Unanticipated acyloxymethylation of sumatriptan indole nitrogen atom and its implications in prodrug design

Sumatriptan is a potent and selective 5-HT(1B) and 5-HT(1D )agonist used in the symptomatic treatment of migraine; it shows poor oral bioavailability ascribed, in part, to its low lipophilicity. In an attempt to develop acyloxymethyl prodrugs of sumatriptan suitable for oral administration, we carried out the reaction of sumatriptan with chloromethyl esters. To our surprise, acyloxymethylation occurred preferentially at the indole nitrogen rather than at sulfonamide nitrogen, reflecting a difference either in product stability or in the nucleophilicities of the indole and sulfonamide anions. The hydrolysis of the corresponding N(1)-acyloxymethyl derivatives was studied in aqueous buffers and in human plasma, by HPLC. N(1)-Acyloxymethyl derivatives of sumatriptan are rapidly hydrolysed to the chemically stable N(1)-hydroxymethylsumatriptan at pH 1-13. Slow formation of the parent drug was observed only at high pH values. Hydrolysis of sumatriptan derivatives is slower in human plasma than in phosphate buffer and also generates N(1)-hydroxymethylsumatriptan rather than the parent drug. These results indicate that N(1)-acyloxymethyl derivatives of sumatriptan cannot be considered as true prodrugs of sumatriptan.