Novel 5-hydroxytryptamine (5-HT3) receptor antagonists. IV. Synthesis and pharmacological evaluation of the oxidation products of (-)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl] -4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride (YM060: ramosetron).
In physicochemical and pharmacokinetic evaluations of (--)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl] -4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride 1 (YM060: ramosetron), which is a highly potent 5-hydroxytryptamine(-HT3) receptor antagonist, 4-hydroxy-6-[(1-methyl-1H-indol-3-yl) carbonyl]4,5,6,7-tetrahydro-1H-benzimidazole 2 was identified as a degradation product and metabolite of 1. The (--)-(4R,6S)-isomer 2 was synthesized from the diketone derivative 3, via the stereoselective reduction of 3 followed by the stereocontrolled epimerization of the (--)-(4S,6S)-isomer 10, the epimer of 2. The stereochemistry of 2 and 10 was determined by NMR and HPLC studies. Compounds 2 and 10 were found to be potent 5-HT3 receptor antagonists, like 1. Among the other oxidation products, the diketone derivatives 3 and 7 and the dihydroxylated derivative 4 retained antagonistic activity similar to that of ondansetron. This is of interest, because they do not possess the amine group which is known to be necessary for high affinity to the 5-HT3 receptor.
Ohta
M
M
Neuroscience/Gastrointestinal Research Laboratories, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Suzuki
T
T
Nagashima
S
S
Tokunaga
T
T
Miyata
K
K
Mase
T
T
D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D003106:Colon; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008968:Molecular Conformation; D009119:Muscle Contraction / Q000187:drug effects; D017294:Ondansetron / Q000494:pharmacology; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
C104608:4-hydroxy-6((1-methyl-1H-indol-3-yl)carbonyl)-4,5,6,7-tetrahydro-1H-benzimidazole; D001562:Benzimidazoles; D012702:Serotonin Antagonists; D012701:Serotonin; D017294:Ondansetron; C071315:ramosetron