Acta Chimica 127. (1990)

1. szám - Hosztafi Sándor–Szilágyi László–Makleit Sándor–Tóth Géza: Morphine alkaloids, 107

Acta Chimica Hungarica 127 (1), pp. 9—19 (1990) MORPHINE ALKALOIDS, 107* PREPARATION OF SUBSTITUTED HYDRAZONE DERIVATIVES OF KETONES WITH MORPHINE SKELETON Sándor Hosztafi1, László Szilágyi2, Sándor Makleit2** and Géza Tóth3 f1 Alkaloid Chemical Works, H-4440 Tiszavasvári, 'Department for Organic Chemistry, Kossuth Lajos University, H-4010 Debrecen and 3Biological Research Centre of the Hungarian Academy of Sciences, H-6701 Szeged) Received November 27, 1987 In revised form April 13, 1988 Accepted for publications June 8, 1988 Several known and new substituted hydrazone derivatives of ketones with morphine skeleton were prepared to study the nature and distribution of opiate recep­tors. In the course of the stereo-chemical investigations, a simple, fast and reliable method of diagnostic value was developed to investigate the E—Z isomer ratio of the 2H7C=N— double bond. Preparation of hydrazone derivatives of the morphine antagonists Naloxone and Naltrexone, and of the morphine agonist Oxymorphone, were described by Pasternak [2] in 1980. In the course of the pharmacological and biochemical studies it turned out that the original activity of the parent molecules remained unchanged, hut the duration of the effect considerably increased. Later it was estabished that the effect of the hydrazones was due to the formation of ketazines [3—5]. Indeed, in vitro selective binding of the appropriate ketazines to the receptors is 20—40 times stronger than that of the hydrazones. Investigating the 13C nmr spectra of hydrazones and ketazines, Kolb et al. [6, 7] found that these were syn and anti isomeric mixtures and the sterically less crowded isomers predominated. At the beginning of our present studies, these substances seemed to be interesting both because of pharmacological reasons and, according to litera­ture data [3—7], for the mapping of opiate receptors. Our studies have been extended to other ketones with morphine skeleton. To investigate the structure­­activity relationships, besides hydrazones and ketazines, substituted hydra­zones (semicarbazones, thiosemicarbazones, phenylhydrazones and 2,4-dinitro­­phenylhydrazones) have also been synthesized. After the completion of our * Part 106: S. Berényi, S. Makleit, Á. Sepsi: Magy. Kém. Foly., 94, 97 (1988) and Acta Chim. Hung., 126, 275 (1989) ** To whom correspondence should be addressed. Acta Chim. Hung. 127, 1990 Akadémiai Kiadó. Budapest

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