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首页> 外文期刊>Acta Crystallographica, Section B. Structural Science >Conformation of the Two Potential Antipsychotic Agents (-)-(S)-3-Bromo-5,6-dimethoxy-N-[(1-ethyl-2-pyrrolidinyl) methyl]benzamide, FLB 457, and its 2-Hydroxy Analogue, FLB 463
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Conformation of the Two Potential Antipsychotic Agents (-)-(S)-3-Bromo-5,6-dimethoxy-N-[(1-ethyl-2-pyrrolidinyl) methyl]benzamide, FLB 457, and its 2-Hydroxy Analogue, FLB 463

机译：两种潜在的抗精神病药（-）-（S）-3-溴-5,6-二甲氧基-N-[（1-乙基-2-吡咯烷基）甲基]苯甲酰胺，FLB 457和其2-羟基类似物的构象，FLB 463

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摘要

The crystal structures and absolute configurations of two potent dopamine-D2 receptor antagonists, FLB 4574 (-)-(S)-3-bromo-5,6-dimethoxy-A'-[(l-ethyl-2-pyrrolidi nyl)methyl]benzamide, and FLB 463, (-)-(S)-3-bromo-5,6-dimethoxy-Ar-[(l-ethyl-2-pyrrolidinyl)methyl]salicyl-amide, have been determined by X-ray diffraction methods. The crystal structure of FLB 457 was derived from its salt with hydrobromide, CI6H24BrN2C3Br-, crystallizing in the orthorhombic space group P2i2u a = 28.900 (18), b = 8.747 (3), c = 7.585 (1) A, Z = 4, and FLB 463 from its methylsulfonate salt, C16H24BrN2OjCH3SOj, crystallizing in the monoclinic space group P2 a = 15.264(5), 6 = 8.087(4), c = 8.541 (3)A, B = 93.44(5)°, Z = 2. FLB 457 and FLB 463 are two potential antipsychotic agents with extremely high and stereospecific blocking affinity for the doparm'ne D2-receptors both in vitro and in vivo. The biological activities are confined to the S-enantiomeric forms. The molecular conformations of the two examined compounds are almost identical, despite differences in their anionic environments. The benzamide moieties are essentially planar, stabilized by an intramolecular hydrogen bond between the amide group and the 6-methoxy (ortho) O atom, reinforced by a second intramolecular hydrogen bond between the other ortho-substituent (2-hydroxyl group) and the carbonyl O atom in FLB 463. In both structures, the 5-methoxy group is coplanar with the benzene ring plane, while the methyl part of the 6-methoxy group is directed away from the aromatic plane. The conformation of the amide side chain, which is associated with the area of greatest conformational flexibility, adopts a folded (+)-perpendi-culax-gauche trend. In both crystals, the molecular packing schemes are mainly achieved through salt bridging. A weak hydrogen bond joins the bromide anion to the protonated pyrrolidine nitrogen of FLB 457, whereas the methylsulfonate anion is more closely connected to the FLB 463 cationic nucleus via a complex hydrogen-bonding scheme, involving the pyrrolidine nitrogen as well as the amide nitrogen. Except for the salt interactions, the intermolecular forces are mainly of normal or weak van der Waals character.
机译：两种有效的多巴胺-D2受体拮抗剂FLB 4574（-）-（（S）-3-bromo-5,6-dimethoxy-A'-[（1-乙基-2-吡咯烷基]）的晶体结构和绝对构型X射线确定了]苯甲酰胺和FLB 463（-）-（S）-3-溴-5,6-二甲氧基-Ar-[（1-乙基-2-吡咯烷基）甲基]水杨酰胺衍射法。 FLB 457的晶体结构是由其与氢溴酸盐Cl6H24BrN2C3Br-的盐衍生而来的，在正交晶空间群P2i2u中结晶a = 28.900（18），b = 8.747（3），c = 7.585（1）A，Z = 4，和FLB 463的甲基磺酸盐C16H24BrN2OjCH3SOj，在单斜晶空间群P2 a = 15.264（5），6 = 8.087（4），c = 8.541（3）A，B = 93.44（5）°，Z = 2时结晶FLB 457和FLB 463是两种潜在的抗精神病药，在体外和体内对doparm'ne D2受体具有极高的立体定向封闭亲和力。生物学活性限于S-对映体形式。尽管两种阴离子化合物的阴离子环境不同，但它们的分子构象几乎相同。苯甲酰胺部分基本上是平面的，通过酰胺基团和6-甲氧基（邻位）O原子之间的分子内氢键稳定，并通过其他邻位取代基（2-羟基）和羰基之间的第二个分子内氢键增强FLB 463中的O原子。在两个结构中，5-甲氧基与苯环平面共面，而6-甲氧基的甲基部分则背离芳族平面。酰胺侧链的构象与最大构象柔性的区域有关，采用折叠的（+）-perpendi-culax-gauche趋势。在两种晶体中，分子堆积方案主要是通过盐桥实现的。弱氢键将溴化物阴离子连接到FLB 457的质子化吡咯烷氮上，而甲基磺酸根阴离子则通过复杂的氢键结方案与FLB 463阳离子核更紧密地连接，涉及吡咯烷氮以及酰胺氮。除盐相互作用外，分子间力主要是正常或弱范德华特性。

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