N-[(1S,5R)-7,9-dimethyl-7,9-diazabicyclo[3.3.1]non-3-yl]-1H-indazole-3-carboxamide dihydrochloride

Base Information

• Chemical Name: N-[(1S,5R)-7,9-dimethyl-7,9-diazabicyclo[3.3.1]non-3-yl]-1H-indazole-3-carboxamide dihydrochloride
• CAS No.: 160472-97-9
• Molecular Formula: C17H23 N5 O . 2 Cl H
• Molecular Weight: 0
• Mol file: 160472-97-9.mol

Synonyms:1H-Indazole-3-carboxamide,N-(3,9-dimethyl-3,9-diazabicyclo[3.3.1]non-7-yl)-, dihydrochloride, endo-;3,9-Diazabicyclo[3.3.1]nonane, 1H-indazole-3-carboxamide deriv.; N 3389

Chemical Property of N-[(1S,5R)-7,9-dimethyl-7,9-diazabicyclo[3.3.1]non-3-yl]-1H-indazole-3-carboxamide dihydrochloride

Chemical Property:

• Vapor Pressure: 3.36E-13mmHg at 25°C
• Boiling Point: 574.4°Cat760mmHg
• Flash Point: 301.2°C
• PSA: 64.26000
• Density: g/cm³
• LogP: 2.94020

Purity/Quality:

99% ^*data from raw suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Description: 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 Cmax 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.