Transformation of Codeine to an Analog of the Potent Analgesic Phenazocine

Abstract

Codeine has been transformed to an analog IX of phenazocine incorporating the 4,5-oxygen bridge originally present in the parent alkaloid. The analgesic activity of IX was found to be approximately twice that of morphine.

Acyl, N-protected .alpha.-aminoacyl, and peptidyl derivatives as prodrug forms of the alcohol deterrent agent cyanamide

“…Treatment of rats with Z-NHCN (8) followed by ethanol gave rise to blood AcH levels of 1212 ± 62 µ at 3 h (Figure 2). Similarly, Z-Gly-NHCN (10) and Z-Gly-L-Leu-NHCN ( 18) elevated blood AcH in excess of 100-fold over controls. Bz-Gly-NHCN (13) and Bz-L-Leu-NHCN ( 14) not only elevated blood AcH levels at 3 h but also were longer acting, with ethanol-derived blood AcH significantly elevated even at 16 h (Figure 2).…”

“…The oral route of administration of selected cyanamide prodrugs was directly compared to the ip route in a sideby-side experiment (Figure 3). It can be seen that except for Z-Gly-NHCN (10), which was more effective by the ip route in raising blood AcH, palmitoylcyanamide (6), as well as phenylacetylcyanamide (23) and acetylcyanamide (1) as their sodium salts, had equivalent activity using the two different modes of drug administration.…”

“…N-Carbobenzoxycyanamide (Z-NHCN, 8), prepared by treating excess cyanamide in aqueous base with benzyloxycarbonyl chloride, was unstable at room temperature and was therefore isolated also as its sodium salt. IV-Phthaloylglycylcyanamide (9), Z-Gly-NHCN (10), Z-L-Leu-NHCN (11), and Boc-L-Leu-NHCN (12) were prepared by condensation of the N-protected amino acids via their IV-hydroxysuccinimide activated esters with excess cyanamide in the presence of varying concentrations of aqueous sodium hydroxide. Interestingly, the urethane-protected (a-aminoacyl)cyanamides were unstable; for example, attempted recrystallization of 10 from hot ethyl acetate, or allowing of 11 and 12 to stand at room temperature, resulted in an intramolecular cyclization reaction.13 Compound 10, however, was successfully recrystallized from THF/petroleum ether.…”

“…The quantities liberated need not be large; for example, >90% of the administered dose of cyanamide is known to be excreted as the inactive acetylated conjugate within 6 h;12 yet, cyanamide is the most potent in vivo AIDH inhibitor known.27 This suggests that the relatively small fraction of cyanamide that is bioactivated by catalase is sufficient to exert a profound inhibitory action on AIDH. 10 To the extent that some of the acyl derivatives of cyanamide-especially, the long-chain fatty acylcyanamides-are highly lipophilic and may deposit in adipose tissues from where they may be slowly released into the circulation via the lymphatic system, these prodrugs are (25) Uliana, J. A.; Doolittle, R. F. Arch.…”

Synthesis of 7β-hydroxy-8-ketone opioid derivatives with antagonist activity at mu- and delta-opioid receptors

“…The epoxidation of morphine proved unsuccessful and a 7β,8β-epoxide could only be obtained from 3-methoxymethylmorphinone, using hydrogen peroxide in aqueous methanol containing sodium hydroxide, revealing the relevance of the C6 substituent on the outcome of this oxidation [23,24]. Oxidations with osmium tetroxide succeeded to give the respective diols [25][26][27][28]. However, they were also highly dependent on the substituent present at C6, with more electron withdrawing substituents giving lower product yields.…”