Bridges A J, Lee A, Schwartz C E, Towle M J, Littlefield B A
Section of Chemistry, Eisai Research Institute, Andover, MA 01810.
Bioorg Med Chem. 1993 Dec;1(6):403-10. doi: 10.1016/s0968-0896(00)82150-1.
Efficient synthesis of structurally novel 4-substituted benzo[b]thiophene-2-carboxamidines 1-3, which selectively inhibit urokinase-type plasminogen activator (uPA) with IC50 values of 70-320 nM, are described. The key intermediate, methyl 4-iodobenzo[b]thiophene-2-carboxylate (7), is prepared from 3-fluoroiodobenzene in two steps in 70% overall yield via fluorine-directed metalation/formylation and subsequent thiophene annulation. Amidination of ester 7 gives the 320 nM inhibitor 1. Palladium-catalyzed arylacetylene and vinyl stannane couplings with ester 7 or 4-iodobenzo[b]thiophene-2-carbonitrile (16, derived from 7), respectively, followed by amidination leads to the more potent inhibitors 2 (IC50 = 133 nM) and 3 (IC50 = 70 nM). These compounds represent an important new class of synthetic uPA inhibitors, with carboxamidine 3 being the most potent selective inhibitor currently described in the literature.
本文描述了结构新颖的4-取代苯并[b]噻吩-2-甲脒1-3的高效合成方法，这些化合物能选择性抑制尿激酶型纤溶酶原激活剂（uPA），IC50值为70-320 nM。关键中间体4-碘苯并[b]噻吩-2-羧酸甲酯（7）由3-氟碘苯经两步反应制得，通过氟导向的金属化/甲酰化以及随后的噻吩环化反应，总收率为70%。酯7的脒化反应得到IC50为320 nM的抑制剂1。钯催化的芳基乙炔和乙烯基锡分别与酯7或4-碘苯并[b]噻吩-2-腈（16，由7衍生而来）偶联，随后进行脒化反应，得到活性更强的抑制剂2（IC50 = 133 nM）和3（IC50 = 70 nM）。这些化合物代表了一类重要的新型合成uPA抑制剂，其中脒3是目前文献中描述的最有效的选择性抑制剂。
