Alkyl chain anesthetics

The local anesthetics can be broadly categorized on the basis of the chemical nature of the linkage contained within the intermediate alkyl chain group. The amide local anesthetics include lidocaine (7.5), mepivacaine (7.6), bupivacaine (7.7), etidocaine (7.8), prilocaine (7.9), and ropivacaine (7.10) the ester local anesthetics include cocaine (7.11), procaine (7.12), benzocaine (7.13), and tetracaine (7.14). Since the pharmacodynamic interaction of both amide and ester local anesthetics with the same Na" channel receptor is essentially idenhcal, the amide and ester functional groups are bioisosterically equivalent. However, amide and ester local anesthetics are not equal from a pharmacokinetic perspective. Since ester links are more susceptible to hydrolysis than amide links. 

Figure 6-1 Generalized molecular structure of a local anesthetic, consisting of a hydrophobic aromatic residue, the linkage site, an intermediate alkyl chain, and a hydrophilic amino group. (Adapted from Lesher GA. General principles of local anesthetics. In Onofrey BE, ed. Clinical optometric pharmacology and therapeutics. Philadelphia JB Lippincott, 1991 Chapter 53.)...

Hundreds of esters were then synthesized, resulting in esters with substituents on the aromatic ring, esters with the alkyl groups bonded to the nitrogen, and esters with the length of the connecting alkyl chain modified. Successful anesthetics obtained through molecular modification were benzocaine, a topical anesthetic, and procaine, commonly known by the trade name Novocain . 

Rh-catalyzed cyclohydrocarbonylation of functionalized homoallyic amine has been successfully applied to the synthesis of (+)-prosopinine (97) and (-)-deoxyprosophyline (98) (Figure 2-4). Both (+)-prosopine and (-)-deoxyprosophyline have been shown to possess both antibiotic and anesthetic properties. This synthesis uses amino acid derivatives that are subjected to CHC conditions to generate the desired substituted piperidine intermediates. The piperidine intermediates are then further converted to the desired alkaloid by subsequent diastereoselective introduction of the alkyl chains at the C-6 position. 

As shovm above, the attachment of the aromatic ring to the carbon chain bearing the basic nitrogen may be accomplished through an ester or an amide configured in either direction. A simple ether linkage fulfills this function in yet another compound that exhibits local anesthetic activity. Thus, alkylation of the mono potassium salt of hydroquinone with butyl bromide affords the ether (77) alkylation of this with w-C3-chloropropyl)morpholine affords pramoxine (78)... 

Shifting the side chain to the 4 position (with the necessary tautomeric change) affords an agent with local anesthetic and coronary vasodilator activity. Cycllzation of compound 147 by means of phosphorus oxychloride gives the amino-l,2,4-oxodiazole (148). Alkylation of that compound with 2-chlorotriethylamine in the presence of sodium hydroxide proceeds via the tautomer,... 

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