348 ON THE TOXICITY OF 



with the pyrrolidine ring 1 instead of the piperidine ring as a 

 nucleus, and these also were found to produce local anaesthesia, 

 but as they did not possess any advantages over substances 

 already known, they were not introduced into practice. 



Further work on the subject followed somewhat different 

 lines. Einhorn and Heintz showed that the alkyl-esters of 

 amido-oxybenzoic acids possess local anaesthetic properties, 

 and they introduced p.amino-m.oxybenzoic acid methyl ester 

 under the name orthoform, 2 and, later, m.amino-p.oxybenzoic 

 acid ethyl ester under the name orthoform-neu. 3 Both are 

 too insoluble in aqueous solutions and their salts are too 

 irritant to be considered as substitutes for cocaine ; but by 

 introducing glycocoll more soluble and less irritant compounds 

 were obtained, and the hydrochloride of diethyl-amino-acetyl- 

 p.amino-o.oxybenzoic acid methyl ester was recommended, 

 under the name nirvanine, as a local anaesthetic. 4 

 HO . C CH 



CH 3 OOC .Or >>C . NH . CO . CH 2 . N(C 2 H 5 ) 2 HC1 



HC ~CH 



Nirvanine. 



Later Ritsert discovered that p.amino-benzoic acid ethyl ester 

 was anaesthetic to nerve-endings, and he introduced this 

 substance as anaesthesin and its p.phenol-sulphonic acid salt 

 as subcutin. The former is too insoluble and the latter too 

 irritant to permit of their being regarded as valuable substi- 

 tutes for cocaine. But the further introduction of a diethyl- 

 amino radical in place of a hydrogen of the ethyl group 

 produced a non-irritant compound (p.amino-benzoic acid 

 diethyl-amino-ethyl ester) with a marked local anaesthetic 

 action. 5 To the hydrochloride of this substance the name 

 novocaine was given. 



1 Pauly, Liebig's Annalen, cccxxii. p. 92 (1902). 



2 Miinch. med. Woch., xliv. p. 931 (1897). 



3 Munch, med. Woch., xlv. No. 42 (1898). 



4 Munch, med. Woch., xlv. p. 1553 (1898). 



5 Cf. Braun, Deut. med. Woch., 1905, ii. p. 1669. 



