(−)‐N‐[(Cyclopropyl) methyl]‐3,4‐dimethoxy‐5‐methylmorphinan‐6‐one, an opioid agonist with preference for kappa opioid receptors

Abstract

N-Allyl-and N-[(cyclopropyl)methyl]-3,4-dimethoxy-5-methylmorphinan-6-one (9 and 10, resp.) were synthesized from 5-methyldihydrothebainone (1). This essential intermediate was prepared from thebaine via 5-methylthebaine (5) employing a novel route. The pharmacological studies showed 9 and 10 to be potent opioid agonists. Compound 10 was found to have preference for kappa rather than mu opioid receptors.Introduction. -The opioid agonistic properties of N-methylmorphinan-6-ones are very much dependent on the substitution pattern at the aromatic ring [l]. Besides the 'natural' substitution pattern 3-hydroxy-4,5-epoxy, the 4-monomethoxy and the 3,4-dimethoxy substitution was found to be most effective. Among the compounds with high antinociceptive potency was 3,4-dimethoxy-5,17-dimethylrnorphinan-6-one (6) [2], which prompted us to replace its N-CH, group by substituents known to introduce in most cases opioid antagonistic effects in morphinans. We chose the N-ally1 and the N-(cyclopropy1)-methyl group which are present in the opioid antagonists naloxone and naltrexone, respectively.

Development of 5-SubstitutedN-Methylmorphinan-6-ones as Potent Opioid Analgesics with Improved Side-Effect Profile

“…Introduction of an alkyl substituent in position 5 of thebaine ( 2 ) can be accomplished by formation of the thebaine anion using n -butyllithium in THF at low temperature [ 18 ], followed by alkylation with the respective alkylating agent (methyl fluorosulfonate, dimethyl sulfate, or benzyl chloride), yielding 5-methylthebaine ( 3 ) and 5-benzylthebaine ( 4 ), respectively [ 18 – 21 ]. Treatment with performic acid afforded 14-hydroxy-5-methylcodeinone ( 5 ) [ 19 , 20 ] and its 5-benzyl analogue 6 ( Scheme 1 ) [ 14 ]. The β -orientation of the 14-hydoxy group was proved by X-ray analysis [ 20 ].…”

“…14-O-Alkylation of 5 with dimethyl or diethyl sulfate in DMF in the presence of NaH gave the respective 14-alkoxycodeinones 7 and 8 which were catalytically hydrogenated to afford 10 and 11 . Ether cleavage of both compounds with 48% HBr solution yielded 77% of 14-methoxymetopon ( 13 ) and 75% of 14-ethoxymetopon ( 14 ) [ 19 , 20 ]. Analogously, 5-benzyl-14- O -methyloxymorphone ( 15 ) (75% from 12 ) was obtained from 14-hydroxy-5-benzylcodeinone ( 6 ) via intermediates 9 and 12 ( Scheme 1 ) [ 14 ].…”

A Novel Method for the Introduction of a 5β-Methyl Group into 4,5α-Epoxymorphinan-6-onesvia the Enol Ether

“…layer dried and evaporated. The resulting brownish foam (760 mg, 78%), which could not be purified by crystallization, was chromatographed (silica gel 60; CH 2 Cl 2 /MeOH/NH 4 17-(Cyclopropylmethyl)-6,7-didehydro-4,5a-epoxy-3,6,14b-triethoxymorphinan (2b). As described for 2a, with 1´HCl (4.0 g, 10.59 mmol), NaH (1.5 g, 62.50 mmol) anh.…”

“…Introduction. ± The 5b-methyl-substituted 14b-alkoxy-4,5a-epoxymorphinan-6-ones [1] [2] are usually prepared from 5-methylthebaine, which is available from thebaine [3] [4]. As this method is restricted to the 5-methylation of thebaine, 4,5aepoxymorphinans containing a 5b-methyl group have to be prepared from this alkaloid.…”