CONFORMATION OF THE 2 POTENTIAL ANTIPSYCHOTIC AGENTS THOXY-N-[(1-ETHYL-2-PYRROLIDINYL)METHYL]BENZAMIDE, FLB-457, AND ITS 2-HYDROXY ANALOG, FLB-463

The crystal structures and absolute configurations of two potent dopam ine-D-2 receptor antagonists, FLB 457,double dagger thoxy-N-[(1-ethyl- 2-pyrrolidinyl)methyl]benzamide, and FLB 463, xy-N-[(1-ethyl-2-pyrroli dinyl)methyl]salicylamide, have been determined by X-ray diffraction m ethods. The crystal structure of FLB 457 was derived from its salt wit h hydrobromide, C16H24BrN2O3+Br-, crystallizing in the orthorhombic sp ace group P2(1)2(1)2(1), a=28.900(18), b=8.747(3), c=7.585(1)Angstrom, Z=4, and FLB 463 from its methylsulfonate salt, C16H24BrN2O4+CH3SO3-, crystallizing in the monoclinic space group P2(1), a=15.264(5), b=8.0 87(4), c=8.541(3)Angstrom, beta=93.44(5)degrees, Z=2. FLB 457 and FLB 463 are two potential antipsychotic agents with extremely high and ste reospecific blocking affinity for the dopamine D-2-receptors both in v itro and in vivo. The biological activities are confined to the S-enan tiomeric forms. The molecular conformations of the two examined compou nds are almost identical, despite differences in their anionic environ ments. The benzamide moieties are essentially planar, stabilized by an intramolecular hydrogen bond between the amide group and the 6-methox y (ortho) O atom, reinforced by a second intramolecular hydrogen bond between the other ortho-substituent (2-hydroxyl group) and the carbony l O atom in FLB 463. In both structures, the 5-methoxy group is coplan ar with the benzene ring plane, while the methyl part of the 6-methoxy group is directed away from the aromatic plane. The conformation of t he amide side chain, which is associated with the area of greatest con formational flexibility, adopts a folded (+)-perpendicular-gauche tren d. In both crystals, the molecular packing schemes are mainly achieved through salt bridging. A weak hydrogen bond joins the bromide anion t o the protonated pyrrolidine nitrogen of FLB 457, whereas the methylsu lfonate anion is more closely connected to the FLB 463 cationic nucleu s via a complex hydrogen-bonding scheme, involving the pyrrolidine nit rogen as well as the amide nitrogen. Except for the salt interactions, the intermolecular forces are mainly of normal or weak van der Waals character.