79499-58-4

The present invention relates to ketamine derivatives of the formula (I), pharmaceutical compositions comprising them, and methods for treating pain comprising administering them, and their use in the manufacture of medicaments for treating pain. The present invention also relates to methods for anaesthetizing and methods for sedating a subject comprising administering ketamine derivatives of the formula (II).

A series of aliphatic esters of the non-opioid anaesthetic/analgesic ketamine were prepared and their properties as shorter-acting analogues of ketamine itself were explored in an infused rat model, measuring the time after infusion to recover from both the anaesthetic (righting reflex) and analgesic (response to stimulus) effects. The potency of the esters as sedatives was not significantly related to chain length, but Me, Et and i-Pr esters were the more dose potent (up to twofold less than ketamine), whereas n-Pr esters were less potent (from 2- to 6-fold less than ketamine). For the Me, Et and i-Pr esters recovery from anaesthesia was 10-15-fold faster than from ketamine itself, and for the n-Pr esters it was 20-25-fold faster than from ketamine. A new dimethylamino ketamine derivative (homoketamine) had ketamine-like sedative effects but was slightly less potent than, but ester analogues of homoketamine had very weak sedative effects.

Two metabolites of the drug ketamine, 2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride (1), have been synthesized.They are the N-demethyl compound, metabolite I (13), and the N-demethyl-5,6-dehydro analogue, metabolite II (15).Three bromo ketone derived from ketamine have also been synthesized and their realtive configuration assigned.In addition, attempted dehydrohalogenation of axial 2-bromoketamine (2a) with sodium amide in liquid ammonia has produced a novel entry into the 6-azabicycloheptane ring system.The structure of the rearrangement product (3) has been confirmed by unequivocal synthesis.Other unusual reactions include the reduction of an N-alkylazetidinone to an N-alkylazetidine and an acid-catalyzed N-alkyl cleavage of a β-lactam.