Axially chiral 1,7-naphthyridine-6-carboxamide derivatives as orally active tachykinin NK1 receptor antagonists:: Synthesis, antagonistic activity, and effects on bladder functions
Axially chiral 1,7-naphthyridine-6-carboxamide derivatives as orally active tachykinin NK1 receptor antagonists:: Synthesis, antagonistic activity, and effects on bladder functions
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DOI：
10.1021/jm990220r
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发表时间：
1999-09-23
影响因子：
7.3
通讯作者：
Doi, T
中科院分区：
文献类型：
--
作者：
Natsugari, H;Ikeura, Y;Doi, T
合成具有6-9元环(6-9)的N-[3,5-双(三氟甲基)苄基]-7,8-二氢-N,7-二甲基-5-(4-甲基苯基)-8-氧代-1,7-萘啶-6-甲酰胺(1)的环状类似物并评估其NK1拮抗活性。 C-(9)位有β-甲基的8元环化合物，(aR,9R)-7-[3,5-双(三氟甲基)苄基]-8,9,10,-11-四氢-9-甲基-5-(4-甲基苯基)-7H-[1,4]二氮杂环[2,1-g][1,7]萘啶-6,13-二酮[(aR,9R)-8b]，是通过手性中间体环化选择性合成的，10g。另一方面，在C-(9)-位上具有β-甲基基团的7元环化合物[(9S)-7b]作为阻转异构体的平衡混合物获得，其比率为约100％。室温下的 3:2 溶液（通过 NMR 在 CDCl3 中测量）。化合物(9S)-7b和(aR,9R)-8b在体外[IC50(对人IM-9细胞中[I-125]BH-SP结合的抑制)分别=0.28和0.45nM]和体内(iv和po)均表现出优异的拮抗活性。值得注意的是，(aR,9R)-8b 的体外活性约为。比其对映体 (aS,9S)-8b 高 750 倍，约 750 倍。比其阻转异构体 (aS,9R)-8b 高 40 倍，约 40 倍。比其非对映异构体(aR,9S)-8b高20倍。该系列中的构效关系以及 (aR,9R)-8b 的 X 射线分析表明 -C-(6)(=O)-N-(7)-CH2Ar 部分周围的立体化学对于 NK1 受体识别非常重要。 NK1拮抗剂在静脉注射后对豚鼠的膀胱功能显示出影响：即拮抗剂增加了扩张引起的节律性膀胱收缩的关闭时间和膀胱容量阈值，并且发现对关闭时间的影响与NK1拮抗活性密切相关。化合物(aR,9R)-8b已被确定为治疗膀胱功能障碍的潜在临床候选药物。
Cyclic analogues of N-[3,5-bis(trifluoromethyl)benzyl]-7,8-dihydro-N,7-dimethyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxamide (1) having a 6-9-membered ring (6-9) were synthesized and evaluated for NK1 antagonistic activities. The 8-membered ring compound with a beta-methyl group at the C-(9)-position, (aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,-11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-di-one [(aR,9R)-8b], was atropodiastereoselectively synthesized by cyclization of a chiral intermediate, 10g. On the other hand, the 7-membered ring compound with a beta-methyl group at the C-(9)-position [(9S)-7b] was obtained as an equilibrium mixture of atropisomers with a ratio of ca. 3:2 in solution at room temperature (measured by NMR in CDCl3). Compounds (9S)-7b and (aR,9R)-8b exhibited excellent antagonistic activities both in vitro [IC50 (inhibition of [I-125]BH-SP binding in human IM-9 cells) = 0.28 and 0.45 nM, respectively] and in vivo (iv and po). Significantly, the in vitro activity of (aR,9R)-8b was ca. 750-fold higher than that of its enantiomer (aS,9S)-8b, ca. 40-fold higher than its atropisomer (aS,9R)-8b, and ca. 20-fold higher than its diastereomer (aR,9S)-8b. The structure-activity relationships in this series, along with the X-ray analysis of (aR,9R)-8b, indicated that the stereochemistry around the -C-(6)(=O)-N-(7)-CH2Ar moiety is important for NK1 receptor recognition. The NK1 antagonists showed effects on bladder functions in guinea pigs upon intravenous injection: i.e., the antagonists increased the shutdown time of distension-induced rhythmic bladder contractions and the bladder volume threshold, and the effects on the shutdown time were found to correlate well with the NK1 antagonistic activities. Compound (aR,9R)-8b has been identified as a potential clinical candidate for the treatment of bladder function disorders.