Pethidine 4 analog

In an effort to more closely mimic the aromatic substitution pattern found in morphine (see A) the pethidine analog containing the m-hydroxy group was prepared as well. Thus, in a synthesis analogous to that used to prepare the parent compound, double alkylation of m-methoxyphenylacetonitrile with the chloroamine. 

Analgesic efficacy and clinical use Diphenoyxlate is a synthetic pethidine analog with a limited access to the brain and minimal analgesic activity. It has mainly peripheral opioid activity and oral administration induces inhibition of gastrointestinal motility and secretion. The compound is used for the treatment of acute and chronic diarrhea (Shee and Pounder, 1980 Lustman et al., 1987). 

The vinylogues of phenylbutazone, and of pethidine (C. G. Wermuth, unpublished results) have the same type of activity than the parent drug, but the duration of action, especially for the pethidine analog, is notably shorter than that of the initial molecule (Figure 14.21). This is probably due to an easier metabolic degradation of the styryl double bond. 

An analog of the above "reversed" pethidine, alphaprodine (114), has found application as an analgesic in the clinic. 

A benzomorphan analog of pethidine, bearing a 6-ethoxycarbonyl group (155) was prepared by May et al.(95) by a modified 1-tetralone synthesis. It... 

Isosteric replacement of phenyl, that is, replacement of phenyl by other aromatic groups of similar size such as furyl, pyridyl, and thienyl, is generally disadvantageous in analgesics (the thiambutenes are a special exception, p. 310). Thus, the 2-thienyl analogs of pethidine(65) and its seven-membered ring... 

The few analogs of pethidine-reversed esters in which phenyl is replaced by nonaromatic groups capable of providing 7r-electrons such as —C=CH and —C=N have proved inactive.(67)... 

Isoprodines (28), related to /3-pethidine, are inactive in mice in doses up to 100 mg/kg(76) the bicyclic analog 29 with the piperidine ring constrained to a boat conformation is about half as active as a-prodine in rats while its diastereoisomer is inactive/77 Results on /3-pethidine and isoprodine should be compared with data on 3-aryl-3-methylpiperidines that lack an oxygen substitutent in the piperidine ring but possess one in the aromatic moiety (p. 279). 

The enhanced activity of a-prodine over that of pethidine in animals holds also in man (40-60 mg = 100 mg pethidine with brief duration of action)00 and the compound (now withdrawn) was marketed as Nisentil. Trimeperidine (y-promedol), a 2,5-dimethyl analog of 3-desmethylprodine described later, is also more active than pethidine and has been in clinical use in the USSR since the 1950s.(12)... 

A detailed study of 3,5-dimethyl analogs has been made.(4l) Of the three diastereoisomers only the y-isomer (t-3Me, c-5Me, r-OCOEt) is active (at least twice as potent as pethidine in mice), and the more active (+)-antipode has an axial 3-methyl group advantageously, and an equatorial 5-methyl disadvantageous placed (see 27). Because axial 3-methyl placed as in dextro-(27) has a potency-raising influence (cf. discussion of /3-prodine), activity is retained in spite of the unfavorably positioned equatorial methyl but at a lower level than that of the desmethyl parent. 

H-nmr spectroscopy readily enables the differentiation of chiral from achiral (meso) diastereoisomers of 3,5- and 2,6-dimethyl-4-phenylpiperidines because in the meso forms the two methyls have identical environments and give rise to the same resonance, while chiral isomers involve an axial-equatorial pair that results in two separate methyl signals (see 39). The configurations of both the chiral 2,6- and 3,5-dimethyl reversed ester analogs of pethidine have been confirmed by X-ray crystallography/27 41)... 

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