160472-97-9

Concomitant with the emesis provoked by radiation and cytotoxic drugs is an increase in 5-hydroxytryptamine (5-HT) concentration in the brain stem and intestinal mucosa, which in turn stimulates the 5-HT₃ receptors on the adjacent vagal afferent nerves. The depolarization of the vagal afferents is responsible for inducing the vomiting reflex. Indisetron, a 5-HT₃/5-HT₄ antagonist, has, therefore, been launched in Japan as an anti-emetic. Since 5-HT4 is implicated in intestinal motility, dual antagonism should improve the anti-emetic effect, although this remains to be demonstrated. The diazabicycloamine portion of indisetron is prepared in four steps starting with methylamine and bromoacetaldehyde dimethylacetal. Coupling to the indazole core is accomplished via the acid chloride of 1H-indazole-3-carboxylic acid. In vitro, indisetron displaced [³H]GR-65630 binding to the 5-HT3 receptor in rat brain membranes in a concentration-dependent manner with a pKi value of 8.77, which is comparable to the activities of other 5-HT₃ antagonists such as granisetron and ondansetron. In animal models (ferrets and dogs), indisetron reduced the number and duration of cisplatin-induced emetic episodes when administered orally at 0.1–1mg/kg prior to cisplatin treatment. Compared to granisetron and ondansetron, there were no significant differences in the frequency of vomiting; however, the duration was significantly reduced with indisetron. After the administration of anticancer agents, including cisplatin, in phase II and phase III clinical trials, indisetron prevented vomiting in 62%of patients (67 of 108) for 24 h. It faired even better in a phase III clinical study where the anticancer agents did not include cisplatin; emesis was averted in 34 of 40 patients (85%). In a single oral dose study (4, 8, 16, and 32mg under fasting conditions or a 16mg dose post-prandial) in healthy males, indisetron showed high oral bioavailability (nearly 100%), and C_max and AUC increased in a dose-dependent manner. While four subjects experienced adverse effects, they were considered mild and not clinically significant. In a phase I study comprised of 16mg of indisetron administered b.i.d. over 7 consecutive days, the adverse reactions were also deemed clinically insignificant although it was noted that two patients presented with constipation and an increase in serum amylase. Steady state plasma levels were achieved by day 3. Repeated administration did not change the pharmacokinetics and accumulation of indisetron. Indisetron is metabolized by a host of CYP enzymes (1A1, 2C9, 2D6, and 3A4) in the liver; however, it is unlikely to cause drug interactions at clinical doses because the plasma concentrations are lower than those necessary for CYP inhibition. Finally, as a 5-HT₃ antagonist, indisetron should avoid the adverse effects of the current dopamine-blocking anti-emetics, such as, sedation, ataxia, diarrhea, and tasikinesia, making it a viable alternative to existing therapy.

Nisshin (Japan)

Sinseron

The synthesis is highlighted in the Scheme. Bromoacetaldehyde dimethyl acetal (44) was condensed with methylamine with KOH in refluxing ethyleneglycol for 3 hr to give 33% yield of bis(2,2-dimethoxyethyl)amine (45), which was cyclized with acetonedicarboxylic acid (46) and methylamine to generate 3,9-dimethyl-3,9-diazabicyclo- [3.3.1]nonan-7-one (47) in 12% yield. Compound 47 was reacted with hydroxylamine in refluxing pyridine and ethanol mixture to give corresponding oxime 48 in 88% yield, which was subsequently reduced with hydrogen over Raney Ni in hot ethanol in the presence of ammonium acetate at 50 kg/cm2 to give amine 49 in 89% yield. Compound 49 was condensed with 1H-indazole-3-carbonyl chloride (50) in pyridine with catalytic amount of DMAP to give crude indisteron free base, which was re-crystallized from chloroform/hexane to give indisteron free base as colorless crystals in 16% yield. Finally, the free base was treated with hydrogen chloride to give indisteron hydrochloride (VII).