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

Abstract

Cyanamide (H2NC identical to N), a potent aldehyde dehydrogenase (AlDH) inhibitor that is used therapeutically as an alcohol deterrent agent, is known to be rapidly metabolized and excreted in the urine as acetylcyanamide (1). On the basis of our observation that 1 is deacetylated to cyanamide in vivo, albeit very slightly, thereby serving as a precursor of prodrug form of the latter, several acyl derivatives of cyanamide were synthesized specifically as prodrugs, including benzoylcyanamide (2), pivaloylcyanamide (3), and 1-adamantoylcyanamide (4), as well as long- and medium-chain fatty acyl derivatives such as palmitoyl- (6), stearoyl- (7), and n-butyrylcyanamide (5). N-Protected alpha-aminoacyl and peptidyl derivatives of cyanamide were also synthesized, and these include N-carbobenzoxyglycyl- (10), hippuryl- (13), N-benzoyl-L-leucyl- (14), N-carbobenzoxyglycyl-L-leucyl- (18), N-carbobenzoxy-L-pyroglutamyl- (22), L-pyroglutamyl-L-leucyl- (19), and L-pyroglutamyl-L-phenylalanylcyanamide (20). All of these prodrugs of cyanamide raised ethanol-derived blood acetaldehyde levels in rats significantly over controls 3 h after ip drug administration, and some of these were still capable of elevating blood acetaldehyde 16 h post drug administration. A selected group of cyanamide prodrugs were also evaluated by the oral route of administration and showed nearly equivalent activity as the ip route in elevating ethanol-derived blood acetaldehyde. These results suggest potential utility of these prodrugs as deterrent agents for the treatment of alcoholism.

Unprecedented Aromatic Homolytic Substitutions and Cyclization of AmideIminyl Radicals: Experimental and Theoretical Study

“…The preparation of N-acetylcyanamides, N-benzoylcyanamides, and some of their derivatives has been reported, but these molecules often show a lack of stability. [31][32][33][34] N-acylcyanamides display properties in different fields, for instance, as prodrugs of cyanamide, [32] enzymatic inhibitors, [35] or heteroanalogues of ethylenes, [36] so there was also interest in finding a practical way of preparing them. Although N-acylcyanamides and their parent compound, cyanamide, have been reported mainly as unstable compounds, the synthesis of a few of the N,N-diacyl and N,N-dialkyl analogues has been described under the experimental conditions that we decided to follow first.…”

“…Although N-acylcyanamides and their parent compound, cyanamide, have been reported mainly as unstable compounds, the synthesis of a few of the N,N-diacyl and N,N-dialkyl analogues has been described under the experimental conditions that we decided to follow first. [33][34]37] Therefore, our preliminary preparation installed the cyanamide moiety by nucleophilic displacement of the mesylate group of quinoline derivative 1 with the cyanamide salt (Scheme 3). [37] As the major product present in the crude material seemed to be the dialkylated cyanamide 2 and in order to prevent the dialkylation process, we treated the cyanamide sodium salt in a one-pot procedure successively with a carboxylic acid chloride [32] and with 2-iodobenzylmesylate.…”

Radical Cyclization of N‐Acylcyanamides: Total Synthesis of Luotonin A

“…Indeed, to the best of our knowledge, no radical reaction involving these moieties has appeared in the literature. Synthesizing the N ‐acylcyanamides substrates was challenging: the preparation of N ‐acetyl‐ and N ‐benzoylcyanamides and some of their derivatives has been reported, but those molecules often show a lack of stability 12–15. As N ‐acylcyanamides display properties in other fields, for instance, as prodrugs of cyanamide,13 enzymatic inhibitors16 and heteroanalogues of ethylenes,17 there is also an interest in their practical synthesis.…”

Synergistic Effect between Ultrasound Irradiation and Na 2 CO 3 in N ‐Acylation Reaction: Applied for the Synthesis of Novel N ‐Acylcyanamide Derivatives

“…In addition to cyanamides, the related N ‐acylcyanamides are one of the substantial categories of pharmaceutical compounds. Cyanamide ( 1 ), N ‐acetylcyanamides ( 2 ) and its derivatives ( 3‐9 ), act as potent aldehyde dehydrogenase (A1DH) inhibitors and have been reported as potent agents for the treatment of alcoholism (Scheme ) …”

“…Taking advantage of radical reactions of N ‐acylcyanamides, several types of these materials have been constructed. This scaffold typically prepared through the N ‐acylation of cyanamide salts, base‐promoted N ‐acylation of cyanamides, two‐step sequence of cyanation/acylation, or acylation/cyanation of amines . Thus, the N ‐acylation of cyanamides seems to be an efficient and general strategy to prepare these materials.…”