Novel Aryl Ether Derivatives as Antiinflammatory and Analgesics

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, 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.


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 approach 1 . The development of preferential COX-2 inhibitors has been considered as a challenging task to improve benefit/risk ratio of NSAIDs. The diaryl or arylheteroaryl ethers are also known to be selective inhibitors 2 of COX-2.
Nimesulide 3 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 cholestasis 4 . 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.

Experimental
The IR spectra of the synthesized compounds were recorded on a fourier transform IR spectrometer (model Shimadzu 8700). 1

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][6][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.
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).

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.