Syntheses of 10-Oxo, 10.ALPHA.-Hydroxy, and 10.BETA.-Hydroxy Derivatives of a Potent .KAPPA.-Opioid Receptor Agonist, TRK-820

Abstract

Syntheses of 10-oxo, 10a a-hydroxy, and 10b b-hydroxy derivatives of a potent k k-opioid receptor selective agonist, TRK-820, are described. These derivatives were supposed to be potential degradation products in formulation of TRK-820 as a result of autoxidation. 10-Oxo-TRK-820 11 was derived from 10-oxo-4,5-epoxymorphinan 14 in 10 steps in 32% overall yield. Reduction of the 10-oxo group in 4,5-epoxymorphinan with NaBH 4 gave 10b bhydroxy-4,5-epoxymorphinan, exclusively. A stepwise inversion method of the 10b b-hydroxy group to produce 10a a-hydroxy-4,5-epoxymorphinan was established. By HPLC analyses, 10a a-hydroxy-TRK-820 12 was confirmed to be one of the degradation products in developing formulation of TRK-820.

Chemoenzymatic Total Synthesis of (+)-10-Keto-Oxycodone from Phenethyl Acetate

“…For the formation of epi - 15 , on the other hand, the hydride served as the nucleophile and thus in the product the methoxy group ended up on the alpha face. The assignment of 15 and epi - 15 as beta and alpha epimers was based on the coupling constants ( J 9-10 ) between the H-10 (benzylic C-H) and H-9 on similar systems [4,60]. For compounds similar to 15 , J values are approximately 5.0 Hz and for epi - 15 , J values are around 0 Hz.…”

“…A highly selective κ-opioid agonist may provide a useful analgesic free from abusive potential [3]. Among the efforts directed toward the preparation of the afore-mentioned 10-keto opiates are those aimed at the preparation of 10-keto, 10α-, 10β-hydroxy-TRK-820 [4], 10-keto-naltrexone, 10-keto-oxymorphone, 10-keto-oxycodone (Figure 1) [5], 10-keto-naloxone, and 10-keto-naloxone 3-methyl ether [6] from the corresponding opiates. These preparations are all conducted from natural morphinans by semi-syntheses.…”

Discovery of Peripheral κ-Opioid Receptor Agonists as Novel Analgesics

“…9,10) ortho-and meta-Phenol derivatives were synthesized as shown in Chart 2. Amine precursor 9 was reacted with 2-or 3-hydroxycinnamic acid to give 11 and 12, respectively.…”

Rapid sp3-Enriched Scaffold Generation via a Selective Aziridine Amide Ring-Opening Reaction

“…Since this motif can fill a space in a unique and tunable direction with its 3D structure, it has been an attractive scaffold in drug discovery for decades. Consequently, this motif is present in a wide range of marketed drugs, including the neuramidase inhibitor Oseltamivir, which contains a multisubstituted cyclohexane central core, Carmegliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, and fused-piperidine core analogue, and κ-opioid receptor (KOR) agonists Spiradoline and Nalfurafine . (Scheme c).…”