Benzomorphan analgesics

In the previous chapter benzomorphan analgesics were considered. They may be thought of as sterically constrained piperidines bearing an axial aromatic ring. Without the fused aromatic ring a 2-azabicyclo[3.3.1]nonane structure (1) remains for which the trivial name morphan was suggested by Robinson/0... 

Table 12.3. Diastereoisomeric Benzomorphan Analgesic-Antagonists (Racemic Mixtures Unless Otherwise Stated) 1...

Variations of the benzomorphan analgesics which have been reported include the bis-desmethyl compound (ll) 5 and compounds v/ith complex nitrogen substituents (l2,K=CIi and 3r H =K, CHj and CgH ), none of which shows marked activity. The 5-phenyl derivatives (13,R=H) are the subject of a patent.25 The levo isomer of the phenvl substituted derivative (l3,2=GIIj) shows morphine level analgesia v/ith no capacity to substitute for morphine in addicted rats on the other hand, the dextro isomer is inactive as an analgesic yet suppresses the abstinence syndrome. A ready synthesis of benzornorphans by cyclization of 2-substituted benzyl-1, 3-diraethyl-4-piperidinols has been patented. 

The 3-benzazepine alkaloid (—)-aphanorphine shares structural features with benzomorphan analgesics such as pentazocine. A short enantioselective approach toward this... 

The search for opioid analgesics which show reduced addiction liability ha.s centered largely on benzomorphan and morphinan derivatives. Some research has, however, been devoted to derivatives of the structurally simpler meperidine series. The preparation of one such compound, picenadol (59), starts with the reaction of N-methyl-4-piperidone with the lithium derivative from m-methoxybromobenzene. Dehydration of the first formed carbinol 51 gives the intermediate 52. Deprotonation by means of butyl lithium gives an anion which can be depicted in the ambident form 53. In the event, treatment of the anion with propyl bromide gives the product 54 from reaction of the benzylic anion. Treatment of that product, which now contains an eneamine function. 

Omission of the phenolic group from cyclazocine results in a molecule which retains analgesic activity. In a classical application of the Grewe synthesis,15 the methylated pyridinium salt 54 is condensed with benzylmagnesium bromide. There is thus obtained the dihydropyridine 55. Treatment of that intermediate with sodium borohydride results in reduction of the iminium function to afford the tetrahydro derivative 56. Cyclization of 56 on treatment with acid leads to the desired benzomorphan nucleus. The cis compound (57) is separated from the mixture of isomers and demethylated by the cyanogen bromide procedure (58,... 

Oxidation of the benzylic methylene group in cyclazocine to a ketone is also consistent with analgesic activity. Acetylation of benzomorphan 62 affords the diacetate 63. Selective hydrolysis of the phenolic acetate (64) followed by methylation of the thus uncovered phenol affords intermediate 65. 

It has been proposed, on the basis of observations made using the benzo-morphan derivative (MR 2034) (8), that all kappa agonists may cause undesired dysophoria and even psychotomimesis in man [27]. Benzomorphans such as MR 2034 with affinity for sigma receptors are well-known to be associated with dysphoria. To date, there has been no report of a dose-ranging clinical study with a truly kappa selective agonist which describes the analgesic effects and the onset of dysphoric symptoms. 

Table 5.2. ANALGESIC ACTIVITIES OF SOME ( )-5,9-DIALKYL-2-METHYL BENZOMORPHANS IN MICE (HOT-PLATE METHOD)...

N. B. Eddy and E. L. May, Synthetic Analgesics, Part IIB, 6,1-Benzomorphans, Pergamon, Oxford, 1966... 

Some l-alkyl-2-benzyl-3-piperideines (185) were used in the Grewe synthesis of the benzomorphane-like analgesics (186). The ring closure between the ortho position of the benzyl residue and position 4 of the 3-piperideine nucleus was usually accomplished by heating in 48% hydrobromic acid or 85% phosphoric acid.41,103,188-193... 

Opioid receptor affinity labels have been reported for other narcotic analgesics, for example, piperidines, 293 294 benzomorphans, 295 296 and mor-phinans, 297,298 and the topic is further discussed in Chapter 13 (p. 445). Not only is the oxo-function in the 4,5-epoxymorphinan C-ring available for ready elaboration, but C-6 substituents, although they affect agonist potency, do not impair unduly receptor affinity. 299 301 ... 

During the 1950s May and his group<6) commenced an extensive study of the benzomorphans as a source of potential powerful analgesics with, it was hoped, reduced side effects. Several synthetic routes were established at that time. 

The presence of an 11-methyl group in 6,7-benzomorphans has been demonstrated to enhance analgesic responses. Synthetic approaches to benzomorphans lacking a 6-alkyl substituent from pyridines usually fail as a consequence, a twelve-step 1-tetralone route was developed(19) (Scheme 4.7). 

Pharmacological conclusions reached during these studies are that 6-alkyl substituents enhance the analgesic activity of benzomorphans somewhat, whereas the inclusion of an 11/3-alkyl substituent causes a substantial increase. 

Although the 11a- and /3-epimers of 3,ll-dimethyl-6-propyl-8-hydroxy-benzomorphans were synthesized and evaluated as analgesics in the early 1960s,(40,41) the corresponding 6-methyl-lla and 11/3-propyl isomers were not synthesized until 1975, when May s group(42) prepared the key pyridine intermediate, 4-methyl-3-propylpyridine, from the condensation of cyanoacetamide and ethyl 2-propylacetoacetate in methanolic potassium hydroxide. 

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