Russell R K, Press J B, Rampulla R A, McNally J J, Falotico R, Keiser J A, Bright D A, Tobia A
Research Laboratories, Ortho Pharmaceutical Corporation, Raritan, New Jersey 08869.
J Med Chem. 1988 Sep;31(9):1786-93. doi: 10.1021/jm00117a019.
A series of thieno[3,4-d]-, thieno[3,2-d]-, and thieno[2,3-d]pyrimidine-2,4-diones with (phenylpiperazinyl)alkyl substitution at N-3 have been synthesized and evaluated for antihypertensive effects in spontaneously hypertensive rats (SHR). These 49 compounds were compared to the vasodilator standards prazosin and the isosteric quinazoline-2,4-dione SGB 1534. Substitution at the 2-, 3-, or 4-position of the phenyl ring was examined, with that at the 2-position more potent than 4-substitution while the isomeric 3-substituted compounds were least potent. Neither alkylation nor acylation at the N-1 position improved the antihypertensive effects as compared to hydrogen. The three thienopyrimidine-2,4-diones (3-5) that contain a [(2-methoxyphenyl)piperazinyl]ethyl moiety at N-3 and hydrogen at N-1 were found to be potent oral antihypertensive agents in the SHR with doses (mg/kg, po) for reducing systolic blood pressure (SBP) by 50 mmHg (ED-50SBP) of 0.21, 0.19, and 1.0, respectively. The compounds 1-5 were further evaluated for alpha blocking potency by measuring the iv doses necessary to antagonize the phenylephrine pressor response by 50% (ED50) in the SHR. The ED50 values (micrograms/kg) are 10.4, 3.3, 1.7, 2.1, and 15.4, respectively. These results clearly show that all three thiophene systems have potent activity as antihypertensive agents and that 3 and 4 are more potent than 1 or 2 as alpha 1-antagonists in vivo.
已合成了一系列在N-3位具有（苯基哌嗪基）烷基取代的噻吩并[3,4-d] -、噻吩并[3,2-d] -和噻吩并[2,3-d]嘧啶-2,4-二酮，并在自发性高血压大鼠（SHR）中评估了它们的降压作用。将这49种化合物与血管扩张剂标准品哌唑嗪和等排体喹唑啉-2,4-二酮SGB 1534进行了比较。研究了苯环2-、3-或4-位的取代情况，发现2-位取代的活性比4-位取代的更强，而3-位取代的异构体活性最弱。与氢相比，N-1位的烷基化或酰化均未改善降压作用。发现三种在N-3位含有[（2-甲氧基苯基）哌嗪基]乙基部分且在N-1位为氢的噻吩并嘧啶-2,4-二酮（3-5）是SHR中有效的口服降压剂，使收缩压（SBP）降低50 mmHg的剂量（mg/kg，口服）分别为0.21、0.19和1.0。通过测量在SHR中拮抗去氧肾上腺素升压反应50%（ED50）所需的静脉注射剂量，对化合物1-5的α阻断效力进行了进一步评估。ED50值（微克/千克）分别为10.4、3.3、1.7、2.1和15.4。这些结果清楚地表明，所有三种噻吩系统作为降压剂均具有强效活性，并且在体内作为α1拮抗剂，3和4比1或2更有效。
