Mertens A, Friebe W G, Müller-Beckmann B, Kampe W, Kling L, von der Saal W
Department of Chemistry, Boehringer Mannheim GmbH, Mannheim, West Germany.
J Med Chem. 1990 Oct;33(10):2870-5. doi: 10.1021/jm00172a031.
A series of substituted indolyldihydropyridazinones and related compounds 1-18 were synthesized and evaluated for positive inotropic activity. In rats, most of these indole derivatives produced a dose-related increase in myocardial contractility with little effect on heart rate and blood pressure. Compound 13, 4,5-dihydro-5-methyl-6-(2-pyridin-4-yl-1H-indol-5-yl)pyrazin-3(2H) -one (BM 50.0430), was further investigated in cats. The increase in contractility in this animal model was not mediated via stimulation of beta-adrenergic receptors. After oral administration of 1 mg/kg to conscious dogs, compound 13 and pimobendan were still active after 6.5 h. However, the cardiotonic effect of 13 was at least 2-fold that of pimobendan after this period of time. The structural requirements necessary for optimal cardiotonic activity within this novel class of indole derivatives are a heterocyclic aromatic ring in position 2, a hydrogen or a methyl group in position 3, and a dihydropyridazinone ring system in position 5 of the indole.
合成了一系列取代吲哚二氢哒嗪酮及相关化合物1 - 18，并对其正性肌力活性进行了评估。在大鼠中，大多数这些吲哚衍生物可使心肌收缩力呈剂量依赖性增加，而对心率和血压影响较小。化合物13，4,5 - 二氢 - 5 - 甲基 - 6 - (2 - 吡啶 - 4 - 基 - 1H - 吲哚 - 5 - 基)吡嗪 - 3(2H) - 酮（BM 50.0430）在猫身上进行了进一步研究。在该动物模型中，收缩力的增加并非通过刺激β - 肾上腺素能受体介导。给清醒犬口服1 mg/kg后，化合物13和匹莫苯丹在6.5小时后仍有活性。然而，在此时间段后，13的强心作用至少是匹莫苯丹的2倍。这类新型吲哚衍生物中产生最佳强心活性所需的结构要求是：2位有一个杂环芳环，3位有一个氢或甲基，吲哚5位有一个二氢哒嗪酮环系统。
