Discovery of potent transient receptor potential vanilloid 1 antagonists: design and synthesis of phenoxyacetamide derivatives.

We aimed to discover a novel type of transient receptor potential vanilloid 1 (TRPV1) antagonist because such antagonists are possible drug candidates for treating various disorders. We modified the structure of hit compound 7 (human TRPV1 IC50=411 nM) and converted its pyrrolidino group to a (hydroxyethyl)methylamino group, which substantially improved inhibitory activity (15d; human TRPV1 IC50=33 nM). In addition, 15d ameliorated bladder overactivity in rats in vivo.

Syntheses of 10-oxo, 10 alpha-hydroxy, and 10 beta-hydroxy derivatives of a potent kappa-opioid receptor agonist, TRK-820.

Syntheses of 10-oxo, 10alpha-hydroxy, and 10beta-hydroxy derivatives of a potent kappa-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 10beta-hydroxy-4,5-epoxymorphinan, exclusively. A stepwise inversion method of the 10beta-hydroxy group to produce 10alpha-hydroxy-4,5-epoxymorphinan was established. By HPLC analyses, 10alpha-hydroxy-TRK-820 12 was confirmed to be one of the degradation products in developing formulation of TRK-820.

The first example of the stereoselective synthesis of 7 beta-carbamoyl-4,5alpha-epoxymorphinan via a novel and reactive gamma-lactone.

7beta-Carbamoyl-4,5alpha-epoxymorphinans 5 were stereoselectively synthesized from the 7alpha-carboxylate intermediate 3 in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and amines under reflux conditions in mesitylene via a novel and reactive gamma-lactone 7. These were the first examples of the stereoselective syntheses of 7beta-substituted 4,5alpha-epoxymorphinans. The mechanism of the reaction process was elucidated as follows: 1) epimerization of 7alpha-carboxylate 3, 2) intramolecular lactonization of 7beta-carboxylate 6, and 3) aminolysis of the resultant gamma-lactone 7. The aminolysis of the isolated reactive gamma-lactone 7 with allylamine and the alcoholysis with MeOH in the presence of NaBH(4) proceeded at room temperature. The gamma-lactone 7 can be a useful intermediate for the preparation of 7beta-substituted 4,5alpha-epoxymorphinans that would be potent selective delta opioid receptor ligands. The stereoselective syntheses of the 7alpha-carbamoyl-4,5alpha-epoxymorphinans 9 from 7alpha-carboxylate 3 via 7alpha-carboxylic acid were also successful.