Solid‐state stereochemistry and activity of 3‐methylnefopam diastereomers: Manipulation of eight‐membered ring conformations in analogues of the non‐narcotic analgesic drug

The solid‐state structures of (±)‐(1R,3S,5S)/(1S,3R,5R)‐and (+)/(‐)‐(1R,3R,5R)/(1S,3S,5S)‐3‐methylnefopam hydrochloride, epimeric 3‐methyl derivatives of the non‐narcotic analgesic drug, were determined by single‐crystal X‐ray diffraction analyses. (±)‐(1R,3S,5S)/(1S,3R,5S)‐3‐Methylnefopam hydrochloride gave crystals belonging to the monoclinic space group P2,/c, and at ambient temperature, a = 7.993(2), b = 34.376(4), c = 11.785(2) Å, β = 93.06°, V = 3234(2) ų, Z = 8, R(F = 0.070, and R_w(F) = 0.053. (+)/(‐)‐(1R,3R,5R)/(1S,3S,5S)‐3‐Methylnefopam hydrochloride gave chiral crystals belonging to the orthorhombic space group P2₁2₁2₁, and at 92 K, a = 9.261 (2), b = 10.280(2), c = 16.668(4) A, V = 1587(1) ų, Z = 4, R(F) = 0.034, and R_w(F) = 0.035. The two molecules in the asymmetric unit of the (1R,3S,5S)/(1S,3R,5R)‐racemic modification had twist‐chair‐(flattened chair) [TCfC] conformational geometries for the eight‐membered ring. Both molecules are virtually identical as shown by a root mean squares fit of 0.077 Å in the superimposition of all nonhydrogen atoms in both molecules. The (+)/(‐)‐(1R,3R,5R)/(1S,3S,5S)‐epimers were found in the same boat‐(flattened chair) [BfC] conformation previously noted for crystalline nefopam hydrochloride. The TCfC and BfC eight‐membered ring conformations of the two 3‐methylnefopam diastereomers differ in the —N+H(CH₃)CH₂CH— fragment chair or boat arrangement vis‐a‐vis the adjacent flattened region. In both 3‐methyl diastereomers, the C(3)‐methyl group was disposed in an equatorial orientation, the phenyl group resided in an exo‐position, and the —OCH(Ph)—o—C₆H₄ —fragment occupied the flattened region of the eight‐membered ring. Both epimers exhibited the same degree of significant inhibition (>50%) at 5‐hydroxytryptamine₂ binding sites (72.4 ± 2.5% for 10⁻⁵ M). In the Formalin Test for antinociceptive activity in mice, the (±)‐(1R,3R)/(1S,3S) diastereomer was inactive (the paw was licked 102 ± 9 s during the first 5 min after formalin injection versus 102 ± 7 s for control animals), and the (±)‐(1R,3S)/(1S,3R) epimer afforded modest but unequivocal activity (68 ± 4 s) relative to the parent nefopam hydrochloride (30 ± 7 s).