Fomocaine (CAS 56583-43-8) is a basic ether-type local anaesthetic used in dermatological practice for surface anaesthesia. For many years, modifications of the fomocaine molecule have been pursued, e.g. to improve its affinity to the sodium channel and also in view of possible new (systemic) applications. In the present study fomocaine and eight fomocaine derivatives with an additional alkyl chain in 2- or 3-position of different length (C1 up to C4), or with a branched C3 chain in 3-position, respectively, at the morpholine ring were evaluated in vitro for possible structure-activity relationships with respect to the interactions with cytochrome P450 (CYP) mediated monooxygenase and oxidase functions using rat liver 9000 g supernatants or microsomes. Results were compared to in vivo data from rats on toxicity (LD50), paresis of the N. ischiadicus and surface and conduction anaesthesia (cornea, N. ischiadicus). In general, the influence of the derivatives on the CYP system was less than that of fomocaine, showing a further decline with enlarging chain length. Toxicity of the derivatives was comparable to that of fomocaine and lower only with the compound with a C4 alkyl chain in 2-position. The derivatives caused a stronger surface anaesthesia than fomocaine, exhibiting an additional increase with enlarging chain length. No clear-cut structure-activity relationships were observed with respect to paresis of the N. ischiadicus and to conduction anaesthesia. Especially the derivatives having a C2 or C4 chain in 2- or a C3 chain in 3-position, respectively, may be of interest for further investigations. In comparison to fomocaine they caused a stronger surface anaesthesia combined with a lower interaction capacity with the CYP system.

Fomocaine (CAS 56583-43-8) is a local anaesthetic (LA) with good surface anaesthesia and low toxicity, monographed in the German Extra Pharmacopoeia (DAC). In previous experiments it could be shown that both fomocaine and a couple of its derivatives need further pharmaceutical investigations. Therefore, five new C-alkylmorpholine derivatives, (OW 1, OW 3, OW 5, OW 9, and OW 11) and five 2-hydroxypropyl-beta-cyclodextrin inclusion compounds of fomocaine or OE 7000, OE 9000, OL/4, and OL/40, respectively, were compared with fomocaine and/or the respective non-cyclodextrin formulations in rats. Basing on standard methods for testing of LA effects and using two methods to characterising toxicity of LA (paresis of the N. ischiadicus, LD50) it can be concluded that: a) The good surface anaesthesia caused by fomocaine is not surpassed by its alkylmorpholine derivatives OW1-11. Only OW 11 seems to induce longer lasting conductance anaesthesia; the other OW substances (1-9) are in the same range like fomocaine. The toxicity is quite comparable for fomocaine and its OW derivatives. b) Substituted cyclodextrins are often a useful help if the water solubility of compounds is insufficient. The use of these cyclodextrin inclusion compounds resulted in slightly improved LA effects of complexed fomocaine, whereas there were nearly no significant differences between OE 7000 or OE 9000 and their cyclodextrin formulations. The toxicity of the complexed fomocaine was lower compared to fomocaine whereas the toxicity of both OE 7000 and OE 9000 was the same for the original compound and their cyclodextrin formulations. Obviously the paresis of N. ischiadicus is less pronounced after administration of the inclusion compounds. c) The cyclodextrin formulations of the new meta-fomocaines (OL/4 and OL/40) are, compared to the complexed fomocaine, without practically relevant LA effect. But OL/4 complexed is even more toxic than complexed fomocaine. On the basis of the experiments done with altogether five new fomocaine derivatives and five complexed fomocaines it can be summarized that neither the new derivatives nor their inclusion compounds seem to have any therapeutic advantage compared with the known mother substance fomocaine. Only the longer lasting effect of high doses of OW 11 as conductance LA could be of practical relevance.

Between the stereoisomers of amide-type local anaesthetics differences have been noticed with respect to pharmacokinetics and side effects, but not regarding local anaesthetic capacity. Therefore, only S-(-)-ropivacaine has been introduced into clinical practice and with bupivacaine both the racemate and the S-(-)-enantiomer (levobupivacaine) are available by now. Based on this background, the aim of the present study was to evaluate if there are also dissimilarities to be found both in the toxicity and in the effectiveness of the enantiomers of two newly synthesized chiral fomocaine alkylmorpholine derivatives, OW3 and OW13, with an additional C2-chain in 2- or an additional C3-chain in 3-position at the morpholine ring, respectively. For this purpose, in vitro the interaction capacity with cytochrome P450 (CYP)-mediated monooxygenase and oxidase functions was investigated using rat liver 9000 g supernatants or microsomes. In vivo LD50, paresis of the N. ischiadicus and surface and conduction anaesthesia (cornea, N. ischiadicus) were tested in rats. The enantiomers of both OW3 and OW13 caused a concentration dependent inhibition of all CYP-mediated model reactions investigated. With all model reactions the (-)-enantiomer of OW3 was less effective than the (+)-form, whereas the opposite was the case with OW13. Also toxicity was lower with the (-)-enantiomer of OW3 and with the (+)-form of OW13 than with the respective counterparts. With both derivatives no clear-cut dissimilarities were noticed in the local anaesthetic capacity of the enantiomers. None of the four compounds caused paresis. Thus, similar to amide-type local anaesthetics, also with the enantiomers of chiral fomocaine alkylmorpholine derivatives differences in pharmacokinetic properties and toxicity could be demonstrated.

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OD Column. -An improved synthesis of the title compound (V) is presented. It is noteworthy that the separation of both enantiomers is achieved on a gram scale by preparative column chromatography on a Chiracel® OD column with better than 99% e.e. -(OELSCHLAEGER*, H.; WANGE, J.; LETSCH, J.; SEELING, A.; Pharmazie 58 (2003) 2, 95-98; Inst. Pharm., Friedrich-Schiller-Univ.,