Isochroman-6-carboxamides as highly selective 5-HT1D agonists:: Potential new treatment for migraine without cardiovascular side effects
Isochroman-6-carboxamides as highly selective 5-HT1D agonists:: Potential new treatment for migraine without cardiovascular side effects
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DOI：
10.1021/jm980137o
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发表时间：
1998-06-18
影响因子：
7.3
通讯作者：
McCall, RB
中科院分区：
文献类型：
--
作者：
Ennis, MD;Ghazal, NB;McCall, RB
偏头痛是一种使人衰弱的慢性疾病，影响着全世界数百万人的生活。偏头痛在工作年龄人群（35-40岁）中最为普遍，仅在美国，其经济影响估计就达数十亿美元。目前，偏头痛的主要治疗方法是舒马曲普坦（1），这是一种非选择性的肾上腺素能药物，与5-HT 1D和5-HT 1B受体具有高亲和力（Ki分别为3.4和7.7 nM）。5，6关于偏头痛病因学的最新理论表明，仅在5-HT 1D位点的选择性激动剂可有效改善偏头痛症状。7，8事实上，已经提出舒马曲普坦的5-HT 1B性质是其血管收缩性质和相关心血管副作用的原因。9、10目前开发的用于治疗偏头痛的几乎所有化合物都是色胺衍生物，其在5-HT 1D和5-HT 1B位点之间具有很少或没有选择性。在本通讯中，我们描述了第一类高选择性的非吲哚5-HT 1D激动剂。这些化合物之一（S）-（-）-10在偏头痛动物模型中比舒马曲普坦显著更有效，但没有血管收缩特性。在探索靶向多巴胺D4受体的一系列异苯并二氢吡喃-芳基哌嗪的结构-亲和力关系时，12我们制备了方案1中所示的6-甲酰胺类似物7。4-溴苯乙醇2与3，3-二乙氧基丙酸乙酯在TiCl 4存在下反应得到异色满3。将3水解成羧酸4，随后与4-甲氧基苯基哌嗪偶联得到酰胺5，将其用硼烷还原得到6。6与t-BuLi进行金属-卤素交换，随后用N-三甲基甲硅烷基异氰酸酯淬灭所得芳基阴离子，得到6-甲酰胺7。当在一组CNS受体结合测定中进行评价时（表1），发现7在D4位点具有差的亲和力（Ki 1054 nM），与未取代的异色满类似物8（Ki 2.4 nM）（选择性多巴胺D4拮抗剂）形成鲜明对比。12然而，酰胺7显示出对5-HT 1D受体的出乎意料的亲和力（Ki 8.6 nM）。此外，7对5-HT 1B位点几乎没有亲和力，对5-HT 1D表现出至少100倍的偏好。因此，似乎异色满-6-甲酰胺，如7可能代表一个新的，非色胺为基础的家庭的选择性5-HT 1D剂。在异色满-6-甲酰胺家族中偶然发现的5-HT 1D选择性促使我们制备7的对映体。为此，我们采用了类似于先前描述的相关D4异色满化合物的酶促拆分程序。如方案2所示，用Amano P-30脂肪酶处理外消旋溴代酯3导致（S）-酯对映体的高度选择性水解，以提供容易分离的羧酸（S）-（-）-4和回收的酯（R）-（+）-3的混合物，产率分别为86%和91%，光学纯度分别为99%和96%ee。从这些拆分的产物制备相应的对映异构体（S）-（-）-7和（R）-（+）-7。从表1中可以看出，5-HT 1D受体的结合亲和力对异色满C-1位的立体化学构型非常敏感，更有效的异构体是（S）-（-）-7化合物。有趣的是，评价的其他5-羟色胺和多巴胺受体对这些化合物的结合亲和力几乎不依赖于立体化学。光学纯的伯酰胺（S）-（-）-7可作为制备中间体的起始原料。
Migraine headache is a debilitating, chronic disease affecting the lives of millions of people worldwide. 1, 2 Migraine is most prevalent in working age populations (35-40 years old), and its economic impact in the United States alone has been estimated in the billions of dollars. 3, 4 Currently, the primary treatment for migraine is Sumatriptan (1), a nonselective serotonergic agent which binds with high affinity to both the 5-HT1D and 5-HT1B receptors (Ki of 3.4 and 7.7 nM respectively). 5, 6 Recent theories regarding the etiology of migraine suggest that selective agonists at only the 5-HT1D site could be effective at ameliorating migraine symptoms. 7, 8 Indeed, it has been proposed that the 5-HT1B properties of Sumatriptan are responsible for its vasoconstrictive properties and associated cardiovascular side effects. 9, 10 Nearly all of the compounds currently in development for treating migraine are tryptamine derivatives which possess little or no selectivity between the 5-HT1D and 5-HT1B sites. 11 In this Communication, we describe the first class of highly selective, non-indole 5-HT1D agonists. One of these compounds,(S)-(-)-10, is significantly more potent than Sumatriptan in animal models of migraine yet devoid of vasoconstrictive properties. While exploring the structure-affinity relationships in a series of isochroman-arylpiperazines targeting the dopamine D4 receptor, 12 we prepared the 6-carboxamide analogue 7 shown in Scheme 1. Reaction of 4-bromophenethyl alcohol 2 with ethyl 3, 3-diethoxypropionate in the presence of TiCl4 provided the isochroman 3. Hydrolysis of 3 to the carboxylic acid 4 and subsequent DECP coupling with 4-methoxyphenylpiperazine provided the amide 5, which was reduced with borane to give 6. Metal-halogen exchange of 6 with t-BuLi and subsequent quenching of the resulting aryl anion with N-trimethylsilylisocyanate afforded the 6-carboxamide 7. When evaluated in a battery of CNS receptor binding assays (Table 1), 7 was found to possess poor affinity at the D4 site (Ki 1054 nM), in sharp contrast to the unsubstituted isochroman analogue 8 (Ki 2.4 nM), a selective dopamine D4 antagonist. 12 However, amide 7 displayed unexpected affinity for the 5-HT1D receptor (Ki 8.6 nM). Furthermore, 7 showed little affinity for the 5-HT1B site, exhibiting at least a 100-fold preference for 5-HT1D. Thus, it appeared that isochroman-6-carboxamides such as 7 may represent a new, nontryptamine-based family of selective 5-HT1D agents. The serendipitous finding of 5-HT1D selectivity within the isochroman-6-carboxamide family prompted us to prepare the enantiomers of 7. For this purpose, we employed an enzymatic-based resolution procedure similar to that previously described for the related D4 isochroman compounds. 12 As illustrated in Scheme 2, treatment of racemic bromo ester 3 with Amano P-30 lipase results in a highly selective hydrolysis of the (S)-ester antipode to provide a readily separable mixture of the carboxylic acid (S)-(-)-4 and the recovered ester (R)-(+)-3 in yields of 86% and 91% and optical purities of 99% and 96% ee, respectively. 14 From these resolved products were prepared the corresponding enantiomers (S)-(-)-7 and (R)-(+)-7. As can be seen from Table 1, binding affinity at the 5-HT1D receptor was exquisitely sensitive to the stereochemical configuration of the isochroman C-1 position, with the more potent isomer being the (S)-(-)-7 compound. Interestingly, the other serotonin and dopamine receptors evaluated showed little dependence upon stereochemistry in their binding affinities for these compounds. The optically pure primary amide (S)-(-)-7 served as a useful starting point for the preparation …