Publisher Summary

This chapter describes morphinans as members of a class of compounds possessing the main structural skeleton of morphine. The chemistry of the morphinan is very closely connected with that of morphine, and it starts from the elucidation of the structure of morphine. The chapter discusses the synthesis of analgesics with morphine-like activity, synthesis of N-methyl-morphinan, and synthesis of N-methyl-morphinan. By subjecting natural products to reactions that were either already well known or recently developed, many investigations were undertaken to confirm the morphine structure and to find compounds of greater pharmacological value. The desirable effect of morphine on pain that sets in rapidly even when the drug is administered in small doses is accompanied by a number of clinically undesirable side effects. These side effects—such as respiratory depression and development of tolerance that soon leads to addiction—limit its application. The primary aim of the chemists in modifying the morphine molecule was to obtain analgesics without side effects, especially without addictive properties. Although this has not yet been fully achieved, partial successes have been obtained.

1 INTRODUCTION

Morphinans are members of a class of compounds possessing the main structural skeleton of morphine. The numbering system (1–17) and designation of the rings (A–D) adopted for these compounds are the same as used for morphine. The close relationship existing between these two classes of compounds is best seen by comparing their main structural features as given below.

Three condensed six-membered rings form the partially hydrogenated phenanthrene fragment, one of which is aromatic (A) while the two others (B and C) are alicyclic. As in decaline the fusion of rings B and C can either be cis or trans depending upon the configuration at C13 and C14. Carbon 13 is quaternary and together with carbon 9 forms the junction with the heterocyclic ring (D). Although morphinan possesses three asymmetric carbon atoms, owing to the rigid structure of the molecule only two racemates are possible.

Morphinan could also be designated as a partially hydrogenated iminoethanophenanthrene or 2-aza-5,9-tetramethylene-6,7-benzo-bicyclo(l,3,3)-nonene-(6)(1). This nomenclature, however, will not be used in this survey. Preference is given to a chemical designation derived from the skeleton “morphinan” adding the appropriate substituents andadhering to the numbering system already mentioned.

Originally, this class of compounds had been named “morphans”, but, on the suggestion of ROBINSON(2), this was modified to “morphinan” since the name morphan had already been adopted for another class of compounds(3).

The chemistry of morphinan is very closely connected with that of morphine and starts from the elucidation of the structure of morphine by ROBINSON(4) and by SCHÖPF(5) shortly afterwards. These two papers made possible the systematic study of the structure of the morphine alkaloids. By subjecting natural products to reactions which were either already well known or recently developed, many investigations were undertaken to confirm the morphine structure proposed by ROBINSON, and to find compounds of greater pharmacological value. The desirable effect of morphine on pain which sets in rapidly even when the drug is administered in small doses, is accompanied by a number of clinically undesirable side-effects. These side-effects, such as respiratory depression(6) and development of tolerance which soon leads to addiction, limit its application.

The primary aim of the chemists in modifying the morphine molecule was to obtain analgesics without side-effects, especially without addictive properties. Although this has not yet been fully achieved, partial successes have been obtained, e.g. dihydrodesoxymorphine (desomorphine, Permonid(R)) is about ten times more active than morphine(7) and methyldihydromorphinone (Metopon(R)) is distinctly less addictive than morphine(8–11).

These partial successes gave rise to the hope that the final goal, to obtain an analgesic without any addictive properties, might still be reached. This naturally stimulated chemical work in the morphine field and led to the understanding of numerous correlations between chemical structure and pharmacological activity7, 12–14. Although we know now of a few exceptions, these generalizations may be summarized as follows(15, 16):

2 SYNTHESIS OF ANALGESICS WITH MORPHINE-LIKE ACTIVITY