Anaesthetics, local groups

The lupinane group has not attracted chemists as a primary material for modification in the hope of developing substances of possible therapeutic interest. Liberalli found lupanine was inactive in avian malaria and Clemo and Swan state that this is also the case for ll-(e-diethylamino- -pentyl)aminolupinane. Lupinine -aminobenzoate has been investigated in Russia and shown to possess marked local anaesthetic action. ... 

Local Anaesthetics. Figure 1 Common structure of local anaesthetics. A lipophilic moiety on the left, an aliphatic spacer containing an ester or amide bond in the middle and an amine group on the right are the typical structural elements for local anaesthetic drugs. 

The synthesis of a local anaesthetic required amino lactone (56) as intermediate. The amino groups could be made from a ketone, but if we use a nitro group instead (57) a reverse Michael disconnection gives a simple condensation product (58). 

The analogous 4- (19, X = H2) and 5-phenyltetrahydro-l-benzazepines are less active than the 3-phenyl isomers [30]. The corresponding 4-phenyl-benzazepin-2-one (19, X = O) shows moderate antiarrhythmic activity [30] and is claimed to be useful for the treatment of neurogenic or carcinogenic auricular and ventricular fibrillation and as an antihistaminic or local anaesthetic agent [37]. Introduction of an aminoalkyl group, such as 2-piperidinyl-... 

Some 2-amino derivatives (36) have been reported to show local anaesthetic, parasympathomimetic, long-lasting myorelaxant, brief hypotensive and mild antiarrhythmic activities [83]. Analogous cyclic amidines (37) with a 3-phenyl group were examined for potential hypoglycaemic agents [7]. Ten of 16 compounds showed weak to moderate activity in the rat. The most active compound was (37, R1 = OMe R2 = R3 = H, R4 = cyclopropyl), although it was less active than tolbutamide [84]. 

Drugs with a chromophore such as that of procaine include procainamide and proxymetacaine. It should be noted that local anaesthetics such as bupivacaine and lignocaine do not fall into this category since they are aromatic amides and the lone pair on the nitrogen atom is not fully available due to electron withdrawal by the adjacent carbonyl group. 

Adrenaline is present as a vasoconstrictor in some local anaesthetic injections in a much smaller amount than the local anaesthetic itself, which obscures the absorption of adrenaline in the UV region. The selectivity of UV/visible spectroscopy for the analysis of adrenaline can be increased by complex formation, which occurs between iron (II) and molecules containing a catechol group (Fig. 4.13). These complexes are purple in colour and absorb at ca 540 nm at much longer wavelengths than for instance local anaesthetics, which do not form such complexes. The adrenaline in the injection is quantified against a standard solution of adrenaline. 

Injections of local anaesthetics often contain low concentrations of adrenaline in order to localise the anaesthetic for a time by constricting blood vessels in the vicinity of the injection. Adrenaline can be analysed by straight-phase chromatography, for instance on silica gel, but this generally requires strongly basic conditions under which the catechol group in adrenaline is unstable. Adrenaline is... 

Figure 14.11 shows the separation of R and S isomers of a series of structurally related local anaesthetics. Wide separations were achieved for the compounds in this series where it was proposed that the fit of the hydrophobic portion of the analyte into the cyclodextrin was optimal when one of the substituents at the chiral centre was able to interact with the chiral hydroxyl groups on the rim of the cyclodextrin cavity. Table 14.3 shows the association constants calculated for the interaction of the enantiomeric pairs with the dimethylcyclodextrin. The larger the value of K, the... 

It is a local anaesthetic belonging to the ester group. It inhibits conduction of nerve impulses from sensory nerves. This action is a result of alteration of cell membrane permeability to ions. It is poorly absorbed from the intact epidermis. 

All typical local anaesthetics contain an aromatic amine head joined to an amino group by an intermediate chain or link (Figure 5.1). 

You already know that disconnections are the reverse of known reliable reactions so you should not make a disconnection unless you have such a reaction in mind. In designing a synthesis for the local anaesthetic benzocaine 1, we see an ester group and know that esters are reliably made from some derivative of an acid (here 2) and an alcohol (here ethanol). We should disconnect the C-0 ester bond. From now on we will usually write the reason for a disconnection or the name of the forward reaction above the arrow. 

Selectivity between two oxygen nucleophiles might sound more difficult but when one is an alcohol and the other a carboxylic acid, there is no problem. The local anaesthetic cyclomethy-caine 12 is obviously made from the carboxylic acid 13 and an amino-alcohol. The acid 13 is our concern. We disconnect the ether linkage 13a on the alkyl side so that the Sn2 reaction works. Chemoselectivity now arises as 15 has OH and CO2H functional groups. Which will act as a nucleophile ... 

The basics of the technique of disconnection is illustrated by considering the synthesis of the local anaesthetic benzocaine. The most appropriate disconnections are the ester and amine groups. At this point it is a matter of experience as to which disassembly route is followed. The normal approach is to pick the synthons that give rise to reagents that can most easily be reformed into the product. Consequently, in this case the ester disconnection would appear to be the most profitable pathway, as ester formation is relatively easy, but it is notpossible to directly introduce a nucleophilic amino group into a benzene ring. 

Rerkasem K, Bond R, Rothwell PM (2004). Local versus general anaesthetic for carotid endarterectomy. Cochrane Database of Systematic Reviews 2 CD000126 SPACE Collaborative Group (2006). 30-day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients a randomised non-inferiority trial. Lancet 368 1239-1247... 

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