e
15g
18
18
appropriate substitution in 6-position with alkylaminomethyl
group, furoflavones exhibited good gastroprotective activity
in the ethanol damage model.
4. Experimental protocols
4.1. Chemistry
Melting points are uncorrected and determined in one end
open capillary tubes using Gallen Kamp melting point appara-
tus (MFB-595-010M). Microanalysis was carried out at the
microanalytical unit, Faculty of Science, Cairo University.
IR spectra were determined using potassium bromide discs on
Shimadzu Infrared Spectrometer (IR-435-Kyoto, Japan), FTIR
1650 (Perkin Elmer) and Genesis II FTIRÔ Spectrometer
1
(Mottson, Madison, USA). H NMR spectra were determined
using Joel NMR Varian Gemini 200 MHz Spectrometer (Jeol,
Tokyo, Japan) and Varian Mercury VX-300 MHz NMR Spec-
trometer (Oxford, England). Chemical shifts (d) are given in
parts per million (ppm) downfield from TMS as the internal
Table 2
Effect of the studied compounds on ulcer index values (P ¼ 0.045)
Compound Number Mean (mm) SD (mm) SE (mm) Min (mm) Max (mm)
Control
5a
5b
6
5
6
6
6
6
6
5
6
6
6
6
6
6
6
5
50.7
40.8
29.7
34.8
33.2
24.0
39.8
37.2
38.3
33.5
37.5
42.5
31.0
36.0
28.2
29.6
8.8
12.6
7.6
3.6
5.7
3.1
4.6
4.8
2.6
6.5
4.8
6.8
2.8
7.0
4.5
5.3
2.0
4.8
4.8
39
29
21
15
18
17
18
20
19
26
17
31
18
29
12
14
62
62
41
49
50
31
62
48
65
45
64
58
51
42
40
43
11a
11b
11c
11d
11e
12a
12b
13a
13b
15a
15e
15g
18
11.4
11.7
6.4
16.0
10.7
16.5
6.9
17.2
10.9
12.9
4.9
11.7
10.7

1122
F.A. Ragab et al. / European Journal of Medicinal Chemistry 42 (2007) 1117e1127
Table 4
Effect of the studied compounds on preventive index values (P ¼ 0.345)
CHCl3 and washed with water. The chloroformic extract was
filtered through dry Na2SO4 and the filtrate was concentrated
under reduced pressure. The product was crystallized from
ethanol. MS for 11a m/z 292.1 (Mþ), 11e m/z 425 (Mþ).
Compound
Number
Mean
SD
SE
Minimum
Maximum
5a
5b
5
6
6
6
6
6
5
6
6
6
6
6
6
6
5
19.5
41.5
31.3
34.5
52.6
21.4
26.6
24.3
33.9
26.0
16.1
38.8
29.0
44.4
41.6
24.9
15.0
22.4
23.0
12.5
31.6
21.0
32.6
13.6
33.9
21.6
25.5
9.6
11.2
6.1
ꢀ22.4
19.1
3.3
42.8
58.6
70.4
64.5
66.4
64.5
60.5
62.5
48.7
66.4
38.8
64.5
42.8
76.3
72.4
11a
11b
11c
11d
11e
12a
12b
13a
13b
15a
15e
15g
18
9.1
9.4
4.1.4. 7-Aryl-4-hydroxy-5H-furo[3,2-g][1]benzopyran-5-one-
8 and 12aeb (Schemes 1 and 2, Tables 5e7)
1.3
5.1
38.8
ꢀ22.4
5.3
12.9
9.4
A mixture of 7, 11a or 11b (0.01 mol) and 48% HBr
(0.01 mol, 1.7 ml) in glacial acetic acid (10 ml) was refluxed
for 1 h, cooled and left in a refrigerator for 48 h. The separated
solid was filtered, dried and crystallized from ethanol (com-
pound 8) or acetic acid/water (compounds 12a, b). MS for
8 m/z 279 (Mþ), 12a m/z 278 (Mþ).
13.3
5.6
ꢀ28.3
11.2
ꢀ26.3
ꢀ14.5
ꢀ0.7
17.1
21.1
15.1
13.9
8.8
10.4
3.9
23.0
21.1
9.4
9.5
4.1.5. 9-Alkylaminomethyl-7-aryl-4-hydroxy-5H-furo[3,2-g][1]-
benzopyran-5-ones 9aec and 13aeb (Schemes 1 and 2,
Tables 5e7)
standard. Mass spectra were recorded using Hewlett Packard
Varian (Polo, USA) and Shimadzu Gas Chromatograph Mass
spectrometer-QP 1000 EX (Japan). TLC were carried out using
Art.DC-Plastikfolien, Kieselgel 60 F254 sheets (Merck), the
developing solvents were CCl4/CH3COOC2H5 (9:1) or (4:1)
and the spots were visualized by UV 366, 254 nm.
To a solution of 8, 12a or 12b (0.01 mol) in glacial acetic
acid (10 ml), the amine hydrochloride (0.011 mol) and para-
formaldehyde (0.02 mol, 0.6 g) were added and refluxed for
8 h, cooled and ice-water was added. The mixture was neutral-
ized with dil. NH4OH and the separated solid was filtered,
dried and crystallized from acetic acid/water. MS for 9c m/z
376 (Mþ), 13b m/z 411 (Mþ).
4.1.1. 7-Alkylaminomethyl-6-hydroxy-4-methoxy-5-
(3-pyridinylacetocarboxy) benzofuran 4a and 4b (Scheme 1,
Tables 5e7)
4.1.6. 6-Hydroxy-4-methoxy (or 4,7-dimethoxy)-5-(3-pyridinyl-
2-alkylaminomethyl acetocarboxy) benzofuran 14aeg
(Scheme 3, Tables 5e7)
A solution of 3a or 3b (0.01 mol) in ethyl nicotinate
(0.05 mol, 7.55 g) was treated with (0.025 mol, 0.57 g) pow-
dered sodium (prepared under toluene). After the initial reac-
tion subsided, the mixture was refluxed for 2 h. It was then left
to stand overnight, treated with ice-water and extracted with
ether. The aqueous solution, after being freed from ether by
a stream of air was neutralized with dil. NH4OH and extracted
with CHCl3. The chloroformic extract was filtered through dry
Na2SO4 and the filtrate was concentrated under reduced
pressure. The residue was crystallized from CHCl3/ether to
give 4a, b. MS for 4b m/z 423.0 (Mþ).
To a solution of 6a (R1 ¼ H) or 6b (R1 ¼ OCH3) (0.01 mol)
in absolute ethanol (50 ml), the amine hydrochloride
(0.011 mol) and paraformaldehyde (0.02 mol, 0.6 g) were
added and refluxed for 24 h. Excess solvent was evaporated
under reduced pressure, cooled and water was added. The mix-
ture was neutralized with dil. NH4OH and extracted with
CHCl3. The chloroformic extract was filtered through dry
Na2SO4 and the filtrate was concentrated under reduced
pressure. The residue was crystallized from CHCl3/ether to
give 14aeg. MS of 14a m/z 369 (Mþ þ 1).
4.1.2. 9-Alkylaminomethyl-4-methoxy-7-(3-pyridinyl)-5H-furo-
[3,2-g][1]benzopyran-5-ones 5a and 5b (Scheme 1, Tables
5e7)
A solution of 4a or 4b (0.03 mol) in 20% H2SO4 (30 ml)
was refluxed for 1 h. The reaction mixture was left to cool
and neutralized with 5% NaHCO3. The separated solid was fil-
tered, washed with water, dried and crystallized from ethanol.
MS for 5a m/z 392.2 (Mþ).
4.1.7. 6-Alkylaminomethyl-7-aryl-4-methoxy (or 4,9-dimethoxy)-
5H-furo[3,2-g][1]benzopyran-5-ones 15aeg (Scheme 4,
Tables 5e7)
Use 14aeg and proceed exactly as above to prepare
compounds 5a, b. The separated solid was crystallized
using CHCl3/ether. MS for 15a m/z 349 (Mþ ꢀ 1), 15d m/z
405.2 (Mþ).
4.1.3. 7-Aryl and 9-alkylaminomethyl-7-aryl-4-methoxy-5H-
furo[3,2-g][1]benzopyran-5-ones 11aee (Scheme 2, Tables
5e7)
4.1.8. 6-Hydroxy-4-methoxy-5-(3-phenyl-2-
morpholinomethyl acetocarboxy) benzofuran 17 (Scheme 4,
Tables 5e7)
A mixture of the propenone 10aee (0.01 mol) and sele-
nium dioxide (0.03 mol, 3.3 g) in amyl alcohol (50 ml) was re-
fluxed for 48 h. The solution was filtered to remove the
precipitated selenium metal and the filtrate was concentrated
under reduced pressure. The residue was extracted with
To a solution of 16 (0.01 mol, 3.1 g) in absolute ethanol
(50 ml), morpholine hydrochloride (0.011 mol, 1.36 g) and
paraformaldehyde (0.02 mol, 0.6 g) were added and applied
the above procedure to prepare compounds 14aeg. The resi-
due was crystallized from CHCl3/ether.

F.A. Ragab et al. / European Journal of Medicinal Chemistry 42 (2007) 1117e1127
1123
Table 5
Physical properties and microanalysis data of the new synthesized compounds
No.
R1
R2
Ar
Molecular formula
(mol. wt.)
Melting point (ꢁC)
147
Yield (%)
65
Microanalysis
Calculated (%)
Found (%)
4a
e
e
C22H22N2O6 (410)
C23H25N3O5 (423)
C22H20N2O5 (392)
C23H23N3O4 (405)
C16H9NO4 (279)
C21H18N2O5 (378)
C22H21N3O4 (391)
C22H20N2O4 (376)
C
H
N
64.39
5.37
6.83
64.40
5.24
7.00
N
O
N
4b
5a
5b
8
e
e
e
e
e
e
e
e
e
e
e
e
e
e
138
300
300
252
210
224
300
75
55
60
85
75
75
65
C
H
N
65.25
5.91
9.93
65.75
5.56
9.60
N
N
N
CH3
C
H
N
67.35
5.10
7.14
67.70
5.20
6.60
O
N
C
H
N
68.15
5.68
10.37
68.50
5.60
10.30
CH3
e
C
H
N
68.81
3.22
5.02
68.78
3.36
5.20
9a
9b
9c
N
N
N
C
H
N
66.67
4.76
7.41
66.56
4.40
7.80
O
N
C
H
N
67.52
5.37
10.74
66.80
5.98
10.73
CH3
C
H
N
70.21
5.32
7.45
70.20
5.10
7.33
11a
11b
11c
11d
H
H
H
e
e
e
e
C6H5
C18H12O4 (292)
C18H11ClO4 (326.5)
C19H14O5 (322)
C23H21NO5 (391)
195
190
160
190
90
85
85
60
C
H
73.97
4.12
73.90
4.19
p-Cl C6H4
p-OCH3 C6H4
C6H5
C
H
66.17
3.37
66.15
3.45
C
H
70.81
4.35
71.20
4.24
N
N
C
H
N
70.59
5.37
3.58
70.75
4.88
3.44
O
O
11e
e
p-Cl C6H4
C23H20ClNO5 (425.5)
174
70
C
H
N
64.86
4.70
3.29
64.86
4.47
3.51
12a
12b
13a
e
e
e
e
e
C6H5
C17H10O4 (278)
237
234
196
90
85
65
C
H
73.38
3.59
73.41
4.04
p-Cl C6H4
C6H5
C17H9ClO4 (312.5)
C22H19NO5 (377)
C
H
65.28
2.88
65.02
3.01
N
N
C
H
N
70.03
5.04
3.71
70.07
5.03
3.70
O
O
13b
14a
14b
e
H
H
p-Cl C6H4
C22H18ClNO5 (411.5)
C20H20N2O5 (368)
C22H22N2O6 (410)
300
142
154
70
50
65
C
H
N
64.16
4.37
3.40
64.00
4.10
3.00
N(CH3)2
e
e
C
H
N
65.23
5.43
7.61
65.70
5.60
7.60
N
C
H
N
64.39
5.37
6.83
64.50
5.50
7.10
O
(continued on next page)

1124
F.A. Ragab et al. / European Journal of Medicinal Chemistry 42 (2007) 1117e1127
Table 5 (continued)
No.
R1
R2
Ar
Molecular formula
(mol. wt.)
Melting point (ꢁC)
138
Yield (%)
60
Microanalysis
Calculated (%)
Found (%)
14c
H
e
C23H24N2O5 (408)
C23H25N3O5 (423)
C21H22N2O6 (391)
C23H24N2O7 (440)
C24H26N2O6 (438)
C20H10N2O4 (350)
C22H20N2O5 (392)
C23H22N2O4 (390)
C23H23N3O4 (405)
C21H20N2O5 (380)
C23H22N2O6 (422)
C24H24N2O5 (420)
C23H23NO6 (409)
C23H21NO5 (391)
C
H
N
67.65
5.88
6.86
67.40
5.50
6.83
N
14d
14e
14f
14g
15a
15b
15c
15d
15e
15f
15g
17
H
e
e
e
e
e
e
e
e
e
e
e
e
e
160
120
170
98
65
50
65
55
50
65
60
60
55
65
60
50
65
C
H
N
65.25
5.91
9.93
65.30
5.40
10.10
N
N
CH3
OCH3
OCH3
OCH3
H
N(CH3)2
C
H
N
63.32
5.73
7.04
63.00
5.20
7.46
N
N
C
H
N
62.77
5.45
6.36
62.40
5.20
5.72
O
C
H
N
65.75
5.94
6.39
65.60
5.60
5.80
N(CH3)2
168
174
190
180
155
185
138
300
246
C
H
N
68.57
5.14
8.00
69.00
5.00
8.30
H
N
N
N
C
H
N
67.35
5.10
7.14
67.50
4.00
7.20
O
H
C
H
N
70.77
5.64
7.18
70.86
6.17
7.50
H
C
H
N
68.15
5.68
10.37
68.50
4.90
10.20
N
CH3
OCH3
OCH3
OCH3
e
N(CH3)2
C
H
N
66.32
5.26
7.37
66.10
5.00
7.30
N
N
N
C
H
N
65.40
5.21
6.64
65.00
5.70
6.52
O
O
C
H
N
68.57
5.71
6.67
68.20
5.30
6.36
C
H
N
67.48
5.62
3.42
67.32
6.00
3.90
18
e
e
C
H
N
70.59
5.37
3.58
70.89
5.12
3.53
4.1.9. 4-Methoxy-6-morpholinomethyl-7-phenyl-5H-furo[3,2-g]-
[1]benzopyran-5-one 18 (Scheme 4, Tables 5e7)
Useasolutionof16(1.0 g)in20%H2SO4 (30 ml)andproceed
exactly as above to prepare compounds 5a, b. The separated solid
was crystallized using ethanol. MS for 18 m/z 392 (Mþ þ 1).
coprophagy. They were deprived of food for 36 h but allowed
free access to water except for the last hour before the exper-
iment. Gastric ulcer was induced by oral administration of
1 ml of 70% ethanol [18,19].
Assessment of gross mucosal damage: Rats were killed by
cervical dislocation 1 h after ethanol administration. The ab-
dominal cavity was opened and the stomach was excised,
opened along the greater curvature, rinsed with saline and
pinned flat on a cardboard to be exposed to gross lesions’ eval-
uation [20].
4.2. Pharmacology
Induction of gastric ulcer: Animals were individually
housed in cages with wide mesh wire bottoms to prevent

F.A. Ragab et al. / European Journal of Medicinal Chemistry 42 (2007) 1117e1127
1125
Table 6
IR (KBr, cmꢀ1) spectra of the new synthesized compounds
Table 7
1H NMR spectra of the new synthesized compounds
Compound
IR (cmꢀ1
)
Compound
1H NMR d (ppm)
4a
4b
3400 (OH), 1720, 1620 (2 C]O)
3400 (OH), 1700, 1620 (2 C]O)
1620 (C]O)
4a
DMSO-d6, D2O: 2.20e2.62 (m, 4H, (CH2)2N), 3.39e3.96
(m, 6H, (CH2)2O and CH2N), 4.16 (s, 3H, OCH3), 4.38
(s, 2H, COCH2CO), 6.80 (d, 1H, furan CH]CHO, J: 2 Hz),
7.76 (d, 1H, furan CH]CHO, J: 2 Hz), 8.20 (t, 1H,
pyridinyl H5), 8.80 (d, 1H, pyridinyl H4, J: 7.8 Hz), 9.00
(d, 1H, pyridinyl H6, J: 4.8 Hz), 9.40 (s, 1H, pyridinyl H2),
13.00 (s, 1H, OH exch.)
5a
5b
1620 (C]O)
8
9a
3400 (OH), 1660 (C]O)
3350 (OH), 1660 (C]O)
3400 (OH), 1640 (C]O)
3400 (OH), 1660 (C]O)
1640 (C]O)
9b
9c
4b
CDCl3eD2O: 2.47e2.84 (m, 8H, (CH2)4N), 3.59 (s, 3H,
NCH 3), 3.95 (s, 2H, CH2), 4.12 (s, 3H, OCH3), 4.78 (s, 2H,
COCH2CO), 6.84 (d, 1H, furan CH]CHO, J: 2 Hz), 7.42
(d, 1H, furan CH]CHO, J: 2 Hz), 8.20 (t, 1H, pyridinyl
H5), 8.61 (d, 1H, pyridinyl H4, J: 7.6 Hz), 8.75 (d, 1H,
pyridinyl H6, J: 4.5 Hz), 9.17 (s, 1H, pyridinyl H2), 13.26
(s, 1H, OH exch.)
11a
11b
11c
11d
11e
12a
12b
13a
13b
14a
14b
14c
14e
14f
14g
15a
15b
15c
15d
15e
15f
16
1660 (C]O)
1640 (C]O)
1640 (C]O)
1620 (C]O)
3350 (OH), 1640 (C]O)
3400 (OH), 1660 (C]O)
3400 (OH), 1640 (C]O)
3350 (OH), 1640 (C]O)
3300 (OH), 1720, 1620 (2 C]O)
3400 (OH), 1720, 1660 (2 C]O)
3400 (OH), 1750, 1620 (2 C]O)
3400 (OH), 1740, 1620 (2 C]O)
3300 (OH), 1750, 1635 (2 C]O)
3350 (OH), 1740, 1640 (2 C]O)
1620 (C]O)
5a
CDCl3eD2O: 2.40e2.96 (broad, 4H, (CH2)2N), 3.50
(m, 4H, (CH2)2O), 3.80 (s, 2H, CH2), 4.10 (s, 3H, OCH3),
6.81 (broad, 2H, g-pyrone H and furan CH]CHO), 7.62
(d, 1H, furan CH]CHO, J: 2 Hz), 8.10 (t, 1H, pyridinyl
H5), 8.64 (d, 1H, pyridinyl H4, J: 8.0 Hz), 8.76 (d, 1H,
pyridinyl H6, J: 4.5 Hz), 9.23 (s, 1H, pyridinyl H2)
DMSO-d6, D2O: 2.20e2.68 (m, 8H, (CH2)4N), 3.17 (s, 3H,
NCH3), 3.49 (s, 2H, CH2), 4.08 (s, 3H, OCH3), 6.90e7.10
(broad, 2H, g-pyrone H and furan CH]CHO), 7.94 (d, 1H,
furan CH]CHO, J: 2 Hz), 8.20e9.40 (m, 4H, pyridinyl H)
DMSO-d6, D2O: 7.12 (d, 1H, furan CH]CHO, J: 2 Hz),
7.22 (s, 1H, g-pyrone H), 7.58 (s, 1H, ArH), 7.68 (m, 1H,
pyridinyl H5), 8.00 (d, 1H, furan CH]CHO, J: 2 Hz), 8.54
(d, 1H, pyridinyl H4, J: 8 Hz), 8.85 (d, 1H, pyridinyl H6,
J: 4.5 Hz), 9.33 (s, 1H, pyridinyl H2), 13.59 (s, 1H, OH exch.)
DMSO-d6, D2O: 2.17e2.43 (broad, 4H, (CH2)2N), 3.32e
3.90 (broad, 6H, (CH2)2O and CH2N), 7.04 (s, 1H,
g-pyrone H), 7.20 (d, 1H, furan CH]CHO, J: 2 Hz), 7.50
(t, 1H, pyridinyl H5), 7.90 (d, 1H, furan CH]CHO, J: 2 Hz),
8.20 (d, 1H, pyridinyl H4, J: 7 Hz), 8.69 (d, 1H, pyridinyl
H6, J: 5.0 Hz), 9.40 (s, 1H, pyridinyl H2), 13.58 (s, 1H, OH
exch.)
5b
8
1640 (C]O)
1620 (C]O)
1640 (C]O)
1620 (C]O)
1640 (C]O)
3400 (OH), 1740, 1640 (2 C]O)
3400 (OH), 1740, 1620 (2 C]O)
1650 (C]O)
9a
17
18
4.2.1. Determination of ulcer number
9c
DMSO-d6, D2O: 2.90e3.43 (broad, 10H, (CH2)5N), 3.85
(s, 2H, CH2N), 6.96 (s, 1H, g-pyrone H), 7.20 (d, 1H, furan
CH]CHO, J: 1.8 Hz), 7.63 (t, 1H, pyridinyl H5), 7.90
(d, 1H, furan CH]CHO, J: 2 Hz), 8.45 (d, 1H, pyridinyl
H6, J: 7.7 Hz), 8.78 (d, 1H, pyridinyl H6, J: 4 Hz), 9.26
(s, 1H, pyridinyl H2), 13.50 (s, 1H, OH exch.)
The gastric mucosal layer was carefully inspected for the
occurrence of ulcers and their numbers were counted with
the aid of an illuminated magnifying lens [21].
4.2.2. Determination of ulcer index
11a
11b
11c
11d
11e
DMSO-d6, D2O: 4.09 (s, 3H, OCH3), 6.82 (s, 2H, g -pyrone
and ArH), 7.28 (d, 1H, furan CH]CHO, J: 1.8 Hz), 7.56
(m, 2H, ArH), 7.72 (d, 1H, furan CH]CHO, J: 2 Hz), 8.09
(m, 3H, ArH)
The length (in millimeters) of individual lesions in the
mucosa was measured using Vernier caliper and the sum of
lengths of all lesions in each stomach was regarded as the
ulcer index [22].
DMSO-d6, D2O: 4.08 (s, 3H, OCH3), 6.83 (s, 2H, g-pyrone
and ArH), 7.27 (d, 1H, furan CH]CHO, J: 2 Hz), 7.59
(d, 2H, ArH, J: 8.8 Hz), 7.68 (d, 1H, furan CH]CHO,
J: 2 Hz), 8.09 (d, 2H, ArH, J: 8.7 Hz)
DMSO-d6, D2O: 3.84 (s, 3H, OCH3), 4.07 (s, 3H, OCH3),
6.71 (s, 2H, g-pyrone and ArH), 7.08 (d, 2H, ArH, J: 9 Hz),
7.27 (d, 1H, furan CH]CHO, J: 2 Hz), 7.69 (d, 1H, furan
CH]CHO, J: 1.8 Hz), 8.05 (d, 2H, ArH, J: 8.7 Hz)
DMSO-d6, D2O: 2.40e2.60 (broad, 4H, (CH2)2N), 3.10e
3.60 (broad, 4H, (CH2)2O), 3.74 (s, 2H, CH2N), 4.13
(s, 3H, OCH3), 6.80e8.00 (broad, 8H, g-pyrone, furan
H and ArH)
4.2.3. Determination of preventive index
The preventive index (PI) of each drug is the percentage
inhibition of gastric mucosal damage produced by such
drug. It was calculated according to the following formula:
Ulcer index of treated group
CDCl3eD2O: 3.20 (broad, 4H, (CH2)2N), 3.80e4.00
(broad, 6H, (CH2)2O and CH2N), 4.27 (s, 3H, OCH3), 6.67
(s, 1H, g-pyrone H), 7.14 (d, 1H, furan CH]CHO, J: 2 Hz),
7.49 (d, 2H, ArH, J: 8.0 Hz), 7.69 (d, 1H, furan CH]CHO,
J: 2 Hz), 7.89 (d, 2H, ArH, J: 8.0 Hz)
PI ¼ 100 ꢀ
ꢂ 100
Ulcer index of control group
Each rat was housed singly and fasted for 36 h. Test com-
pounds were suspended in 1% Tween 80 and administered
by i.p. injection (20 mg/kg) to the appropriate groups while
(continued on next page)

1126
F.A. Ragab et al. / European Journal of Medicinal Chemistry 42 (2007) 1117e1127
Table 7 (continued)
Table 7 (continued)
Compound
1H NMR d (ppm)
Compound
1H NMR d (ppm)
12a
DMSO-d6, D2O: 7.04 (s, 1H, g-pyrone H), 7.13 (d, 1H,
furan CH]CHO, J: 2 Hz), 7.48 (s, 1H, ArH), 7.58e7.62
(m, 5H, ArH), 8.09 (d, 1H, furan CH]CHO, J: 2 Hz),
13.67 (s, 1H, OH exch.)
15b
DMSO-d6, D2O: 2.08e2.60 (broad, 4H, (CH2)2N), 3.20e
3.80 (broad, 6H, (CH2)2O and CH2N), 4.09 (s, 3H, OCH3),
7.10 (d, 1H, furan CH]CHO, J: 2 Hz), 7.25 (s, 1H, ArH),
7.80 (d, 1H, furan CH]CHO, J: 2 Hz), 8.00 (t, 1H,
pyridinyl H5), 8.60 (d, 1H, pyridinyl H4, J: 7.5 Hz),
8.80 (d, 1H, pyridinyl H6, J: 4.5 Hz), 9.40 (s, 1H,
pyridinyl H2)
12b
13a
DMSO-d6, D2O: 7.06 (s, 1H, g-pyrone H), 7.40 (d, 1H,
furan CH]CHO, J: 2 Hz), 7.61 (d, 2H, ArH, J: 7 Hz), 8.02
(d, 1H, furan CH]CHO, J: 2 Hz), 8.12 (d, 2H, ArH,
J: 7 Hz), 13.60 (s, 1H, OH exch.)
15c
15d
15e
DMSO-d6, D2O: 2.00e2.90 (broad, 10H, (CH2)5 N), 3.90
(s, 2H, CH2N), 4.13 (s, 3H, OCH3), 7.08 (s, 1H, ArH), 7.33
(d, 1H, furan CH]CHO, J: 2 Hz), 7.80 (d, 1H, furan
CH]CHO, J: 2 Hz), 8.10 (t, 1H, pyridinyl H5), 8.30
(d, 1H, pyridinyl H4, J: 7.5 Hz), 8.70 (d, 1H, pyridinyl H6,
J: 4.5 Hz), 9.30 (s, 1H, pyridinyl H2)
DMSO-d6, D2O: 2.30e2.43 (m, 4H, (CH2)2N), 3.20e3.80
(m, 6H, (CH2)2O and CH2N), 7.03 (s, 1H, g-pyrone H),
7.19 (d, 1H, furan CH]CHO, J: 2 Hz), 7.60e8.11
(broad, 6H, ArH and furan CH]CHO), 13.50 (s, 1H, OH
exch.)
13b
14a
DMSO-d6, D2O: 3.20 (broad, 4H, (CH2)2N), 3.55 (broad,
4H, (CH2)2O), 4.02 (s, 2H, CH2N), 6.96 (s, 1H, g-pyrone
H), 7.04 (d, 1H, furan CH]CHO, J: 2 Hz), 7.64 (d, 2H,
ArH, J: 7.4 Hz), 8.00 (d, 1H, furan CH]CHO, J: 2 Hz),
8.17 (d, 2H, ArH, J: 7.8 Hz), 13.65 (s, 1H, OH exch.)
DMSO-d6, D2O: 3.36 (s, 6H, N(CH3)2), 3.82 (d, 2H,
CH2N), 4.05 (s, 3H, OCH3), 7.29 (s, 1H, ArH), 7.36e7.48
(m, 2H, furan CH]CHO and COCHCO), 7.93e8.05
(broad, 3H, furan CH]CHO, pyridinyl H4 and pyridinyl
H5), 8.58 (d, 1H, pyridinyl H6, J: 4.5 Hz), 8.79
DMSO-d6, D2O: 2.00e2.80 (broad, 8H, (CH2)4N), 3.16
(s, 3H, NCH3), 3.92 (s, 2H, CH2N), 4.20 (s, 3H, OCH3),
6.90 (s, 1H, ArH), 7.15 (d, 1H, furan CH]CHO, J: 2 Hz),
7.90 (d, 1H, furan CH]CHO, J: 2 Hz), 8.10 (t, 1H,
pyridinyl H5), 8.30 (d, 1H, pyridinyl H4, J: 7.5 Hz), 8.70
(d, 1H, pyridinyl H6, J: 4.5 Hz), 9.20 (s, 1H, pyridinyl H2)
DMSO-d6, D2O: 2.30e2.70 (broad, 4H, (CH2)2N), 3.20e
3.50 (broad, 4H, (CH2)2O), 3.88 (s, 2H, CH2N), 4.05 (s, 3H,
OCH3), 4.23 (s, 3H, OCH3), 7.20 (d, 1H, furan CH]CHO,
J: 2 Hz), 7.80 (d, 1H, furan CH]CHO, J: 2 Hz), 8.13
(t, 1H, pyridinyl H5), 8.50 (d, 1H, pyridinyl H4, J: 7.5 Hz),
8.80 (d, 1H, pyridinyl H6, J: 4.5 Hz), 9.20 (s, 1H, pyridinyl
H2)
(s, 1H, pyridinyl H2), 13.00 (s, 1H, OH exch.)
14b
14c
14e
14f
14g
15a
DMSO-d6, D2O: 2.20e2.60 (broad, 4H, (CH2)2N), 3.17e
3.89 (broad, 6H, (CH2)2O and CH2N), 4.11 (s, 3H, OCH3),
6.97 (s, 1H, ArH), 7.20 (t, 1H, COCHCO), 7.31 (d, 1H,
furan CH]CHO, J: 1.8 Hz), 7.80 (d, 1H, furan CH]CHO,
J: 1.8 Hz), 8.08 (t, 1H, pyridinyl H5), 8.30 (d, 1H, pyridinyl
H4, J: 7.5 Hz), 8.50 (d, 1H, pyridinyl H6, J: 4.5 Hz), 9.30
(s, 1H, pyridinyl H2), 13.20 (s, 1H, OH exch.)
15f
17
DMSO-d6, D2O: 2.20e2.85 (m, 10H, (CH2)5N), 3.80
(s, 2H, CH2N), 3.97 (s, 3H, OCH3), 4.17 (s, 3H, OCH3),
7.08 (d, 1H, furan CH]CHO, J: 2 Hz), 7.92 (d, 1H, furan
CH]CHO, J: 2 Hz), 8.13 (t, 1H, pyridinyl H5), 8.59 (d,
1H, pyridinyl H4, J: 7.5 Hz), 8.98 (d, 1H, pyridinyl H6,
J: 4.5 Hz), 9.20 (s, 1H, pyridinyl H2)
DMSO-d6, D2O: 2.90e3.99 (broad, 12H, (CH2)5 N and
CH2N), 4.11 (s, 3H, OCH3), 6.70 (s, 1H, ArH), 6.90 (t, 1H,
COCHCO), 7.20 (d, 1H, furan CH]CHO, J: 2 Hz), 7.70
(d, 1H, furan CH]CHO, J: 2 Hz), 7.90(t, 1H, pyridinyl
H5), 8.30 (d, 1H, pyridinyl H4, J: 7.5 Hz), 8.80 (d, 1H,
pyridinyl H6, J: 4.5 Hz), 9.01 (s, 1H, pyridinyl H2),
13.00 (s, 1H, OH exch.)
DMSO-d6, D2O: 2.79 (broad, 4H, (CH2)2N), 3.15 (broad,
4H, (CH2)2O), 4.00 (s, 3H, OCH3), 4.11 (d, 2H, CH2N, J:
6.4 Hz), 6.98 (s, 1H, ArH), 7.20 (d, 1H, furan CH]CHO, J:
2 Hz), 7.46 (t, 1H, COCHCO), 7.69e7.77 (m, 5H, ArH),
8.05 (d, 1H, furan CH]CHO, J: 2 Hz), 12.75 (s, 1H, OH
exch.)
DMSO-d6, D2O: 2.30e2.60 (broad, 4H, (CH2)2N), 3.10e
3.60 (broad, 6H, (CH2)2O and CH2N), 3.95 (s, 3H, OCH3),
4.10 (s, 3H, OCH3), 7.23 (t, 1H, COCHCO), 7.30 (d, 1H,
furan CH]CHO, J: 2 Hz), 7.70 (d, 1H, furan CH]CHO,
J: 1.8 Hz), 8.12 (t, 1H, pyridinyl H5), 8.40 (d, 1H, pyridinyl
H4, J: 7.5 Hz), 8.50 (d, 1H, pyridinyl H6, J: 4.5 Hz), 9.10
(s, 1H, pyridinyl H2), 13.10 (s, 1H, OH exch.)
18
DMSO-d6, D2O: 2.78 (broad, 4H, (CH2)2N), 3.07 (broad,
4H, (CH2)2O), 3.65 (s, 3H, OCH3), 4.04 (s, 2H, CH2N),
7.25 (d, 1H, furan CH]CHO, J: 2 Hz), 7.47e7.69 (m, 6H,
ArH), 8.03 (d, 1H, furan CH]CHO, J: 2 Hz)
CDCl3 eD2O: 2.04e2.88 (broad, 10H, (CH2)5N), 3.48
(d, 2H, CH2N, J: 7 Hz), 3.99 (s, 3H, OCH3), 4.28 (s, 3H,
OCH3), 6.92 (d, 1H, furan CH]CHO, J: 2 Hz), 7.49 (t, 1H,
COCHCO), 7.85 (d, 1H, furan CH]CHO, J: 2 Hz), 8.22 (d,
1H, pyridinyl H4, J: 7.6 Hz), 8.52e8.93 (m, 2H, pyridinyl
H5 and pyridinyl H6), 9.36 (s, 1H, pyridinyl H2), 13.06
(s, 1H, OH exch.)
control group received equivalent volume of 1% Tween 80.
One-hour later gastric ulcer was induced in 36 h fasted
animals by oral administration of 1 ml 70% ethanol in distilled
water. Animals were sacrificed by cervical dislocation 1 h post
ulcer induction and stomachs were dissected. In each stomach,
ulcers were counted (Table 1) and the length of each lesion
was measured using Vernier caliper, then the sum of lengths
was calculated and served as ulcer index (Tables 2 and 3);
the preventive index was calculated regarding the effect of
drug on ulcer index (Table 4).
DMSO-d6, D2O: 2.96 (s, 3H, NCH3), 3.10e3.70 (broad,
10H, (CH2)4N and CH2N), 3.92 (s, 3H, OCH3), 4.08 (s, 3H,
OCH3), 7.10 (t, 1H, COCHCO), 7.30 (d, 1H, furan
CH]CHO, J: 2 Hz), 7.60 (d, 1H, furan CH]CHO, J:
2 Hz), 8.20 (t, 1H, pyridinyl H5), 8.40 (d, 1H, pyridinyl H4,
J: 7.5 Hz), 8.70 (d, 1H, pyridinyl H6, J: 4.5 Hz), 9.20
(s, 1H, pyridinyl H2), 12.80 (s, 1H, OH exch.)
References
DMSO-d6, D2O: 3.41e3.45 (s, 6H, N(CH3)2), 4.05 (s, 3H,
OCH3), 4.12 (s, 2H, CH2N), 7.00 (s, 1H, ArH), 7.29 (d, 1H,
furan CH]CHO, J: 2 Hz), 7.51 (m, 1H, pyridinyl H5), 8.00
(d, 1H, furan CH]CHO, J: 2 Hz), 8.12 (d, 1H, pyridinyl
H4, J: 7.5 Hz), 8.60 (d, 1H, pyridinyl H6, J: 4.5 Hz), 8.79
(s, 1H, pyridinyl H2)
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