Steroids and related studies. Part LIV. The crystal and molecular structure of 17aβ-(2-hydroxyethyl)-3β-pyrrolidino-17a-aza-d-homo-5-androstene dimethiodide (hs-626)

Abstract

The crystal structure of the potent synthetic aza steroidal neuromuscular blocking agent 17aβ-(2-hydroxyethyl)-3β-pyrrolidino-17a-aza-D-homo-5-androstene dimethiodide (HS-626), (C₂₇H₄₈N₂O)²⁺2I⁻, has been determined by the heavy-atom method and refined by block diagonal least squares toR _o =0.044 for 3041 observed reflections andR=0.072 for 4313 reflections measured on a four-circle diffractometer in the ω/2θ scanning mode, employing Nb-filtered MoKα radiation. The crystals are orthorhombic,P2₁2₁2₁,a=14.671(2),b=17.594(3),c=10.908(2) Å,Z=4. RingsA, C, andD-homo have chair conformations, ringB is a half-chair, and the pyrrolidine ringE has an envelope conformation. The N⁺---N⁺ distance of 10.33 Å is within the usual range associated with potent neuromuscular blocking. The hydroxyethyl side group appended to N⁺ (17a) forms part of an acetylcholine-like moiety which is observed to adopt thet,-g conformation commonly found in acetylcholine. This feature probably accounts for the dramatic increase in potency of HS-626 compared to similar drugs lacking this feature. Potential-energy calculations for the free HS-626 molecule indicate that the side chain may adopt a variety of conformations in the ranget, (⁺ g to⁻ g).