Synthesis of some floctafenine derivatives of expected anti-inflammatory/ analgesic activity

Article abstract of DOI:10.1002/ardp.200400959

New derivatives related to floctafenine were synthesized and representative examples were screened for their anti-inflammatory and analgesic activities. All compounds tested were found to exhibit anti-inflammatory and analgesic activities and some were more potent than the references, floctafenine and indomethacin, in carragenan-induced rat's paw edema. None of the tested compounds showed an ulcerogenic effect on the p-benzoquinone-induced writhing test in mice.

Full text of DOI:10.1002/ardp.200400959

378
DOI 10.1002/ardp.200400959
Arch. Pharm. Chem. Life Sci. 2005, 338, 378−384
Synthesis of Some Floctafenine Derivatives of
Expected Anti-inflammatory/Analgesic Activity
Gehan Hegazy Hegazya, Azza Taherb, Asmaa Ahmed El-Zahera
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
b Department of Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
New derivatives related to floctafenine were synthesized and representative examples were screened
for their anti-inflammatory and analgesic activities. All compounds tested were found to exhibit anti-
inflammatory and analgesic activities and some were more potent than the references, floctafenine
and indomethacin, in carragenan-induced rat’s paw edema. None of the tested compounds showed an
ulcerogenic effect on the p-benzoquinone-induced writhing test in mice.
Keywords: Floctafenine; Esters; Antipyrine; Anti-inflammatory/Analgesic activity
Received: November 15, 2004; Accepted: June 2, 2005
Introduction
Aryl pyrazole derivatives including celecoxib, a market
launched anti-inflammatory drug which could selectively in-
hibit COXII [10Ϫ12], encouraged us to carry out another
reaction in which a pyrazole nucleus was attached to the
anthranilic acid moiety via condensation of an aminopyr-
azole and the terminal aldehyde group of floctafenine.
Keeping this purpose in mind, our studies have focused on
floctafenine derivatives to develop more potent and safer
profile NSAIDs potentially without gastric side effects.
Although there are many nonsteroidal anti-inflammatory
drugs (NSAIDs) on the market, there is still a need for new
research focusing on these drugs due to their serious side
effects including gastric toxicity and kidney damage [1].
Most NSAIDs act through the inhibition of cyclooxygenase
producing their side effects [2, 3]. Therefore, investigations
on new anti-inflammatory agents devoid of serious side ef-
fects are still a challenge and the goal of many researchers.
Studies on floctafenine, one of the clinically used anti-in-
flammatory agents [4, 5] and a relatively weak cyclooxy-
genase (COX) inhibitor, indicate that it can be used as a
valid alternative for many patients who show adverse effects
to other NSAIDs [6, 7]. Floctafenine is primarily recom-
mended for the short term treatment of moderately to severe
pain [6]. In recent work [8], certain modifications were car-
ried out on a clinically related anti-inflammatory drug,
glafenine and some of the new derivatives exhibited even
more activity than the parent drug in the models used. Ap-
plication of some modifications to the related anti-inflam-
matory drug, floctafenine, were carried out keeping in mind
that the anthranilic acid ring should not be coplanar with
the quinoline ring for better binding at the hypothetical re-
ceptor site and that the quinoline ring must be in ortho-
position to the anthranilic acid [9]. Modifications involve
only the glyceryl ester which is not important for activity.
The analogues were synthesized in reactions in which the
glyceryl ester moiety is degraded to the corresponding alde-
hyde, replaced by other esters as n-butyl, 2-metyl propyl,
and isopropyl esters or converted to hydrazone derivatives.
Results and discussion
Chemistry
The synthetic pathways utilized to prepare the target com-
pounds are illustrated in Schemes 1-3. Floctafenine 1 was
treated with potassium periodate to give aldehyde derivative
2
which was reacted with aminopyrazolones, namely
4-amino-1-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one
and 5-amino-2-phenyl-1,2-dihydro-3H-pyrazol-3-one, to af-
ford compounds 3 and 4, respectively. The reaction between
compound 2 and different ketones, i.e. acetone, cyclohexa-
none, and p-methylacetophenone yielded compounds 5Ϫ7
(Scheme 1).
Compound 1 was hydrolyzed with sodium hydroxide to give
floctafenic acid 8a [13], which upon reacting with thionyl
chloride gave the intermediate acid chloride derivative 8b
(Scheme 2). This intermediate was reacted without isolation
with different alcohols namely n-butanol, isobutanol, and
isopropanol to give compounds 9Ϫ11. Hydrazinolysis of 1
with hydrazine hydrate 99% gave the hydrazide derivative
12 which condenses with p-fluorobenzaldehyde, anisal-
dehyde, and vanillin to give 13Ϫ15 (Scheme 3). In con-
clusion, a small library was synthesized.
Correspondence: Gehan Hegazy Hegazy, Department of Pharma-
ceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo,
Egypt, Phone: ϩ20 2 382-1041, Fax: ϩ20 2 362-8426, e-mail:
elzaher a@yahoo.com
Ϫ
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2005, 338, 378−384
Anti-inflammatory/analgesic Floctafenine Derivatives
379
Scheme 1. Synthesis of compounds 2-7.
Pharmacology
tinctly less active in carragenan-induced edema [16] indo-
methacin was included in rat’s paw edema model.
Anti-inflammatory activities of the compounds were as-
sessed by utilizing carragenan-induced rat’s paw edema
model [14] while analgesic activities were investigated by p-
benzoquinone-induced writhing test [15]. Since floctafenine
is very effective in some acute inflammation but it is dis-
Evaluation of anti-inflammatory activity
The inhibitory activity of the studied newly synthesized
compounds on carragenan-induced rat’s paw edema was de-
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

380
Hegazy et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 378−384
Scheme 2. Synthesis of compounds 9-11.
termined according to the method of Winter et al. [14] test-
ing the ability of the synthesized compounds to suppress
the development of edema in the right hind paw induced by
sub-planter injection of carragenan.
protection of edemas ranged from 90,29%Ϫ72,13%, while
compounds 4, 12, and 14 had no significant anti-inflamma-
tory activity compared to indomethacin.
Evaluation of analgesic activity
Results of testing the anti-inflammatory ac-
tivity
Potential analgesic activity of the new compounds was
evaluated following a modification of the p-benzoquinone-
induced writhing in mice [15]. In this test, both central and
peripheral analgesics are detected. The test, therefore, has
As shown in Table 1, compounds 5, 9, 10, and 11 as well
as indomethacin showed a significant activity, the percent
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2005, 338, 378−384
Anti-inflammatory/analgesic Floctafenine Derivatives
381
Scheme 3. Synthesis of compounds 12-15.
been used by many investigators and can be recommended
as a simple screening method. In this method pain is in-
duced by injecting irritants into the peritoneal cavity of
mice. The animals react with a characteristic stretching be-
havior, which is called writhing. For scoring purposes, a
writhe is indicated by stretching of the abdomen with simul-
taneous stretching of at least one hind limb.
Results of analgesic activity test
As shown in Table 2, compounds 5, 9, 11, and 15 showed
a significant analgesic activity compared to the untreated
control group. The percent inhibition of writhing ranged
from 85% with compound 15 to 68% with compound 9,
with no significant difference from floctafenine (66%).
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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Hegazy et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 378−384
Table 1. Effects of compounds on carragenan-induced rat’s
paw edema model and ulcerogenic effect.
Results of the ulcerogenic side effect test
None of the compounds tested showed an ulcerogenic effect
compared to untreated control (Table 1). This indicates that
the new compounds may exert their anti-inflammatory ef-
fect via mechanisms that have no adverse impact on the
gastric mucosa.
Compound
Increase in weight of Protection
paw edema SEM
[%]
Gastric-
ulcerogenic
effect
[%]
Control
Indomethacin
Floctafenine
60.59 0.48
13.87 0.32
53.12 0.12
52.26 0.14
5.88 0.15†
26.98 0.08
12.38 0.08†
16.89 0.07†
10.58 0.21†
46.67 0.18
45.21 0.13
32.54 0.15
Ϫ
Ϫ
76.95
12.32
13.75
90.29
55.47
79.57
72.13
82.54
22.98
25.39
46.30
5/6
2/6
0/6
0/6
0/6
0/6
0/6
0/6
0/6
0/6
0/6
Conclusion
4
5
As expected, the prepared compounds showed marked anti-
inflammatory activity. Compound 5 showed the highest
anti-inflammatory activity in this series. Compounds 14, 15
showed moderate anti-inflammatory activity. Replacement
of glyceryl esters by n-butyl, isobutyl, and isopropyl esters
as shown in compounds 9Ϫ11 increase the anti-inflamma-
tory activities indicating that the ester function imparts
more potent anti-inflammatory activity rather than the hy-
drazone function. The type of esters did not significantly
affect the activity. Compound 15 showed moderate anti-in-
flammatory activity but showed a strong analgesic effect.
Compounds 5, 9, and 11 showed high anti-inflammatory
activity and strong analgesic effect. In contrast to the anti-
inflammatory activity, the analgesic activity increases in hy-
drazone derivatives. The glyceryl ester moiety can be re-
placed by other esters without largely affecting the activity,
moreover, in some cases it may lead to an increase in ac-
tivity. Glyceryl esters may be replaced by 2Ϫ4 carbon skel-
etons or even by aromatic spacer as in compound 15 with-
out a drastic change in activity. Fortunately, none of the
tested compounds showed ulcerogenic effects.
6
9
10
11
12
14
15
†
Significantly different from control group at p < 0.05 (One-way
ANOVA followed by Tukey-Kramer multiple comparison test).
Table 2. Effect of compounds on p-benzoquinone-induced
writhing.
Compound
Number of writhes
(mean SEM)
Inhibition of
writhing [%]
Control
Floctafenine
24.25 0.48
8.25 4.87†
5.00 3.11†
10.75 3.50
7.75 3.47†
7.50 2.75†
3.75 1.25†
Ϫ
65.98
79.38
55.67
68.04
69.07
84.54
5
6
9
11
15
Experimental
†
Significantly different from control group at p < 0.05 (One-way
ANOVA followed by Tukey-Kramer multiple comparison test).
Chemistry
All chemicals were obtained from Aldrich (Steinheim, Germany) or
Merck Chemical Co. (Darmstadt, Germany). Melting points were
determined on electrothermal Graffin apparatus (London, UK) and
are uncorrected. Microanalyses were carried out at the microana-
lytical center, Cairo University, and are within 0.4% unless other-
wise stated. IR spectra were determined using potassium bromide
discs on Shimadzu IR-435 spectrometer Shimadzu, Kyoto, Japan).
1H-NMR spectra were made on Joel NMR Varian Gemini 200
MHz spectrometer (Jeol, Tokyo, Japan; Varian, Palo Alto, CA,
USA); chemical shifts (δ) are given in parts per million (ppm) down
field from TMS as the internal standard. Mass spectra were re-
corded on Hewlett Packard 5988 spectrometer at 70ev (Hewlett-
Packard, Palo Alto, CA, USA). Progress of the reactions were
monitored by TLC using precoated aluminum sheets silica gel
Merck 60 F 254 using benzene: acetone 8:2 or chloroformmethanol
9.5:0.5 and were visualized by UV lamp.
Compound 6 had no significant analgesic action though
statistically comparable to floctafenine. On the other hand,
compounds 4, 10, 12, and 14 were found to be inactive in
this test.
Evaluation of ulcerogenic effect
The risk of gastrointestinal ulceration, bleeding and even
perforation with nonsteroidal anti-inflammatory drug ther-
apy is well known. The mechanisms by which these drugs
cause gastrointestinal irritation are complex. Deleterious ef-
fects may result from local actions, which cause injuries to
the submucosal capillaries with subsequent necrosis and
bleeding, or from inhibition of the formation of protective
prostaglandins. Gastric irritation properties of orally ad-
ministrated compounds were evaluated.
2-Oxoethyl 2-{[8-(trifluoromethyl)quinolin-4-yl]amino}benzoate 2
To a solution of 1 (4.06 g, 0.01 mol) in1% acetic acid, potassium
periodate (2.76 g, 0.01 mol) was added with stirring for 15 min. The
precipitate formed was filtered and washed with water, crystallized
from ethanol (Table 3). IR: 2: 3300 (NH), 1680 (CO). 1H-NMR
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Arch. Pharm. Chem. Life Sci. 2005, 338, 378−384
Anti-inflammatory/analgesic Floctafenine Derivatives
383
Spacing allyl 2-{[8-(trifluoromethyl)quinolin-4-yl]amino}benzoate
5Ϫ7
Table 3. Molecular formula, yields, and melting points of the
synthesized compounds.
A mixture of 1 (4.06 g, 0.01 mol) and the corresponding ketone
(0.01 mol) in sodium ethoxide solution (0.46 g, 0.02 mol) was re-
fluxed for 4 h. The reaction mixture was acidified with 10% hydro-
chloric acid and cooled. The precipitate formed was filtered and
crystallized from ethanol (Table 3). IR: 5: 3400 (NH), 1680 (CO),
1620 (CO). 1H-NMR (DMSO): 5: 2.53 (s, 3H, CH3), 4.14 (d, 2H,
O-CH2), 6.81 (d, 2H, CHϭCH), 7.48Ϫ8.91, (m, 9H, aromatic),
11.15 (s, 1H, NH) exchanged by D2O. 1H-NMR (DMSO): 6:
0.82Ϫ1.9 (m, 8H, cyclohexyl), 4.42 (d, 2H, O-CH2), 7.02Ϫ8.72 (m,
10H, -CHϭ and aromatic), 13.6 (s, 1H, NH) exchanged by D2O.
Mϩ M/Z: 7: 491.2 (1%). 1H-NMR (DMSO):7: 2.51 (d, 3H, CH3),
4.26 (d, 2H, O-CH2), 7.22Ϫ8.72 (m, 15H, aromatic and olefinic
protons CHϭCH), 10.6 (s, 1H, NH) exchanged by D2O.
Compound
Mol. formula
(Mol. weight)
Yield
[%]
M.P.
[°C]
2
3
C19H13F3N2O3
(374.31)
95
71
72
90
71
70
79
44
36
80
60
66
76
150
226
145
165
175
130
216
261
245
165
140
162
120
C29H22F3N5O3
(545.51)
4
C28H20F3N5O3
(531.00)
5
C22H17F3N2O3
(414.37)
Alkyl 2-{[8-(trifluoromethyl)quinolin-4-yl]amino}benzoate 9Ϫ11
6
C25H21F3N2O3
(454.44)
A mixture of 8a (3.32 g, 0.01 mol), thionyl chloride (15 mL) and
one drop dimethylformamide was refluxed for 2 h. The excess
thionyl chloride was distilled under reduced pressure using dry ben-
zene. The appropriate alcohol (0.01 mol) was added and refluxed in
dichloromethan and one drop of triethylamine for 2 h. The precipi-
tate formed was filtered off and crystallized from ethanol/ether
(Table 3). Mϩ M/Z: 9: 388.19 (37%). 1H-NMR (DMSO): 9: 0.6 (t,
3H, CH3), 0.78 (m, 2H, CH2- CH3), 1.33 (m, 2H, CH2-CH2-CH3),
4.10 (t, 2H, -O-CH2), 6.69Ϫ8.95 (m, 9H, aromatic), 11.19 (s, 1H,
NH) exchanged by D2O. 1HNMR (DMSO):10: 2.77Ϫ2.88 [d of d,
6H, 2(CH3)], 4.6 (m, 1H, -CH), 6.5 (d, 2H, -O-CH2), 7.54Ϫ8.36
(m, 9H, aromatic), 11.30 (s, 1H, NH) exchanged by D2O. 1H-NMR
(DMSO):11: 3.72 [d, 6H, 2(CH3)], 6.25 (m, 1H, CH-O), 7.62Ϫ8.33
(m, 9H, aromatic), 11.22 (s, 1H, NH) exchanged by D2O.
7
C28H21F3N2O3
(490.47)
9
C21H19F3N2O2
(388.38)
10
11
12
13
14
15
C21H19F3N2O2
(388.38)
C20H17F3N2O2
(374.35)
C17H13F3N4O
(346.31)
C24H16F4N4O
(452.40)
2-{[8-Ttrifluoromethyl)quinolin-4-yl]amino}benzohydrazide 12
A mixture of 1 (8.12 g, 0.02 mol) and hydrazine hydrate (1.35 g
,0.03 mol) in absolute ethanol (50 mL) and glacial acetic acid (one
drop) was refluxed for 12 h. The solvent was distilled under reduced
pressure and the residue formed was crystallized from aqueous etha-
nol (Table 3). 1H-NMR (DMSO):12: 4.43 (s, 2H, NH2) exchanged
by D2O, 7.18Ϫ8.69 (m, 9H, aromatic), 8.93(s, 1H, OϭC-NH) ex-
changed by D2O, 10.82 (s, 1H, -NH) exchanged by D2O.
C25H19F3N4O2
(464.43)
C25H19F3N4O3
(480.43)
2-{[8-(Trifluoromethyl)quinolin-4-yl]amino}substituted methylene
benzohydrazide 13Ϫ15
(DMSO): 2: 4.08 (d, 2H, -CH2), 6.16 (t, 1H, CHO) exchanged by
D2O, 7.25Ϫ8.72 (m, 9H, aromatic), 9.96 (s, 1H, NH) exchanged
by D2O.
A mixture of 12 (3.46 g, 0.01 mol) and the corresponding aldehyde
(0.01 mol) was refluxed in absolute ethanol (20 mL) and one drop
of glacial acetic acid for 4 h. The reaction was then poured on ice/
water and the precipitate formed was filtered off and crystallized
from aqueous ethanol (Table 3). IR: 13: 3400, 3300 (NH and
OϭC-NH), 1680 (CO). 1H-NMR (DMSO): 13: 6.95Ϫ8.66 (m, 13H,
aromatic), 9.88 (s, 1H, NϭCH-), 10.31(s, 1H, NH-CϭO) exchanged
2-[(1-Methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)imino]-
ethyl 2-{8-(trifluoromethyl)quinolin-4-yl]amino}benzoate (3) and
2-[(5-Oxo-1-phenyl-2,5-dihydro-1H-pyrazol-3-yl)imino]ethyl 2-{[8-
(trifluoromethyl)quinolin-4-yl]amino}benzoate 4
1
by D2O, 11.9 (s, 1H, NH-) exchanged by D2O. H-NMR (DMSO):
14: 4.23 (s, 3H, O-CH3), 6.98Ϫ8.67 (m, 13H, aromatic), 9.88 (s, 1H,
NϭCH-), 10.34 (s, 1H, NH-CϭO) exchanged by D2O, 11.92 (s, 1H,
NH-) exchanged by D2O. IR: 15: 3300Ϫ3500 (NH, OH), 1680 (CO).
1H-NMR (DMSO):15: 3.85 (s, 3H, O-CH3), 6.92Ϫ8.57 (m, 12H,
aromatic), 9.78 (s, 1H, NϭCH-), 10.00 (s, 2H, OH, NH-CϭO) ex-
changed by D2O, 11.91 (s, 1H, NH-) exchanged by D2O.
A mixture of 2 (3.74 g, 0.01 mol) and the appropriate amine (0.01
mol) were kept under reflux in absolute ethanol in the presence of
one drop glacial acetic acid for 5 h. At the end of the reaction time,
the precipitate formed was filtered and crystallized from aqueous
ethanol (Table 3). IR: 3: 3400 (NH), 1660 (CO). 1H-NMR (DMSO):
3: 1.21 (s, 3H, CH3 -N), 3.95 (d, 2H, -OCH2), 7.08Ϫ8.68 (m, 16H,
aromatic, azomethane, CH- of pyrazole ring), 10.18 (s, 1H, NH)
exchanged by D2O. IR: 4: 3300(NH), 1680(CO). 1H-NMR
(DMSO): 4: 5.00 (d, 2H, O-CH2), 7.00Ϫ8.60 (m, 16H, aromatic,
azomethane, CH of pyrazole ring), 10.00 (s, 2H, 2(NH)) exchanged
by D2O.
Pharmacology
Carragenan- induced rat’s paw edema
Groups of adult male albino rats (150Ϫ200 g) of six animals each
were given the tested compounds orally at a dose level of 5g/kg one
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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Hegazy et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 378−384
hour before carragenan injection. Rat paw edema was induced by
sub-planter injections of 0.05 ml of 1% suspension of carragenan
in saline into the planter tissue of one paw. An equal volume of
saline was injected into the other paw and served as control. Four
hours after drug administration the animals were decapitated and
the paws were rapidly excised. The average weight of edema was
estimated for the treated group as well as for control group and the
percentage inhibition of the weight of edema was also evaluated.
Indomethacin and floctafenine were employed as standards against
which the tested compounds were compared. Results are shown in
Table 1.
index finger and the presence or absence of gastric irritation was
determined. The presence of a single or multiple lesions (erosion,
ulcer or perforation) was considered to be positive. The number of
ulcers and the occurrence of hyperemia were recorded. Results are
shown in Table 1.
Statistical analysis of data
Data obtained from the animal experiments were expressed as the
mean standard error ( SEM). Statistical differences between the
treatments and the control were tested by ANOVA test. Data with
p < 0.05 value was considered to be significant.
p-Benzoquinone-induced writhing test
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nary one-way ANOVA followed by Tukey-Kramer multiple com-
parison test, with p < 0.05 considered significant. Results are shown
in Table 2.
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© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim