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 P21/c,and at ambient temperature, a = 7.993(2), b = 34.376(4), c = 11.785(2) Å, β = 93.06°, V = 3234(2) Å3, Z = 8, R(F = 0.070, and RW(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) Å, V = 1587(1) Å3, Z = 4, R(F) = 0.034, and RW(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—C8H4—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 ± 9s during the first 5min after formalin injection versus 102 ± 7s 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).