Synthesis of novel triplet drugs with 1,3,5-trioxazatriquinane skeletons and their pharmacologies. Part 2: Synthesis of novel triplet drugs with the epoxymethano structure (capped homotriplet)

Synthesis of novel triplet drugs with 1,3,5-trioxazatriquinane skeletons and their pharmacologies. 3: Synthesis of novel triplet drugs with the bis(epoxymethano) or bis(dimethylepoxymethano) structure (double-capped triplet)

“…3). 6 In contrast, double-capped triplet drugs with the N-CPM group demonstrated sufficient binding to each type of opioid receptor independently of their configurations.…”

“…This substituent effect was also observed in other morphinan derivatives. [8][9][10][11] Among compounds with N-Me substituent, SYK-385 (19b) was the most selective for the l receptor and was more selective than KNT-123, 6 which was a capped homotriplet drug with an N-Me group and was reported to show the highest selectivity for the l receptor over the j receptor among the reported l-selective nonpeptide ligands. [12][13][14][15] The affinities of compounds with bulky substituents (iBu or Bn group) on the nitrogen were very low.…”

“…Naltrexone methyl ether (3a) was treated with p-toluenesulfonylmethyl isocyanide (TosMIC) in the presence of K 2 CO 3 , and then 2 M HCl. 6 The thus obtained a-hydroxyaldehyde was converted into oxazoline 4a by the treatment with glycolaldehyde dimer in 50% yield from 3a. The reaction of oxazoline 4a with glycolaldehyde dimer afforded the mixture of double-capped triplets 5a and 6a in 18% and 45% yield, respectively.…”

“…6 One of the synthesized capped triplet drugs, KNT-123 (R 3 , R 4 = OH, R 5 = Me) showed the highest selectivity for the l opioid receptor over the j opioid receptor among the reported l-selective nonpeptide ligands. 6 For the comparison with pharmacological effects induced by triplet drugs 1 or capped triplet drugs 2, we considered the importance of the synthesis of the corresponding double-capped triplet drugs 7 and 8 (Scheme 1), which have a pharmacophore unit and two cap structures. Double-capped triplet drugs 7 and stereoisomer 8 were expected to provide insights into the effect of the 0960-894X/$ -see front matter Ó…”

Synthesis and Pharmacology of a Novel κ Opioid Receptor (KOR) Agonist with a 1,3,5-Trioxazatriquinane Skeleton

“…According to the previously reported method, 11,12 we prepared compounds 1a−c (R = m-OH), 8a−d, and 11a,b. The synthesis of compounds 1a−c (R = m-OH) commenced with m-methoxyacetophenone (2).…”