Axially chiral 1,7-naphthyridine-6-carboxamide derivatives as orally active tachykinin NK1 receptor antagonists: Synthesis, antagonistic activity, and effects on bladder functions

Cyclic analogues of N-[3,5-bis(trifluoromethyl)benzyl]-7,8-dihydro-N,7-dime thyl-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-tetrah ydro-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 cy clization 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 relat ionships in this series, along with the X-ray analysis of (aR,9R)-8b, indic ated that the stereochemistry around the -C-(6)(=O)-N-(7)-CH2Ar moiety is i mportant for NK1 receptor recognition. The NK1 antagonists showed effects o n bladder functions in guinea pigs upon intravenous injection: i.e., the an tagonists increased the shutdown time of distension-induced rhythmic bladde r contractions and the bladder volume threshold, and the effects on the shu tdown time were found to correlate well with the NK1 antagonistic activitie s. Compound (aR,9R)-8b has been identified as a potential clinical candidat e for the treatment of bladder function disorders.