Az. J. Pharm. Sci. Vol. 35 March, 2007.
22
SYNTHESIS OF NEW IMIDAZOLYL ACETIC ACID DERIVATIVES OF
POTENTIAL ANTI-INFLAMMATORY AND ANALGESIC ACTIVITIES
By
Maha M. Khalifaa and Nayira A. Abdelbakyb
From
a
Pharmaceutical Chemistry and bPharmacology Departments Faculty of Pharmacy,
Al-Azhar University(Girls), Cairo, Egypt.
ABSTRACT
In the following study 2-(4-(4-fluorobenzylidene)-2-(4-fluorophenyl) 5-oxo-4,5dihydroimidazol-1-yl) acetic acid 3 was synthesized. Chlorination of the latter afforded the
chloro derivative 4 which reacted with different amines and hydrazine to afford compounds 58. Pyrazole, pyrazolone and thiazolidinone derivatives were also synthesized from Imidazol-1ylacetic acid hydrazide 8 to give compounds 9-12. All of the target compounds were then
evaluated for their anti-inflammatory activity against carrageenan-induced rat paw edema and
also for their analgesic activity using writhing test in albino mice. Compounds 5, 9, 10, 12
exhibited maximum anti-inflammatory activity, however all the compounds showed excellent
protection in the writhing test, compounds 10 and 12 were two times more potent than the
reference standard.
INTRODUCTION
The use of non steroidal anti-inflammatory drugs (NSAIDs) for treatment of
inflammation and pain by blocking the metabolism of arachidonic acid through the inhibition
of cyclooxygenase ( COX-1 and COX-2) and thereby production of prostaglandins
(Lombardino,G 1985; Mehanna A.S. 2003) Recently, it was discovered that most of the
NSAIDs in the market show greater selectivity for COX-1 which provides cytoprotection in the
gastrointestinal (GI) tract than COX-2 which mediates inflammation. Highly selective COX-2
inhibitors have recently been developed and marketed as promising gastroprotective agents
(Talley, J.J. 1999). Later on, some potential limitations of long COX-2 inhibitor therapy
include ulcer exacerbation in high-risk patients, delayed gastroduodenal ulcer healing,
thrombosis due to prostacyclin deficiency and kidney toxicity. Thus COX-2 inhibitors
(Bandarage, U.K.; et al., 2000) have not eliminated the need for improved drugs in the
NSAIDs area. Imidazolones have been found to be associated with anti-inflammatory activity
(Pande K; et al., 1984; Pande K, et al., 1987; Tuyen, T.N., et al., 2005; Wright W.B.; et
al., 1966 and Pande K.; et al., 1985). In this investigation we tried to join some biologically
active well established anti-inflammatory agents or moiety such as aminoantipyrine, naproxen
salt of acid and phenylaminoacetic acid to the imidazolone nucleus in hope to obtain
compounds with better anti-inflammatory activity. However, pyrazole, pyrazolones and
thiazolidinones which were reported earlier as potential anti-inflammatory agents (Burger, A.
1970; Goel B.; et al., 1999) was also joined to the parent imidazolone nucleus by 2 carbon
linkage to obtain new structural hybrid template with better anti-inflammatory potential
Hence the reaction sequence followed for the synthesis of the target compounds is
outlined in the following scheme.
23
Az. J. Pharm. Sci. Vol. 35 March, 2007.
CHEMISTRY
The p-fluorohippuric acid 1 was synthesized according to reported procedure12.13. The
corresponding oxazolone 2 was prepared using p-fluorobenzaldehyde in glacial acetic acid /
sodium acetate, reaction of the latter with glycine in equimolar ratio in an oil bath afforded
compound 3. Chlorination of the latter with POCl3 gave us the chloro derivative 4 which was
subjected to react in basic medium14 with different agents of known anti-inflammatory
activity namely, 2-aminoantipyrine, 2-aminophenyl acetic acid , naproxen salt of acid in order
to observe the change in their activity as anti-inflammatory agents and study their analgesic
activity as well, compounds 5-7 respectively. Hydrazinolysis of compound 4 with Hydrazine in
dry benzene to obtain Imadazol-1ylacetic acid hydrazide 8. Reaction of 8 with acetylacetone15
yielded the pyrazolo derivative 9. However reaction with ethylacetoacetate in ethanol afforded
pyrazolone 10. Schiff’s base 11 was obtained by reacting the hydrazide with pfluorobenzaldehyde Cyclocondensation of 11 with thioglycolic acid in dry benzene for 20 h
afforded the corresponding thiazolidinone derivative 12 Scheme
O
Ar
O
Ar
N
H
COOH
N
O
A
Ar 2
1
B
O
Ar
N
O
N
OH
3
Ar
C
HOOC
O
Ar
N
O
N
N
N
H
Ar
O
N
N
Cl
Ar
N
N
Ar
O
N
O
N N
Ph
O
O
N
NHNH2
OMe
O
CH3
7
Ar
8
NH
J
O
N
10
N
Ar
I
O
N
N
9
H3C
Ar
H
CH3
O
N
H3 C
Ar
O
Ar
O
Ar H3C
6
F
G
N
E
4
5
O
N
N
D
Ar
Ar
O
O
Ar
O
Ar
O
N
CH3
O
Ar
K
N
N
Ar
O
Ar
O
N
O
N
NH
NH
11
N
Ar
N
Ar
12
Ar
S
O
Ar=C6H4-F-4
Az. J. Pharm. Sci. Vol. 35 March, 2007.
24
Scheme Synthesis of compounds 1-12: A; 4-fluoro benzaldehyde, Ac2O/AcONa, reflux; B;
glycine, oil bath, 150ºC; C : POCl3, water bath, D; 2-aminophenylacetic acid; E-4aminoantipyrine, DMF, w.b; F; naproxen salt, Ethanol, piperidine, G; N2H4, drybenzene,
reflux H; acetylacetone, ethanol/ KOH, reflux, I; ethylacetoacetate, ethanol, reflux; J; pfluorobenzaldehyde, ethanol, reflux, K; thioglycolic, dry benzene, reflux.
Experimental
Elemental analyses were performed on Perkin-Elmer 2400 analyzer (Perkin-Elmer,
Norwalk, CT, USA) at the Microanalytical Unit of Cairo University. Melting points were
determined in open capillaries on an electrothermal LA 9000 Series (Electrothermal
Engineering Ltd., Essex, UK) and are uncorrected. TLC chromatography was performed on
precoated silica gel 60F 254 plates (Merck CO., Darmstadt, Germany). Infrared spectra were
recorded on Pye Unicam SP 1000 IR spectrophotometer (Thermoelectron CO., Egelsbach,
Germany). 1HNMR spectra were recorded on Varian Gemini EM-300 MHz NMR
spectrophotometer (Varian CO., Fort Collins, USA).
DMSO-d6 was used as solvent, TMS was used as internal standard and chemical shifts
were measured in δ ppm. Mass spectra were recorded on Varian MAT 311-A 70 e.v. (Varian
CO., Fort Collins, USA).
Compound 1 was synthesized according to reported procedure12,13
4-(4-Fluorobenzylidene)-2-(4-Fluorophenyl)-4H-oxazol-5-one 2:
The compound 2 was prepared according to a reported procedure:
Mp: 199-201oC
2-(4-(4-fluorobenzylidene)-2-(4-fluorophenyl)-5-oxo-imidazol-l-ylacetic acid 3
Oxazolone 2 ( 0.01 mol, 2.84 g ) was heated with an equimolar quantity of glycine
(0.01 mol, 0.75 g ) in an oil bath at 150ºC for 3 hr, the product was recrystallized from ethanol.
2-(4-(4-fluorobenzylidene)-2-(4-fluorophenyl)-5-oxo-4-dihydroimidazol-1-yl)
chloride 4.
acetyl
Compound 3 (0.34 mol, 1.16 g ) was refluxed with POCl3 (3 ml) for 2 h in a water bath. The
excess POCl3 was distilled off and the residual solid was recrystallized from dry benzene.
Mp: 160-162 oC
1-(2-(4-(4-fluorobenzylidene)-2-(4-fluorophenyl)5-oxo-4,5-dihydroimidazol-1-yl)
acetamido-2-phenylacetic acid 5.
A mixture of compound 4 ( 0.001mol, 0.36 g) and (0.001 mol, 0.15 g) of 2aminophenylacetic acid in 20 ml DMF, heated in a w.b for 5 h . The reaction mixture poured
onto ice H2O, the resulting residue was filtered dried and recrystallized from absolute ethanol
N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) 2-(4-(4-fluorobenzyldene)2-(4-fluorophenyl)-5-oxo-4,5-dihydroimidazol-1-yl) acetamide. 6
0.001 mol of compound 4 (0.36g) together with (0.001 mol, 0.20 g) of 2-aminoantipyrine in
20 ml DMF, heated in a water bath for 5 h. The reaction mixture poured onto ice H2O, the
resulting residue was filtered dried and recystallized from absolute ethanol
2-(4-(4-fluorobenzylidene)-2-(4-fluorophenyl)-5-oxo-4,5-dihydroimidazol-1-yl)
(7-methoxynaphthalene 2-yl) propanoic anhydride 7.
acetic-2-
Az. J. Pharm. Sci. Vol. 35 March, 2007.
25
A mixture of compound 4 (0.001 mol, 0.36 g) and sodium salt of Naproxen (0.001 mol, 0.25 g)
in ethanol (20 ml) , 2 drops piperidine was heated at reflux for 6 h. The resulting solution was
cooled, the solid product was filtered, dried and recystallized from absolute ethanol.
2-(4-(4-fluorobenzylidene)-2-(4-fluorophenyl)-5-oxo-4,5-dihydroim-idazol-1-yl)
acetohydrazide 8.
A mixture of compound 4 (0.01 mol) and 99% hydrazine hydrate (0.012 mol) in absolute
ethanol was heated at reflux for 6 h. Excess solvent was evaporated, residue washed with ether,
recystallized from ethanol to give the product.
4-(4-fluorobenzylidene)-2-(4-fluorophenyl)-1-(2-(3,5-dimethyl-1H-pyrazol-1-yl)-2oxoethyl)-1H-imidazol-5(4H)-one 9.
A mixture of carbohydrazide (0.001 mol, 0.37 g)) and acetylacetone (0.001 mol, 0.10 g ),
KOH, absolute ethanol (20 ml) heated at reflux for 3h. the reaction mixture was cooled and the
formed precipitate was filtered off and recrystallized from absolute ethanol to give compound
9.
1-(2-{4-(4-fluorophenyl)-42-(4-fluorophenyl)-5-oxo-4,5-dihydroimidazol-1-yl)acetyl}-3methyl-1H-pyrazole-5(4H)-one 10.
A mixture of carbohydrazide (0.001 mol, 0.37 g) and ethylacetoacetate (0.001 mol. 0.12 g) in
absolute ethanol (20 ml) was heated at reflux temperature for 3 h. The reaction mixture was
treated according to the procedure described above to give compound 10.
2-4-(4-fluorobenzylidene)-2-(4-fluorophenyl)-5-oxo-4,5-dihydroimidazol-1-yl)-N'-4(substitutedbenzylidene)acetohydrazide 11.
A mixture of compound 9 (0.001 mol, 0.37 g) and p-fluorobenzaldehyde (0.001 mol, 0.12 g)
was refluxed in absolute ethanol (20 ml) for 5 h. The reaction mixture was concentrated,
cooled and the formed precipitate was filtered off, dried and then recrystallized from absolute
ethanol to give compound 11
N-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-2-(4-(4-fluorobenzylidene)-2-(4fluorophenyl)-5-oxo-4,5-dihydroimidzol-1-yl) acetamide 12.
A mixture of compound 12 (0.005 mol, 2.31 g) and thioglycolic (0.006 mol, 0.42 g ) was
refluxed in dry benzene (50 ml) for 20 h. The solvent was evaporated and the reaction mixture
was neutralized with cold dilute sodium bicarbonate solution, then was filtered off and
recrystallized from ethanol/ether to give the product
Az. J. Pharm. Sci. Vol. 35 March, 2007.
26
Table 1: Spectral data of the synthesized compounds
No
2
Spectral data
1H 1
HNMR (DMSO-d6): 7.34-7.50 (m, 5H, ArH), 8.17-8.40 (m, 4H,ArH).;
M.S ( m/z): 284 (10.3%, M+), 123 (100%), 108 (1.8%), 95 (44.7%).
3
IR IR (KBr, cm-1): 1726 (C = O, COOH), 1642 (C= O, imidazolone), 3064
(ArH).
1
HNMR:(DMSO-d6) : 4.32 (s, 2H, N–CH2), 7.21 (s, 1H, arylidene H), 7.26 – 7.41
(m,
4H, ArH), 7.85-7.89 (m, 2H, ArH), 8.31-8.36 (m, 2H, ArH), 10.1 (s, 1H, OH).
M.S (m/z) 342 (87.8%), 123 (100%), 108 (10.4%), 95 (36.5%).
II IR (KBr, cm-1): : 1708 (COCl), 1665 (C = O, imidazolone), 1600 (C = N).
IR (KBr, cm-1): 3400 (OH), 3200 (NH) , 1642 (C=O, imidazolone), 1694 (C=O,
COOH), 1596 (CN).
1
HNMR:(CDCl3): 2.85 (s, 2H, CH2COOH), 4.48 (s, 2H, CH2) 7.05-7.16 (m, 7H,
ArH), 7.68-7.73 (m, 4H, ArH) 8.17-8.23 (m, 2H, ArH), 9.02 (s, 1H, NH), 9.10 (s,
1H, OH).
IR (KBr, cm-1): 3412 (NH), 2928 (CH-aliphatic) 1716 (C=O pyrazolone), 1650
(C=O, imidazolone), 1600 (C=N).
1
HNMR (DMSO-d6) : 2.21 (s, 3H, CH3), 2.97 (s, 3H, CH3), 4.39 (s, 2H, CH2)
7.06 – 7.19 (m, 7H, ArH), 7.33-7.46 (m, 4H, ArH), 8.02-8.20 (m, 3H, ArH), 9.8
(s,1H,NH).
IR (KBr, cm-1) : 1720 (OC–O–CO), 1648 (C=O), imidazolone), 1600 (CN).
1
HNMR (DMSO-d6): 1.43-1.45 (d, 3H, CH3, J= 6.9 Hz), 3.78 (q, 1H, CHCH3),
3.86 (s, 3H, OCH3), 4.14 (S, 2H, CH2), 7.12-7.13 (d, 2H, ArH, J=2.4 Hz), 7.157.16 (d, 2H, ArH, J=2.7 Hz) 7.24 (s, 1H, arylidene H), 7.27 – 7.45 (m, 4H, ArH)
7.70-7.80 (m, 2H, ArH) 7.88 – 7.92 (m, 2H, ArH), 8.35 – 8.40 (m, 2H, ArH).
I IIR (KBr, cm-1): 3470-3316 (NH2), 3208 (NH), 1628 (C=O), 1662 (C=O,
hydrazide)
1 1
HNMR (DMSO-d6): 3.82 (s, 2H, N–CH2), 7.10-7.38 (m, 5H, ArH), 7.91-7.96
(m, 4H,
ArH), 8.70 (s, 2H, NH2), 10.37 (s, 1H, NH).
4
5
6
7
8
9
10
11
12
II IR (KBr, cm-1): 2990 (CH), 1662 (C=O)
1
HNMR: (DMSO-d6) 8: 1.23 (s, 3H, CH3), 2.07-2.11 (m, 3H, CH3 of pyrazoline),
3.82 (s, 2H, N-CH2) , 7.24- 7.42 (m, 10H, ArH+1H olefinic+ 1H of pyrazoline).
IR (KBr, cm-1): 2990 (CH), 1716 (C=O, pyrazolone), 1642 (C=O, imidazolone),
1602 (C=O, amide), 1510 (CN).
1
HNMR (DMSO-d6): 1.88 (s, 3H, CH3), 2.26 (s, 2H,CH2 of pyrazolone), 4.13 (s,
2H,
N-CH2), 7.22 (s, 1H, arylidene H), 7.24-7.37 (m, 4H, ArH), 7.73-7.78 (m, 4H,
ArH).
II IR (KBr, cm-1) of 11 :3100 (NH), 2990 (CH), 1665 (C=O, imidazolone), 1600
(CN).
IR IR (KBr, cm-1): 3421 (NH), 1715 (C=O of thiazolidinone), 1647 (C=O of
imidazolone), 111610 (C=O, amide), 1507 (CN)
27
Az. J. Pharm. Sci. Vol. 35 March, 2007.
Table 2: Physical properties and molecular formula of the synthesized compounds.
Compd
No
3
Mp (oC)
255-58
Yield
%
70
Mol.Formula
M. wt
C18H12F2N2O3
342.3
5
200-02
45
C26H19F2N3O4.1 H2O
493.4
6
141-42
45
C29H23F2N5O3
527.5
7
129-31
40
C32H24F2N2O5
554.5
8
105-07
42
9
123-25
30
C18H14F2N4O2.0.5 H2O
360.6
C23H18F2N4O2
420.4
10
162-64
32
C22H16F2N4O3
422.3
11
130-32
30
C25H17F2N4O2
462.4
12
180-82
20
C27H19F3N4O3S
536.5
Elemental Analysis
Calcd
Found
C 63.13
63.23
H 3.53
3.09
N 8.18
8.22
C 63.22
63.57
H 4.26
4.64
N 8.52
9.01
C 66.03
H 4.39
N 13.28
C 69.31
H 4.36
N 5.05
C59.89
H 3.88
C 65.71
H 4.32
N13.33
C 62.56
H 3.82
N 13.26
C 64.93
H 3.71
N12.12
C 60.44
H 3.57
N10.44
66.77
4.72
13.55
69.68
4.64
5.25
59.66
4.26
65.83
3.93
13.76
63.20
3.61
13.66
65.34
4.09
12.02
60.64
3.86
11.01
28
Az. J. Pharm. Sci. Vol. 35 March, 2007.
PHARMACOLOGY
4.1-Anti-inflammatory activity:
Materials and Methods:
The anti-inflammatory testing was performed according to the method of Winter et al 16,17 .
Edema was induced in the left hind paw of all rats by subcutaneous injection of 0.1 ml of 1%
(w/v) carrageenan in distilled water into their footpads. Fifty four rats weighing 150-180g of
both sexes were divided into nine groups of 6 rats each. The 1st group was Kept as control, was
given the respective volume of the solvent(few drops of tween 80 in distilled water).The 2nd-8th
groups were orally given the compound in a dose of 25mg/Kg, The last group was
administered indomethacin (IndocidR) in a dose of 10mg/Kg orally as a standrard reference.
The paw thickness of each rat was measured using Vernier caliper before carrageenan injection
and then 4 hours post administration of the tested compounds.
Edema rate and inhibition rate of each group were calculated as follows:
Edema rate%= Tht-Tho/tho, Inhibition rate%=Ec-Et/Ec
Where: Tht- is the thickness before carragenan injection(mm) Tho is the thickness after
carrageenan injection (mm).
Ec& Et is the edema rate of control and treated groups respectively.
Table 3: Anti-inflammatory activity ( Rat Paw Edema % inhibition ):
Compound No
Control
3
5
6
7
9
10
12
Indomethacin
Edema rate%
86.6±5.93 b
57.88±5.24a
33.82±2.58a
69.61±5.66 b
69.50±3.13a
32.34±1.43 a
36.77±2.87 a
28.00±2.78 a
31.41±2.40 a
Inhibition rate%
0
33.19
60.96
19.65
19.77
62.66
64.48
67.67
63.74
Potency %
0
52
95.7
30
31.1
98.3
101
106
100
Values represent the mean±S.E of six animals for each group.
a
P<0.05 statistically significant from control (Dunnett's test)
Analgesic activity:
Writhing test:
An acetic-induced abdominal constriction in mice ( Writhing effect) was determined
by the method described by (Collier et al., 1968).
Fifty mice of both sexes weighing 18-25 gm were divided into nine groups and pretreated as
follows: group I served as control,orally received distilled water in appropriate volumes, group
2-8 orally received the test compounds at a dose of 25mg/Kg. Group 9 orally received
acetylsalicyclic acid in a dose of 150 mg/Kg. After 30 minutes, the animals were injected
intraperitoneally with 0.7 % of an aqueous solution of acetic acid (10 ml/ Kg of animal
weight). The number of abdominal constrictions of injected mice was recorded during 30 min
after I. P injection.
29
Az. J. Pharm. Sci. Vol. 35 March, 2007.
The values obtained were compared with those obtained on untreated control mice and
the activity expressed as percent of protection using the following ratio %protection= Control
mean-Treated mean/control mean X 100
Mean values were analyzed statistically ( Table 4).
Table 4: Peripheral analgesic activity (Writhing test)
Compound No
Control
3
5
6
7
9
10
12
Acetylsalicyclic acid
No of writhes/20 min
45.4±1.29 b
15.6±2.25a b
1.8±0.80 a
29.4±2.80 a
29.6±2.79 a
2.0±0.18 a
1.2±0.58 a
0.2±0.18 a
26.2±1.16 a
Protection %
0
65.60
96.10
35.22
34.80
95.70
97.40
99.60
42.3
Values represent the mean± S.E of five animals for each groups.
a
P< 0.05: Statistically significant from control. (Dunnett's test)
b
P<0.05: Statistically significant from aspirin. (Dunnett's test)
RESULTS AND DISCUSSION
Results of the carrageenan induced rat paw edema (CPE) showed that compound 5 as
well as 9, 10 and 12 were potent anti-inflammatory agents. The parent imidazolone showed
only moderate potency. Compounds 6 & 7 didn't exhibit much potency may be due to their
bulkiness which restrict their binding to the COX enzyme. .The argument around the
importance of an acidic functionality as a criteria for binding is still undetermined, however
most potent compounds were those holding a diarylheterocycle nucleus bound with a labile
linkage to a five membered heterocyclic nucleus. On the other hand, most of the compounds
showed good to excellent analgesic activity. Compounds 5,9,10 & 12 were twice as potent as
the reference standard.
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‫يل حمض الخليك الجديدة كمضادات‬-1-‫تحضير لبعض مشتقات الداي ايريل ايميدازول‬
‫لاللتهاب و مسكن‬
‫للســــــادة‬
2‫الباقى‬
‫ نيرة عبد‬، 1‫مها محمد خليفة‬
‫مـــــــن‬
. ‫ قسم الفارماكولوجى كلية الصيدلة – جامعة األزهر بنات‬2 ‫قسم الكيمياء الصيدلية و‬
1
.
‫ يي مويا اييكريال ات ي م ة كري ليرك ايو م ي م موضي ام‬-1- ‫قد تم تحضير شتيات م شيل اييدار ا يي ا وريدا‬
. ‫ مأةضي اي ن ص‬12 11 9 5 ‫يالياه ب قد تم اخا ر اةضي اي ن ص يدراس ايف رش مويوجى قد ت رل ة عكر ش م‬