Synthesis, Crystal Structural and Pharmacological Study of N-Cyclopropylmehtyl-7α-[(R)-1-hydroxyl-1-methyl-3-(thien-2-yl)propyl]-6,14-endoethanotetrahydronooripavine

He Liu,* Bo-hua Zhong, Chun-he Liu, Bo Wu, and Ze-Hui Gong
No. 7 Department, Institute of Pharmacology and Toxicology Academy, Beijing 100850, P. R. China

N-Cyclopropylmethyl-7α-[(R)-1-hydroxyl-1-methyl-3-(thien-2-yl)propyl])-6,14-endoethanotetrahydrooripavine (thienorphine, I), has been synthesized and evaluated for its in vivo analgesic activities. Thienorphine was structurally characterized by infrared (IR), NMR spectra, FAB-MS and X-ray diffraction. The crystal structure indicates that thienorphine maintained the main rigid structure of morphine and contains a C6-C14 enthano bridge. The C7 substituent is 1-hydroxyl-1-methyl-3-(thien-2-yl)propyl group adopting R-configuration. The cyclopropylmethyl group is located at the equatorial position as expected. The packing diagram of thienorphine showed the presence of the intramolecular and intermolecular OHO hydrogen bond linking the molecules into an infinite quasi-one-dimensional chain structure. In vivo pharmacological study thienorphine exhibited excellent analgesic activity.

Key words: crystal structure, oripavine derivative, analgesic