Process for the preparation of hydroxy-pyrrolidinyl hydroxamic acid derivatives being opioid kappa receptor agonists

A method for preparing hydroxamic acid derivatives of the formula: and the salt thereof, wherein A is hydroxy, Ar is phenyl, or phenyl substituted with up to three substituents selected from chloro, methyl and CF3, more preferably 3,4-dichlorophenyl, R is hydrogen, and X is phenyl, naphthyl, biphenyl, indanyl, benzofuranyl, benzothiophenyl, 1-tetralone-6-yl, C1-C4alkylenedioxy, pyridyl, furyl and thienyl, these groups optionally being substituted with up to three substituents selected from halo, C1-C4alkyl, C1-C4alkoxy, hydroxy, NO2, CF3 and SO2CH3. This invention also provides novel intermediates which are useful for preparing compounds of Formula I. The hydroxamic acid derivatives of formula (I), wherein A is hydrogen or hydroxy and R is hydrogen or C1-C4alkyl, exhibit significant agonist activity toward opioid kappa -receptor. Therefore these kappa agonists are particularly useful as an analgesic agent in mammals, especially humans. They are also useful as antiinflammatory, diuretic, anesthetic or neuroprotective agents, or an agent for treatment of stroke or functional bowel diseases such as abdominal pain, for the treatment of a mammalian subject, especially a human subject.