Benzomorphans isomers

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,... 

Many benzomorphan derivatives with morphine-like potencies or better have a low physical dependence capacity (PDC) in monkeys especially potent members, however, such as phenazocine and the /3-isomers (Table 5.2, Nos. 8 and 16) have high to intermediate PDC properties [5, 63, 68]. Unusual results have been reported. for the enantiomorphs of a-(X) (R = Me, R = = Et) the... 

Treatment of (16-3) with sodium borohydride leads to the selective reduction of the enamine bond to lead to the tetrahydropyridine (16-4). This intermediate undergoes ring closure with a strong acid to give the benzomorphan (16-5) in direct analogy to the more complex morphinans. The product consists predominantly of the isomer that bears the equatorial secondary methyl group [18],... 

Inoue and May(21) later modified the preceding synthesis with the presence of an 8-methoxyl substituent (Scheme 4.8). The key intermediate dihydronaphthalene (66) gave on treatment with mercuric acetate 8-methoxy-2,lla-dimethyl- la-hydroxybenzomorphan (67) in 49% yield, 5% of the 11/3-methyl isomer (69) and 13% of the la-acetate (68) corresponding to 67. Transformation to the desired 11-epimeric benzomorphans 70 and 71 was by standard methods. 

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. 

Other substituted piperidines, particularly piperidinols, have been exploited as benzomorphan precursors. The first 6,7-benzomorphan lacking a 6-alkyl substituent, the parent heterocycle, was reported by May et al. in 1968<43,44) in a synthesis from 2-cyano-4-phenylpyridine (102) (Scheme 4.15). The 2-carbomethoxypiperidine (103) was prepared readily, but it proved resistant to direct cyclization to 3-methylbenzomorphan-l-one (105) with polyphosphoric acid, presumably because the more stable 2,4-diequatorial isomer is not favorable for ring closure for geometric reasons. Hydrolysis to the corresponding acid (104), however, gives an intermediate that closes to 105 in 94% yield. The parent heterocycle 106 is produced by standard techniques. 

The benzomorphan structure with an oxygen function in either the 1- or 11-position offers a means of building an acetylcholine moiety onto a sterically constrained support, and such compounds could afford evidence for the steric requirements of acetylcholine at its nicotinic and muscarinic receptors. Pairs of a- and /3-isomers of 1- and 11-acetoxybenzomorphan quaternary salts 182 and 183 have been synthesized and their stereochemistry established by Hnmr spectroscopy.01S)... 

Benzomorphans bearing antagonist N-substituents<191) show a similar separation of activities. Where antagonist properties are found predominantly within the (-)-isomers, some activity is seen in the (+)-antipodes. However, the level depends very much upon the nature of the N-substituent and the geometry at C-ll. In several series, activity of the (-)-isomer is consistently more than 2x that of the racemate, suggesting antagonism of the analgesic properties of the (-)-isomer by the (+)-isomer. 

Although the benzomorphan ring system was first synthesized in 1947 by Barltrop (386), it was the synthesis of 2,5-dimethylben-zomorphan (92, R = R = CHg) by May and Murphy (387) that began the investigation into the synthesis and pharmacology of this structural family. As is the case for the mor-phinans, the benzomorphans are prepared synthetically and therefore are obtained as racemic mixtures. A number of these racemates have been resolved and the activities of the individual isomers examined (see Refs. 283, 388 for reviews, also see Ref. 389). The active isomers are the levo isomers, which have the same absolute configuration at the bridgehead... 

A variety of benzomorphans have been prepared with various combinations of alkyl substituents (methyl, ethyl, propyl) at the 5 and 9 positions (seeRefs. 283,388). The alkyl group at the 9 positioncan be oriented either a, in which the substituents in the 5 and 9 positions are cis, or /3, in which these substituents are trans (see 92, Fig. 7.21). The synthetically minor /3 isomers, which have the opposite stereochemistry from that of the corresponding position in morphine (C,), are more potent than the a isomers as antinociceptive agents (see Refs. 283, 388). Attachment of a 3-alkanone side chain at the 9/3 position of metazocine (94) yielded a series of potent compounds... 

A series of analogs of the benzomorphans were prepared in which the amino group is exocyclic (99 and 100) (401). In contrast to the benzomorphans and other rigid opiates, the receptor binding of (99) and its analogs exhibits almost no stereoselectivity [K- (jit) = 2.0 and 2.2 nAf for the (+) and (-) isomers] in vivo, both isomers of (99) were inactive. Racemic (100) exhibits an almost 10-fold increase in K-receptor affinity (K = 6.6 nAQ compared to that of the isomers of (99) while retaining nanomolar affinity for ix receptors = 2.0 nM) this compound is a full k agonist in vivo. 

The most striking result of this chemical manipulation is exemplified by the last pair of benzomorphans. The cis isomer is a weak antagonist that is negative in the D Amour-Smith test. The trans isomer on the other hand is the more potent antagonist. The exact figure was difficult to determine, but an AD50 as low as 0.087 mg. per kg. vs. meperidine was obtained. Equally surprising was the observation that the trans isomer was about three times as active as morphine in the D Amour-Smith test. 

B. Benzomorphans - Clinical trials of the d 1 isomers of pentazocine (k) have shown "16 th both analgesic activity and side effects reside in the levo-isomer. Other trials, double-blind in many patients, confirm" 7,18 the activity of the compound at about one-third that of morphine, while measurements of respiratory depression in treated patients suggest" 9,20 this to be less than morphine at equianalgesic doses. The oral absorption has been determined2 1 and metabolic breakdown found22 to occur predominantly at the terminal methyl groups of the side chain. Reports of addiction to the injected form of pentazocine have been published ,24,25 including one to the oral form. 

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. 

Tullar BF, Harris LS, Perry RL, Pierson AK, Soria AE, Wetterau WF, Albertson NF. Benzomorphans. optically active and trans isomers. J. Med. Chem. 1967 10(3) 383-386. 

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