Natsugari H, Ikeura Y, Kamo I, Ishimaru T, Ishichi Y, Fujishima A, Tanaka T, Kasahara F, Kawada M, Doi T
Pharmaceutical Research Division and Technology Development Department, Takeda Chemical Industries, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
J Med Chem. 1999 Sep 23;42(19):3982-93. doi: 10.1021/jm990220r.
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 NK(1) 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-dione [(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 CDCl(3)). Compounds (9S)-7b and (aR,9R)-8b exhibited excellent antagonistic activities both in vitro [IC(50) (inhibition of [(125)I]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))-CH(2)Ar moiety is important for NK(1) receptor recognition. The NK(1) 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 NK(1) antagonistic activities. Compound (aR,9R)-8b has been identified as a potential clinical candidate for the treatment of bladder function disorders.
合成了具有6至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，并对其NK(1)拮抗活性进行了评估。在C((9))位带有β-甲基的8元环化合物，即(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]二氮杂环辛并[2,1-g][1,7]萘啶-6,13-二酮[(aR,9R)-8b]，通过手性中间体10g的环化反应以非对映选择性方式合成。另一方面，在C((9))位带有β-甲基的7元环化合物[(9S)-7b]在室温下于溶液中（通过CDCl(3)中的NMR测量）以约3:2的比例作为阻转异构体的平衡混合物获得。化合物(9S)-7b和(aR,9R)-8b在体外[IC(50)（抑制人IM-9细胞中[(125)I]BH-SP结合）分别为0.28和0.45 nM]和体内（静脉注射和口服）均表现出优异的拮抗活性。值得注意的是，(aR,9R)-8b的体外活性比其对映体(aS,9S)-8b高约750倍，比其阻转异构体(aS,9R)-8b高约40倍，比其非对映异构体(aR,9S)-8b高约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))-CH(2)Ar部分周围的立体化学对于NK(1)受体识别很重要。这些NK(1)拮抗剂在豚鼠静脉注射后对膀胱功能有影响：即拮抗剂增加了扩张诱导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NK(1)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。
