Phenylpiperidine Analogues

The 4-phenylpiperidine analogue led to the synthesis of much simpler compoimds having potent analgesic properties. Discuss the synthesis of any one compound stated below ... 

The dopamine D2 agonist SAR area has been reviewed by Hacksell and coworkers from the perspective of stereochemistry and pharmacological profiles of the enantiomers of the compounds synthesized by that research group during a period of 10 years. The structural classes surveyed were 3-phenylpiperidines, 2-aminotetralins and their ring-methylated analogues and octahydrobenzo[/]quinolines (OHB[f]Qs) [60]. 

By conventional tests, secondary amine analogues of 4-phenylpiperidine analgesics lack activity (normorphine is equi-potent with morphine by the intra-cisternal route [48]) many secondary bases of the thebaines,(VII), however, are morphine-like analgesics. These findings lend support to the view that the low potencies reported for many nor-analogues of analgesics are due to distribution factors and not to the failure of such derivatives to associate at the receptor. 

In an analysis of stereochemical factors in narcotic analgesics, Portoghese considers that the conformational requirements for most of the 4-phenylpiperidine analgesics appear to be minimal [282]. His argument was based, in part upon (1) the fact that endo and exo isomeric azabicyclo [2,2,1] heptane analogues (LXXXII) of pethidine have similar orders of potency in mice (benzoquinone... 

Etiolates. Asymmetric addition of enolates to enantiopure sulfinimines is an important method for the preparation of P-amino esters.21,84,85 For example, treatment of (Ss)-sulfinimine 47 with the sodium enolate of methyl acetate in ether afforded P-amino ester 149 in 84-85% yield and in >98% de.86,87 After removal of the N-sulfinyl group, P-amino esters 150 were obtained in >90% yield.84 The P-amino esters were further elaborated into the Taxol C-13 side chain 151a,21 its fluoro analogue 151b,85 (+)-2-phenylpiperidine (152a), and (+)-dihydropinidine (152b).87... 

Dimelor acetohexamide. dimenhydrinate diphenhydramine, dimepheptanol [ban, inn] (methadol NIH 2933) is one of the phenylpiperidine series, an OPIOID RECEPTOR AGONIST, which is active as an OPIOID ANALGESIC. It is also elaborated in a number of close analogues, derivatives or diastereoisomers with similar properties. These include methadyl acetate [ban, usan] = acetylmethadol [inn] alphamethadol (ban, inn] alphacetylmethadol [inn] levomethadyl levacetylmethadoi [inn] = levomethadyl acetate (usan) betamethadol [ban, usan) betacetylmethadol (inn) = betacemethadone. dimepropion [ban] (metamfepramone [inn]) is an ephedrine-like agent with SYMPATHOMIMETIC and CNS STIMULANT properties. It can be used as an appetite SUPPRESSANT. 

Wei Z-Y, Brown W, Takasaki B et al (2000) N,N-Diethyl-4-(phenylpiperidin-4-ylidene-methyl)benzamide a novel, exceptionally selective, potent delta opioid receptor agonist with oral bioavailability and its analogues. J Med Chem 43 3895-3905... 

A number of other aryl-cyclic amine functionalities were examined as replacements for the 1,2,3,6-tetrahydro-4-phenylpiperidine of 36 (Table 6). Thiophene analogue 41 was found to have somewhat weaker DA D2 receptor affinity. In the 1,4-cyclohexenyl series 2-pyridylpiperazine attached to the phenyl cyclohexene produced potent compounds. The 1,5-cyclohexenyl analogue 42 having a 2-pyridylpiperazine group was also an interesting compound. However, the parent tetrahydropyridine 36 caused greater decreases in DA synthesis than piperazine 42. Replacement of the 2-pyridyl group with phenyl (43) or 2-pyrimidyl (44) resulted in compounds with decreased receptor affinity and in vivo activity. 

Morphinic analgesics. Probably more than a thousand more or less simplified analogues of the alkaloid morphine have been investigated. Many of them were inactive, but it was soon recognized that the phenylpiperidine unit was crucial for the central analgesic properties (Fig. 14.30). In contrast to what was observed for cocaine, no clear discrimination between the analgesic and the narcotic properties could be achieved. 

The phenylpiperazine moiety can be replaced by 4-phenyl-l,2,3,6-tetrahydropyridine or by 4-phenylpiperidine without loss in affinity and selectivity. The 4-(4-fluorobenzoyl) piperidine analogue is potent but less selective (cf. Table 2). 

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