A series of close analogues of the potent, long-acting cardiotonic bemoradan (2a) was synthesized and examined in both in vitro and in vivo test systems. Changing the oxygen heteroatom at the 1-position of the benzoxazine ring of bemoradan to sulfur gave 4a, a more potent enzyme inhibitor and in vivo cardiotonic compound by the iv route. Intraduodenal administration of bemoradan, however, showed a superior response compared to its sulfur analogue, possibly due to oxidation of sulfur followed by a facile Pummerer rearrangement. Model studies were performed to examine the effect of the oxidation state of sulfur. Lack of a heteroatom at the 1-position, 3a (Y-590), afforded a compound with activity and potency very similar to those of bemoradan while the 1-selena compound gave a much less potent analogue 5. Analogues having a methyl group on the 4-nitrogen (2b, 3b, and 4b) were less potent than the desmethyl compounds, but all of these compounds have potent PDE III inhibiting activity and the ability to increase cardiac force in an anesthetized dog preparation when given iv.

中文翻译：

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Bemoradan的杂原子类似物：1,4-苯并噻嗪基吡啶并吡嗪酮的化学性质和强心活性。

合成了一系列强效长效强心型bemoradan（2a）的紧密类似物，并在体外和体内测试系统中进行了检查。通过静脉途径将伯莫拉丹的苯并恶嗪环的1位上的氧杂原子更改为硫，得到4a，这是一种更有效的酶抑制剂和体内强心化合物。然而，与硫类似物相比，十二指肠十二指肠内给药显示出更好的反应，这可能是由于硫的氧化和随后的Pummerer重排。进行模型研究以检验硫的氧化态的影响。在1位3a（Y-590）处缺少杂原子，提供了一种与伯莫拉丹非常相似的活性和效价的化合物，而1-selena化合物所提供的效价低得多的类似物5。