Stereochemistry of gabapentin and several derivatives: Solid state conformations and solution equilibria

摘要

Gabapentin (1-(aminomethyl)cycloheaxaneacetic acid; Gpn) is a widely used anti-epileptic drug. The target site of action of Gpn remains controversial. Gpn can exist in two isomeric chair forms. The crystal structures of Gpn I and eight derivatives, Gpn hydrochloride 2, Gpn lactam 3, Boc-Gpn-OH 4, Ac-Gpn-OH 5, Piv-Gpn-OH 6, Tosyl-Gpn-OH 7, Boc-Gpn-OSu 8 and Boc-Gpn-NHMe 9, are described. The aminomethyl group occupies an axial position in 1, 3, 6 and 7, while it lies in an equatorial orientation in 2, 4, 5 and 8. The structure of Boc-Gpn-NHMe 9 reveals that the crystals contain both chair forms of the derivative in the ratio 0.7 : 0.3, favouring the aminomethyl group in an axial position. In all cases, the torsional angles about the C-alpha-C-beta (theta(1)) and C-beta-C-gamma (theta(2)) bonds of the gamma-amino acid residue are characteristic of a gauche, gauche (g, g) conformation. In solution, NMR studies establish rapid conformational exchange, as anticipated, at room temperature. Low temperature NMR studies permit conformational freezing and determination of the free-energy difference between the two 1,1-disubstituted cyclohexane conformers. The largest free-energy difference is observed in the free amino acid (0.38 kcal mol(-1)), with the most stable conformer having the aminomethyl group in the equatorial position. The free-energy difference between the two forms is significantly reduced in the protected derivatives, with almost equal populations observed in solution for the fully protected neutral derivatives, Boc-Gpn-NHMe and Gpn lactam.