Sanfilippo P J, McNally J J, Press J B, Fitzpatrick L J, Urbanski M J, Katz L B, Giardino E, Falotico R, Salata J, Moore J B
R.W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477-0776.
J Med Chem. 1992 Nov 13;35(23):4425-33. doi: 10.1021/jm00101a020.
The synthesis and antihypertensive activity of novel 7-(cyclic amido)-6-hydroxy-5,5-dimethylthieno[3,2-b]pyrans and related compounds are described. The compounds were tested for oral antihypertensive activity in spontaneously hypertensive rats (SHR) and selected compounds were evaluated in vitro for increases in 86Rb efflux in rabbit isolated mesenteric arteries. The effects on activity in SHR of lactam ring size, the presence of heteroatoms in the lactam ring, the relative stereochemistry at C-6 and C-7, and the substituents on the thiophene ring are examined. The best racemic compound in this series is 32, trans-5,6-dihydro-6-hydroxy-5,5-dimethyl-2-nitro-7-(2-oxopiperidin -1-yl)-5H- thieno[3,2-b]pyran, which is 10-fold more potent than cromakalim with an ED30 = 0.015 mg/kg in SHR. Compound 32 could be resolved and the antihypertensive activity determined to reside primarily in the (6S,7S)-(-)-enantiomer 41. Surprisingly, the elimination of water to give the enamides 50-52, thiophene isosteres of bimakalim, diminishes activity significantly.
本文描述了新型7-(环酰胺基)-6-羟基-5,5-二甲基噻吩并[3,2-b]吡喃及相关化合物的合成与降压活性。在自发性高血压大鼠(SHR)中测试了这些化合物的口服降压活性，并在体外评估了选定化合物对兔离体肠系膜动脉中86Rb外流增加的影响。研究了内酰胺环大小、内酰胺环中杂原子的存在、C-6和C-7处的相对立体化学以及噻吩环上的取代基对SHR活性的影响。该系列中最佳的外消旋化合物是32，即反式-5,6-二氢-6-羟基-5,5-二甲基-2-硝基-7-(2-氧代哌啶-1-基)-5H-噻吩并[3,2-b]吡喃，其效力比克罗卡林高10倍，在SHR中的ED30 = 0.015 mg/kg。化合物32可以拆分，其降压活性主要存在于(6S,7S)-(-)-对映体41中。令人惊讶的是，脱水生成双马卡林的噻吩异构体烯酰胺50-52会显著降低活性。
