Axially chiral 1,7-naphthyridine-6-carboxamide derivatives as orally active tachykinin NK(1) receptor antagonists: synthesis, antagonistic activity, and effects on bladder functions.
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.
Natsugari
H
H
Pharmaceutical Research Division and Technology Development Department, Takeda Chemical Industries, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. Natsugari_Hideaki@takeda.co.jp
Ikeura
Y
Y
Kamo
I
I
Ishimaru
T
T
Ishichi
Y
Y
Fujishima
A
A
Tanaka
T
T
Kasahara
F
F
Kawada
M
M
Doi
T
T
D000818:Animals; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D006168:Guinea Pigs; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008958:Models, Molecular; D009119:Muscle Contraction / Q000187:drug effects; D009287:Naphthyridines / Q000737:chemistry* / Q000494:pharmacology*; D064729:Neurokinin-1 Receptor Antagonists; D011487:Protein Conformation; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology*
C115421:N-(3,5-bis(trifluoromethyl)benzyl)-7,8-dihydro-N,7-dimethyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxamide; D009287:Naphthyridines; D064729:Neurokinin-1 Receptor Antagonists