Carbon-14 labelling of DIOVAN™ in its valine-moiety

Abstract

As a highly specific and non peptide AT1‐antagonist Valsartan 2 is marketed under the tradename DIOVAN™ for effective treatment of hypertension. This paper describes the synthesis of C‐14 labelled Valsartan 2, which incorporates two C‐14 isotopes in the valine‐moiety. Reaction of (−)‐bromo‐[1,2‐14C]acetyl bornane‐10.2‐sultam 8a ((−)‐[14C2]BABS) with benzophenone imine gave (−)‐diphenyl‐methylene[1,2‐14C2]glycinyl bornane‐10.2‐sultam 9 ((−)‐[14C2]DPMGBS), which was alkylated with 2‐iodopropane to build‐up the valine structure 10. Initially the resulting sultam‐protected valine 11 was treated with the benzyl bromide 12 to produce the precursor 13. However, under conditions routinely used for sultam‐cleavage deprotection resulted in the racemization of the amino acid. Successful cleavage was accomplished via N‐Boc‐protection of 11 followed by hydrolytic cleavage of the auxiliary and esterification to give the L‐[14C2]valine benzyl ester 18. Finally [14C2]Valsartan 2 was synthesised in a 10 step synthesis in an overall radiochemical yield of 10 % relative to the (−)‐[1,2‐14C]BABS 8a employed. Copyright © 2000 John Wiley & Sons, Ltd.

Tautomerism in drug discovery

“…The tetrazole ring appears in a number of drugs affording N1 to N2 tautomerism, including Diovan (3) [18], Benicar (4) [19], Avapro (5) [20], Atacand (6) [21] and Hyzaar (7) [22]. 15 N CPMAS experiments showed that at room temperature (295 K), the four tetrazole nitrogen atoms gave a very broad signal compared to the imidazole signals, but became sharp at 253 K. These findings are consistent with fast prototropic exchange as proposed by Harris et al [23].…”

“…Drugs with potential NH to N tautomerism include those used for the treatment of HIV 15 [34,35], 16 [36], epilepsy (17) [37], and skin (18) [38,39], lung and pancreatic cancers (19) [40][41][42]. They all involve amine (NH 2 or NH) to imine tautomerism a change that decreases the aromaticity of each heteroaromatic system.…”