Chapter I

Chemistry of Morphinans

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.

(1) morphine oh

(1) morphine

(2) morphinan

(2) morphinan

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 imino-cthanophenanthrene 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 and adhering 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 Ro-binson(4) and by SchOpf(5) shortly afterwards. These two papers made pos sible 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. dihydrodesoxymorphinc (desomorphine, Permonid(R)) is about ten times more active than morphine(7) and methyldihydromorphi-none (Metopon00) is distinctly less addictive than morphine(8-1

These partial successes gave rise to the hope that the final goal, to obtain an analgesic without any addictive properties, might still be readied. This naturally stimulated chemical work in the morphine field and led to the understanding of numerous correlations between chemical structure and pharmacological activity (7'12_14). Although we know now of a few exceptions, these generalizations may be summarized as follows(15,16):

(a) Replacement of the phenolic hydroxyl group of morphine by an ether group diminishes its analgesic effect considerably. On the other hand, esterification increases the analgesic and addictive properties.

(b) Modification of the alcoholic hydroxyl group (by etherification, replacement by keto group, halogen etc.) increases the analgesic activity and the toxicity, at the same time diminishing the duration of the effect.

(c) Opening the furan ring reduces the efficacy as well as the toxicity.

(d) Substitution in the aromatic ring (A) lowers the analgesic activity.

(e) Substitution in the alicyclic ring (C) does not basically modify the activity.

(f) The formation of an TV-oxide causes the activity to disappear; on quater-nization of the tertiary amine a curare-like activity is observed.

(g) Replacing the TV-methyl grouping with iV-alkyl or iV-alkenyl groups leads to compounds with an antagonistic effect and, most important, the undesirable respiratory depression caused by morphine is significantly di-minishcd(17). There are well controlled studies showing that nalorphine retains some morphine-like respiratory depressant effect.

(3) Desomorphine

(4) Methyldihydromorphinone

(3) Desomorphine

(4) Methyldihydromorphinone

(h) The tertiary character of the nitrogen is essential for the specific activity of morphine.

(i) Opening the piperidine ring (morphimetine) destroys the analgesic activity completely.

2. Synthesis of analgesics with morphine-like activity

(a) Introduction

The elucidation of the structure of morphine and the knowledge of the relationship between chemical structure and physiological activity in morphine derivatives stimulated investigations directed towards the preparation of fragments of the complicated morphine molecule. It was hoped to obtain simpler compounds by total synthesis which would possess similar analgesic and antitussive properties but would be free of side-effects, especially of addictive properties. Following fragmentary efforts by various chemists around the turn of the century and during the next 25 years, synthetic work in the U.S.A. was supported mainly by the Committee on Drug Addiction of the National Research Council (USA) under the guidance of Small. Eddy et al. determined the pharmacological properties of these synthetic substances(7).

Other research centres became involved later in these endeavours to "improve" morphine by synthetic studies with morphine fragments.

Table I summarizes these synthetic accomplishments. In most of the groups 1-13 some analgesic activity was found in a few of the representatives, but in spite of intensive work on groups which at first seemed very promising, no useful compounds were discovered. For details we recommend the excellent surveys of Bergel and Moriuson(16) and Beckett(18).

On the other hand, work on groups 14 and 15 was very successful. The first representative of group 14, pethidine(19) (meperidine) proved to be of great importance and became the model for many other valuable compounds.

Group 15, methadone (Amidon(R) and/or Polamidon(R)) and analogues, is described in detail in the first volume of the series on Synthetic Analgesics(2 0 *.

In this second volume the rt^ults of chemical and pharmacological work with the morphinans 17 as well as the benzomorphans (group 16) shall be discussed.

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