Sharma A P, Saeed A, Durani S, Kapil R S
Medicinal Chemistry Division, Central Drug Research Institute, Lucknow, India.
J Med Chem. 1990 Dec;33(12):3216-22. doi: 10.1021/jm00174a019.
A series of 2,3-diaryl-2H-1-benzopyrans carrying a tertiary aminoethoxy chain at the ortho, meta, or para position of 2-phenyl or an alkyl at position 4 of the pyran ring were synthesized and evaluated for their affinity for estrogen receptor (ER) and for microsomal antiestrogen specific binding site and for their uterotrophic-antiuterotrophic activities in rodents. The analogues bearing the side chain at the para position of 2-phenyl were found to be active while those substituted at the meta and ortho positions were inactive as ER ligands as well as estrogen agonists-antagonists. Among para-substituted ethers, the 2-piperidinoethoxy analogue 5 was found to be a more effective antiestrogen than the corresponding pyrrolidino, dimethylamino, and related analogues. Incorporation of a methyl or an ethyl at C4 in the pyran nucleus was found to increase receptor affinity of the prototypes. The ethyl was also found to potentiate agonist activity of the prototype while abolishing its antagonist activity. The piperidino analogue 5 was found to be a better antiestrogen than tamoxifen as well as LY-117018 in rats as well as mice. The prototypes were also found to have high affinity for the microsomal antiestrogen specific binding sites. The benzopyrans have thus emerged as a new group of potent antiestrogens.
合成了一系列在2-苯基的邻位、间位或对位带有叔氨基乙氧基链或在吡喃环4位带有烷基的2,3-二芳基-2H-1-苯并吡喃，并评估了它们对雌激素受体（ER）、微粒体抗雌激素特异性结合位点的亲和力，以及它们在啮齿动物中的子宫营养-抗子宫营养活性。发现2-苯基对位带有侧链的类似物具有活性，而在间位和邻位取代的类似物作为ER配体以及雌激素激动剂-拮抗剂则无活性。在对位取代的醚类中，发现2-哌啶基乙氧基类似物5比相应的吡咯烷基、二甲基氨基及相关类似物是更有效的抗雌激素。发现在吡喃核的C4处引入甲基或乙基可增加原型物的受体亲和力。还发现乙基可增强原型物的激动剂活性，同时消除其拮抗剂活性。在大鼠和小鼠中，发现哌啶基类似物5比他莫昔芬以及LY-117018是更好的抗雌激素。还发现原型物对微粒体抗雌激素特异性结合位点具有高亲和力。因此，苯并吡喃已成为一类新的强效抗雌激素。
