14-Methoxymetopon ( = 5,1443 -dimethyloxymorphone; 4) and 14-ethoxymetopon (5) were synthesized from 14-hydroxy-5-methylcodeinone (6). In the AcOH-writhing test in mice, compound 4 was found to be ca. 20000 times more potent than morphine.Introduction. -5-Methyloxymorphone ( = 14-hydroxymetopon; 1) was found to possess slightly less opioid-agonist properties than oxymorphone (2) [2]. When compared to the highly potent opioid agonist 14-0-methyloxymorphone (3) [3], compound 1 CH3 '"/ R2 1 R'=R3=H,R2=CH, 2 R' = R2 = R3 = H (oxymorphone) 3 R'=CH,,R2=R3=H 4 R'=R2=CH3,R3=H 5 R' = C, H, , R2= CH,, R3 = H 9 R'=R2=R3=CH3 10 R'=C,H,, RZ=R3=CH3 12 R'=C2H,,R2=R3=H N /cH3 6 R' = H, R2 = CH, 7 R'=R2=CH3 11 R'=CH,, R 2 = H 8 R' = C2H,, R~ = CH,showed ca. 1/100th the antinociceptive potency in the AcOH-writhing test [2]. It was of interest if a 14-0-alkylation of 1 (to give compounds 4 and 5) would enhance its opioid agonist properties to a similar extent as a 14-0-alkylation of oxymorphone into compound 3 could [3]. I)part 7: [I].

14-0-Ethyl-5-methylnaloxone (7) and 14-0-ethyl-5-methylnaltrexone (8) have been prepared starting from 14-0-ethyl-5-methyloxycodone (9) in several steps. Both, 7 and 8, were found to be opioid antagonists in vitro and in vivo. Compound 7 exhibited some selectivity forp opioid receptors, whereas compound 8 did not show selectivity for any of the receptor types. In the AcOH-writhing antagonism test, 8 was not able to antagonize morphineinduced antinociception, but antagonized fentanyl-and sufentanil-induced antinociception.

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284ChemInform Abstract The title compound (IIIa) is 20000 times more potent than morphine and (IIIb) is 130 times less potent than (IIIa).