Novel aryl ether derivatives as antiinflammatory and analgesics

Article abstract of DOI:10.1155/2011/545403

The diaryl ether moieties have attracted considerable attention of medicinal chemists as they are endowed with a wide range of diverse biological activities. The present study involves synthesis, characterization of some new aryl ethers and evaluation of their antiinflammatory and analgesic activity. A series of new aryl ether derivatives [4(a-h), 5] were prepared by Ullmann's ether condensation. The structures of new compounds are supported by their IR, 1H NMR and Mass spectra. The new derivatives were evaluated for their antiinflammatory and analgesic activity. Among the tested, compound 3 has shown better antiinflammatory and analgesic activity.

Full text of DOI:10.1155/2011/545403

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2011, 8(3), 1401-1407
http://www.e-journals.net
Novel Aryl Ether Derivatives as
Antiinflammatory and Analgesics
P. RASHMI*, GOPAL KRISHNA RAO, KSHAMA DEVI§,
B.G. SHIVANANDA§, G. R. SWETHA and SUNEETHA GA§
*Department of Pharmaceutical Chemistry
§Department of Pharmacology Al-Ameen College of Pharmacy
Hosur Road, Bangalore-560027, India
Nargund College of Pharmacy
II Main Dattatreyanagar, Bangalore-560085, India
rshvsh@gmail.com
Received 26 September 2010; Accepted 27 November 2010
Abstract: The diaryl ether moieties have attracted considerable attention of
medicinal chemists as they are endowed with a wide range of diverse biological
activities. The present study involves synthesis, characterization of some new
aryl ethers and evaluation of their antiinflammatory and analgesic activity. A
series of new aryl ether derivatives [4(a-h), 5] were prepared by Ullmann’s
ether condensation. The structures of new compounds are supported by their
1
IR, H NMR and Mass spectra. The new derivatives were evaluated for their
antiinflammatory and analgesic activity. Among the tested, compound 3 has
shown better antiinflammatory and analgesic activity.
Keywords: Aryl ethers, Antiinflammatory activity, Analgesic activity.
Introduction
Classical NSAIDs are nonselective inhibitors of COX. Their long term use leads to ulceration.
After the discovery of COX-2, its selective inhibition is considered as an alternative
pharmacotherapeutic approach1. The development of preferential COX-2 inhibitors has been
considered as a challenging task to improve benefit/risk ratio of NSAIDs. The diaryl or aryl-
heteroaryl ethers are also known to be selective inhibitors2 of COX-2.
Nimesulide3 an antiinflammatory agent with an aryl ether linkage is a preferential COX-2
inhibitor. But nimesulide induced liver injury gained investigative interest and was found to
cause hepatocellular necrosis or cholestasis4 So there is a need for synthesis of new
.
derivatives which are as effective as nimesulide, overcoming its side effects. So the
objective of present project is to synthesize and characterize some new aryl ethers and
evaluate their antiinflammatory and analgesic activity.

Novel Aryl Ether Derivatives as Antiinflammatory and Analgesics
1402
Experimental
The IR spectra of the synthesized compounds were recorded on a fourier transform IR
1
spectrometer (model Shimadzu 8700). H NMR spectra were recorded on DMM X - 200
MHz NMR, Bruker Daltonics, Karsruhe, Germany. Mass spectra were recorded on mass
spectrophotometer (model Shimadzu) by LC-MS. Merck GF254 pre-coated silica plates
were used for TLC. The melting points are uncorrected.
NO2
NO2
O
Cl
HO
DMF/K2CO3
+
(1)
Fe/HCl
NH2
O
O
Cl
R
NH
NH
O
O
O
2°Amines
ClCOCH2Cl
C6H6
1,4-dioxane
(2)
(4a-4h)
(3)
Scheme 1
O
O
NH2
O
C6H6
HN
Cl
+
O
(2)
(5)
Scheme 2
Preparation5 of o-phenoxynitrobenzene (1)
To a solution of o-chloronitrobenzene (0.15 M) in DMF, equimolar quantities of K2CO3 and
phenol were discharged and refluxed with stirring for 8 h. After completion added water,
then extracted with methylene chloride which was distilled off to get yellow liquid product.
% Yield: 86.5%, boiling point: 237 0C.
Preparation of o-phenoxyaniline (2)
o-Phenoxynitrobenzene (0.05 M) in ethanol (50% w/w) was subjected to reduction with iron
(0.05 M) and dil.HCl [in 10 mL of 50% w/w ethanol]. After addition, stirred for another 1 h,
cooled and added 15% KOH in pure ethanol. Filtered, concentrated and mother liquor
cooled in ice. Crystals formed were recrystallised from hexane. % Yield: 54.05%, melting
point: 256 0C.
Preparation6 of 2-chloro-N-(2-phenoxyphenyl)acetamides (3)
To ice cold solution of o-phenoxyaniline (0.01 M) in dry benzene added chloroacetylchloride
(0.05 M) in benzene drop wise with stirring. The reaction mixture refluxed for 4 h and
benzene distilled off. The residue was extracted with petroleum ether and evaporated to get
yellow solid. % Yield85.25%, Melting point: 64 0C.

1403
P. RASHMI et al.
1
IR(KBr) cm-1: 3366.79 (NH str.), 1695.31 (C=O str), 1604.66, H NMR (CDCl3)δ :-
8.90 {s, NH (1H)}, 7.37-6.88 {m, Ar-H (9H)}, 2.17-2.14 {d, CH2 (2H)}, 589.23 (C=C
Ar str.), 1319.22 (C-N str.), 1217.00 (C-O-C str). : Base peak (262), M+ (262), M+1
(263), M+2 (264.).
General procedure7 for the preparation of 2-substituted-N-(2-phenoxyphenyl)
acetamides (4a-4h)
The compound (3) [(0.01 M)], different secondary amines [(0.03 M)] and freshly distilled 1,
o
o
4-dioxan were heated for 4 h at 50 C to 100 C with occasional swirling. The reaction
mixture was added to ice cold water. The contents were cooled in ice; precipitate was
filtered and crystallized from aqueous ethanol.
Spectral data of selected compounds
2-Morpholin-4-yl-N-(2-phenoxyphenyl)acetamide (4a)
IR(KBr) cm-1: 3255.62 (NH str.), 1703.03 (C=O str), 1585.32, 1531.37 (C=C Ar str.),
1
1263.6 (C-N str.), 1218.93 (C-O-C str). H NMR (CDCl3) δ :- 9.70 {s, NH (1H)}, 7.3-6.9
{m, Ar-H (9H)}, 3.5-3.4{t, OCH2 (4H)} 3.1-3.0 {s, Ali CH2 (2H)}, 2.5-2.4 {t, N-CH2 (4H)}.
Mass : Base peak (313), M+ (313).
N-(2-phenoxyphenyl)-2-piperazin-1-ylacetamide (4b)
IR(KBr) cm-1: 3286.48 (NH str.), 3263.33 (ring NH1 str), 1681.81 (C=O str), 1587.31,
1531.37 (C=C Ar str.), 1249.79 (C-N str.), 1215.07 (C-O-C str). 1H NMR (CDCl3)
δ :- 10.01{s NH-piperazine ring (1H)}, 8.5 {s, NH (1H)}, 7.3-6.9 {m, Ar-H (9H)}, 3.25{s,
CH2 (2H)}, 2.8-2.6 {t, NH-CH2 (4H)}, 2.5-2.4 {t, N-CH2 (4H)}. Base peak (312), M+1
(312), M+2 (313).
2-(Dimethylamino)-N-(2-phenoxyphenyl)acetamides (4c)
IR(KBr) cm-1: 3391.77 (NH str.), 1691.06 (C=O str), 1602.74, 1560.08 (C=C Ar str.),
1
1317.29 (C-N str.), 1215.07 (C-O-C str). H NMR (CDCl3) δ :- 8.9 {s, NH (1H)}, 7.4-6.6
{m, Ar-H (9H)}, 4.2-4.0 {s, CH2 (2H)}, 1.6-1.2 {s, 2CH3 (6H)}.
2-(1H-Imidazol-1-yl)-N-(2-phenoxyphenyl)acetamides (4e)
IR(KBr) cm-1: 3217.04 (NH str.), 1701.00 (C=O str), 1606.59, 1546.80(C=C Ar str.),
1
1301.86 (C-N str.), 1211.21 (C-O-C str). H NMR (CDCl3) δ:- 9.84 {s, NH (1H)},
7.59-6.6 m, Ar-H (12H)}, 4.9 {s, CH2 (2H)}. 2.2-1.5 {m, 2CH2 (4H)}, 1.4 {t, 2CH3
(6H)}. 1101.3 (Ar-Cl), 3.2 - solvent impurity. Mass : Base peak (294), M+ (294),
M+1 (295).
(1-{2-Oxo-2-[(2-phenoxyphenyl)amino]ethyl}-1H-indol-3- yl) acetic acid (4f)
IR(KBr) cm-1: 3390.63 (OH str), 3134.11 (NH str.), 1703.03 (C=O str), 1606.59, 1537.
1
16(C=C Ar str.), 1303.79 (C-N str.), 1217. (C-O-C str). H NMR (CDCl3) δ :- 12.13
{s, COOH (1H)}, 10.89 {s, NH (1H)}, 8.05-6.6 {m, Ar-H (14H)}, 4.3 {s, CH2 (2H)}, 3.3
{s, CH2 of CH2COOH (2H)}.
Preparation of N-(2-phenoxyphenyl)benzamide (5)
To ice cold solution of o-phenoxyaniline (0.01 M) in dry benzene added
benzoylchloride (0.01 M) in benzene with stirring. Stirring continued for half an hour.

Novel Aryl Ether Derivatives as Antiinflammatory and Analgesics
1404
The reaction mixture refluxed for 4 h and benzene distilled off. The residue was
extracted with petroleum ether and evaporated to get solid. IR(KBr) cm-1: 3230.54 (NH
str.), 1656.74 (C=O str), 1587.31, 1525.59 (C=C Ar str.), 1217.00 (C-O-C str). Base
peak (290), M+ (290), M+1 (291).
Table 1. Physicochemical properties
O
R
NH
O
Compound code
R
% Yield
47.9
Melting point, 0C
Morpholine
Piperazine
-N(CH3)
118
94
4a
4b
4c
4d
4e
4f
63.05
54.81
43.34
38.7
78
-N(C2H5)
Imidazole
88
184
148
210
78
Indole-3-acetic acid
-NC4H10
56.43
61.23
56.33
44.86
4g
4h
5
-NHNH2
-COC6H5
114
Pharmacological studies
In the present study we evaluated the analgesic and anti-inflammatory activities of the
synthesized compounds and nimesulide was standard. A simple technique to evaluate
inflammatory pain along with anti-inflammatory studies in carrageenan–induced paw edema
developed by Jain et al.5-7 was used.
Percentage protection was calculated by using the formula, % protection = (1- Vt / Vc)
X 100, where Vt is the mean increase in the paw volume in the test group. Vc is the mean
increase in the paw volume in the control group.
Results and Discussion
In the present work, series of new analogues of diaryl ethers were synthesized and the
structures were supported by their spectra. Of the ten synthesized, eight were (3, 4(a-e),
4g and 4h) were subjected to evaluation.
Anti-inflammatory activity and analgesic activity
Nimesulide shown onset antiinflammatory action at 90 min. It exhibited significant
antiinflammatory activity at 120 min and retained the same significance level even at 180 min.
The onset of analgesic action was by 30 min, maximum activity was between 90 and 120 min
and showed decline in the activity by 180 min.
The compound (3) exhibited onset of action and significant anti-inflammatory activity
at 120 min. A d ecline in the activity at 180 min indicated its short duration of action.

1405
P. RASHMI et al.
It has shown onset at 60 min and significant analgesic activity from 90 min to 120 min.
Compared to the standard the potency of compound (3) was found to be less.
Substitutions to Ω chlorine of compound (3) have not augmented the anti inflammatory
and analgesic potency significantly. (4b) with piperazine substitution to (3) also exhibited
similar analgesic activity. Imidazole substitution (4e) exhibited early onset of action when
compared to compound (3).
The results are shown in Table 2 & 3 and Figures 1,2,3 & 4.
Table 2. Antiinflammatory activity
Groups
90 min
120 min
180 min
Control
14.58 0.49
11.33 0.55**
13 0.57 ns
20.83 0.47
7.67 0.21***
14.17 0.47***
14.83 0.47***
13.83 0.40***
15.00 0.36***
15.33 0.33***
14.67 0.49***
15.67 0.21**
14.33 0.33***
6.97***
18.67 0.77
13.33 0.42***
15.50 0.76*
16.17 0.30*
15.67 0.21**
15.50 0.61**
15.83 0.47*
16.00 0.25**
16.50 0.56*
15.33 0.21 **
6.73 ***
Nimesulide
3
4a
13.67 0.42ns
13 0.51 ns
4b
13 0.36 ns
4c
15.67 0.21ns
14.17 0.16 ns
14.83 0.40ns
13.17 0.16ns
7.96***
4d
4e
4g
4h
F value
ns→ non significant, *→ p < 0.05, **→ p < 0.01, ***→ p < 0.001
Table 3. Analgesic activity
Groups
60 min
90 min
120 min
180 min
Control
5.33 0.84
9.33 0.44**
6.94 1.66*
7.44 0.32*
8.50 0.35*
6.39 0.49 ns
8.83 1.20*
7.39 0.26*
6.39 0.21 ns
6.22 0.49 ns
8.07***
3.83 1.88
9.14 0.82***
6.81 0.33**
6.50 0.28*
7.89 0.22**
4.56 0.81 ns
6.20 0.43*
6.98 0.30**
5.22 0.14 ns
5.44 0.07 ns
3.88***
3.94 0.26
9.17 0.89***
6.33 1.31**
6.27 0.56**
6.17 0.44**
4.28 0.67 ns
6.18 0.29**
6.17 0.11**
4.22 0.22 ns
5.14 0.11 ns
4.35***
1.78 0.26
4.03 0.73*
4.17 1.45*
3.78 0.22*
3.39 0.49*
3.78 0.42*
2.11 0.22 ns
3.28 0.10*
3.33 0.86*
3.85 0.37*
4.43***
Nimesulide
3
4a
4b
4c
4d
4e
4g
4h
F value
ns→ non significant, *→ p < 0.05, **→ p < 0.01, ***→ p < 0.001

Novel Aryl Ether Derivatives as Antiinflammatory and Analgesics
1406
80
70
60
50
40
30
20
10
0
Nimesulide
3
4a
4b
4c
30 min
60 min
90 min 120 min 180 min
Time in min
Figure 1. GraphicTiamlec, moimn parison of antiinflammatory activity
80
70
60
50
40
30
20
10
0
Nimesulide
3
4d
4e
4g
4h
30 min
60 min
90 min
Time, min
120 min
180 min
Figure 2. Graphical comparison of antiinflammatory activity
80
60
40
20
0
Nimesulide
3
4a
4b
4c
30 min 60 min 90 min 120 min 180 min
Time, min
Figure 3. Graphical comparison of analgesic activity
80
70
60
50
40
30
20
10
0
Nimesulide
3
4d
4e
4g
4h
30 min
60 min
90 m in
120 min
180 min
Time, min
Figure 4. Graphical comparison of analgesic activity

1407
P. RASHMI et al.
Conclusion
The main focus of this research work was to synthesize, purify, characterize and evaluate
pharmacological activities of the newly synthesized aryl ethers. A novel and single method
was used to perform both the anti-inflammatory and analgesic activities using the rat paw
edema method. Most of the compounds tested showed good anti-inflammatory and analgesic
activity at the dose of 20 mg / kg.
Acknowledgment
The author expresses his sincere gratitude to Al-Ameen College of Pharmacy, Bangalore,
for their kind help and guidance. Dr.K.S.Bhide, Director R.& D, Astra-Zeneca Pharma India
1
Ltd., for providing H-NMR spectra and to members of Quest, Bangalore for providing
Mass spectra of the synthesized compounds.
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1.
Leval X, Delarge J, Somers F, Tullio P, Henrotin Y, Pirotte B and Dogne J M, Curr
Med Chem., 2000, 7, 1041-1062.
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Pericherla S, Mareddy J, Rani G D P, Gollapudi P V and Pal S, J Braz Chem Soc.,
2007, 18(2), 384-390.
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Kulkarni S K, Curr Sci., 2002, 83(12), 1442-1443.
Thawani V, Sontakke S, Gharpure K and Pimpalkhute S, Indian J Pharm., 2003, 35,
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Gupta S K, Bansal P, Bharadwaj R K and Velpandian T, Pharmacol Res., 2000,
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