1282449-07-3

Upstream product

• 371-40-4 4-fluoroaniline 
• 66053-11-0 ethyl 2-(2-(4-fluorophenyl)hydrazono)-3-oxobutanoate 
• 433233-28-4 ethyl 5-amino-3-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxylate 
• 443666-61-3 ethyl 5-cyano-1-(4-fluorophenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate 

Downstream Products

• 1391030-17-3 3-(4-fluorophenyl)-4,5-dioxo-3,4,5,7-tetrahydrothieno[3,4-d]pyridazine-1-carboxylic acid 
• 1391029-78-9 5-amino-3-(4-fluorophenyl)-4-oxo-N-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxamide 
• 1282449-11-9 5-amino-3-(4-fluorophenyl)-N-isopropyl-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxamide 
• 1282449-12-0 5-amino-N-cyclopropyl-3-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxamide 

Relevant academic research and scientific papers

Ring-opened aminothienopyridazines as novel tau aggregation inhibitors

Aminothienopyridazines (ATPZs) have demonstrated efficacy, in vitro, as tau protein aggregation inhibitors. Modifications were made to the ATPZ scaffold to determine the importance of certain structural features for activity. More specifically, ring-opened analogues detached at the nitrogen-nitrogen bond of the pyridazine, were synthesized and their inhibitory activity evaluated. Preliminary data suggests that the ring-opened structures retain inhibitory activity, independent of tau oxidation. The structures detailed represent the beginnings of a deconstruction-reconstruction-elaboration study, with the aim of identifying simpler scaffolds, which retain activity and can be optimized in terms of physiochemical properties.

Aminothienopyridazine inhibitors of tau aggregation: Evaluation of structure-activity relationship leads to selection of candidates with desirable in vivo properties

Previous studies demonstrated that members of the aminothienopyridazine (ATPZ) class of tau aggregation inhibitors exhibit a promising combination of in vitro activity as well as favorable pharmacokinetic properties (i.e., brain-penetration and oral bioavailability). Here we report the synthesis and evaluation of several new analogues. These studies indicate that the thienopyridazine core is essential for inhibition of tau fibrillization in vitro, while the choice of the appropriate scaffold decoration is critical to impart desirable ADME-PK properties. Among the active, brain-penetrant ATPZ inhibitors evaluated, 5-amino-N-cyclopropyl-3-(4-fluorophenyl)-4-oxo-3,4- dihydrothieno[3,4-d]pyridazine-1-carboxamide (43) was selected to undergo maximum tolerated dose and one-month tolerability testing in mice. The latter studies revealed that this compound is well-tolerated with no notable side-effects at an oral dose of 50 mg/kg/day.

AMINOTHIENOPYRIDAZINE INHIBITORS OF TAU ASSEMBLY

The present invention is directed to methods of inhibiting a tauopathy in a patient by administration of a compound of formula (I): Novel aminothienopyridazine compounds are also described.