Gu L, Strickley R G
Institute of Pharmaceutical Sciences, Syntex Research, Palo Alto, California 94304.
Pharm Res. 1988 Dec;5(12):765-71. doi: 10.1023/a:1015984617472.
The degradation kinetics, products, and mechanisms of RS-10029 (2), 2-[2-[(1-carboxylic acid)-3-phenylpropyl]amino-1-oxopropyl] 6,7-dimethoxy- 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (S,S,S), in aqueous solutions from pH 1 to pH 13 were studied at 50, 60, and 80 degrees C. Pseudo-first-order kinetics were obtained throughout the entire pH range studied, and the log(rate)-pH profile reflected four kinetic processes (ko, k'o, k"o, and kOH) as well as the three pka's of 2. Excellent mass balance (greater than 96%) was obtained for the four major products 3-6 throughout the entire pH range studied even though four other minor products can be detected by high-performance liquid chromatography (HPLC). At pH 8.0 and below, intramolecular aminolysis leading to diketopiperazine (DKP) 5 accounted for greater than 65% of the neutral or water-catalyzed (ko and k'o) processes. Amide hydrolysis leading to products 3 and 4 and epimerization of DKP 5 to the (R,S,S) diastereomer 6 accounted for the remaining 35% of the neutral or water catalyzed processes. At pH values above 8.0, DKP 5 formation begins to decrease as the amide hydrolysis increases so that both mechanisms account for the neutral or water-catalyzed k"o process. Above pH 11.0 amide hydrolysis dominates and is responsible for the specific base-catalyzed (kOH) process. The four minor products detected by HPLC are two diastereomers (7 and 8) of 2 and the two diastereomers (9 and 10) of the DKP 5. The stability results between 2 and its ester prodrug (1) are compared.
