Piperidinol, substituted

Replacement of the hydrazine function by a substituted 4-piperidinol leads to a compound that has been investigated as a cardiotonic agent that acts by increasing the contractile force of cardiac smooth muscle. The preparation is quite analogous to those above. The key step involves the displacement of chlorine from the substituted chlorophthalazine (68-1) with the ethyl carbamate from 4-piperidinol (68-2) to afford the alkylation product carbazeran (68-3) [77]. 

G. Rosse, F. Ouertani and H. Schroeder, Efficient solid-phase synthesis of fi-amino-substituted piperidinols, J. Comb. Chem., 1999, 1, 397-401. 

An Sn2 reaction with anchimeric assistance (via formation of a bicyclic aziridinium ion intermediate) has been proposed for the nucleophilic substitution of trans-2-substituted 3-piperidinol mesylates by nitrogen nucleophiles with retention of trans... 

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. 

Complete removal of the 4-phenyl substituent of the reversed ester of pethidine results in a drastic fall in potency as judged from tests in mice (see 23, R = Et). However, certain esters of l-methyl-4-piperidinol formed from aromatic acids display antinociceptive activities in the morphine to codeine range of potency (23).<68) A QSAR study of such esters has been made and a substitution pattern of the phenyl group defined for optimal activity/69 The relevance of these compounds to morphine-type analgesics is doubtful since the more active members show marginal or no affinity for opioid receptors of rat brain homogenates and display no physical dependence in monkeys. 

A series of A -substituted D-araiwo-piperidinol phosphates, e.g. 253, were prepared from the 1,2,3-inositol triphosphate 251, by periodate cleavage yielding 252, which was converted to 253 by aminolysis and NaBH4 reduction. A wide range of alkyl and functionalized R groups were used. ... 

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. 

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