Synthesized local anaesthetic

A hydrophilic centre may be suitably linked to either an amide frmction or an ester moiety either by S, N, 0-atoms or apporpriately by a short hydrocarbon rmit. However, it has been observed that the latter i.e., short hydrocarbon unit) happens to be the most preferred choice in majority of synthesized local anaesthetics,... 

C. It is secreted along with noradrenaline by the adrenal medulla, from which it may be obtained. It may be synthesized from catechol. It is used as the acid tartrate in the treatment of allergic reactions and circulatory collapse. It is included in some local anaesthetic injections in order to constrict blood vessels locally and slow the disappearance of anaesthetic from the site of injection. Ultimately it induces cellular activation of phosphorylase which promotes catabolism of glycogen to glucose. 

Suggest syntheses for these esters. The starting materials might 10. Suggest a synthesis for this local anaesthetic. 

Semisynthetic amides of retronamine (66), itself prepared from retronecine (65) in three steps, have been synthesized by coupling with the appropriate acid using AW -dicyclohexylcarbodi-imide. Several of the compounds prepared, notably the p hydroxy benzoyl-, cinnamoyl-, and benzoyl-retronamines, had marked hypotensive activity. The amides could not be crystallized and details of their characterization were not given. Atal and his co-workers have also prepared - a number of semisynthetic diesters of retronecine, heliotridine, and platynedne by esterification of the necine base with the appropriate acid chloride. Several of the compounds prepared had marked local anaesthetic activity. 

This tactic was used successfully with the alkaloid cocaine (Fig. 7.21). It was well known that cocaine had local anaesthetic properties and it was hoped to develop a local anaesthetic based on a simplified structure of cocaine which could be easily synthesized in the laboratory. Success resulted with the discovery of procaine (or Novocaine) in 1909. 

In further attempts to obtain useful drugs related to cocaine (30) with modified pharmacological activity, a series of tropane esters (31) has been synthesized in which the aromatic ring is attached directly to position 3. In most of the compounds synthesized a 5—60-fold increase in some biological parameters was observed, but a 10-fold reduction in local anaesthetic activity and a four-fold lowering of intravenous toxicity were also noted. 

A final example is the tme-step, three-component variant of the Ugi reacticm (Scheme 8.10), according to which an important local anaesthetic agent, xylocaine (28), was synthesized from formaldehyde, diethylamine and 2,6-dimethyl-pheny-lisocyanide [45]. 

This compound, 1,3-bis-(2-ethylhexyl)-5-methyl-5-amino-hexahydropyrimidine, was synthesized as long ago as 1946 but has in recent years been more widely advertised (and presumably used) as an oral disinfectant. In the concentration normaUy employed (1 mg/ml) it has an antibacterial and antifungal effect in vitro. When applied to the mucosa it also appears to have mild local anaesthetic properties. Very little critical clinical work with this substance has been published. 

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