A series of 3-(aminoalkyl)- and 3-[(4-aryl-1-piperazinyl)alkyl]oxazolo[4,5-b]pyridin-2(3H)-ones were prepared from their respective oxazolo[4,5-b]pyridin-2(3H)-ones. Several members of this group were found to possess potent analgesic activity in the mouse during a p-phenylquinone writhing induced test. Among them, phenylpiperazine compounds with two-carbon length alkyl chains, 2a and 2b, appeared by high analgesic with little toxicity having neither an antiinflammatory effect nor opioid receptor affinity. The synthesis and structure-affinity relationships for this series are detailed.
A series of 1-(aminoalkyl)- and 1-[(4-aryl-1-piperazinyl)alkyl]oxazolo[5,4-b]pyridin-2(1H)-one derivatives of oxazolo[5,4-b]pyridin-2(1H)-one, incorporating modifications to the length of the alkyl side chain and to the amino or 4-aryl-1-piperazinyl substituents, were tested for safety and analgesic efficacy in mice and rats. Some compounds with 4-(substituted or nonsubstituted phenyl)-1-piperazinyl substituents and a 3-4-carbon alkyl side chain had significantly greater analgesic activity than that of the oxazolo[4,5-b]pyridin-2(3H)-one analogs. To reduce the metabolic N-dealkylation of the piperazine observed in our previous work on oxazolo[4,5-b]-pyridin-2(3H)-ones, analogs of the most active compounds with steric hindrance on the alkyl side chain were prepared and tested. The compound with the maximal combination of safety and analgesic efficacy was 1-[[4-(4-fluorophenyl)-1-piperazinyl]propyl]oxazolo[5,4-b]pyridin- 2(1H)-one (compound 3b), with ED50 values of 5.6 mg/kg po (mouse, phenylquinone writhing test) and 0.5 mg/kg po (rat, acetic acid writhing test). Compound 3b is a potent, rapid-acting, non-opioid, nonantiinflammatory analgesic with low acute toxicity and sustained effect.
Different enzymatic routes for the production of (R)-seudenol
were investigated. The Novozym 435-catalyzed reaction of
racemic seudenol with vinyl butyrate proved to be the most
promising route. By using vinyl laurate as an acyl donor, (R)-seudenol laurate could be separated from (S)-seudenol by an
extractive work-up procedure. A nonaqueous hydrolysis allowed
the isolation of pure (R)-seudenol. Scaling up to 7 kg resulted
in a robust reproducible process.
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