ChemInform Abstract: Strategies and Progress Towards the Ideal Orally Active Thrombin Inhibitor

Abstract

organic chemistry, review organic chemistry, review Z 0200 09 -262 Strategies and Progress Towards the Ideal Orally Active Thrombin Inhibitor -[137 refs.]. -(REWINKEL, J. B. M.; ADANG, A. E. P.; Curr. Pharm. Des. 5 (1999) 12, 1043-1075; Dep. Med. Chem., Sci. Dev. Group, NV Organon , NL-5340 BH Oss, Neth.; EN)

Synthesis and antiproliferative activity of 2-(([1,2,4]triazolo[4,3-b]- pyridazin-6-yloxy)methyl)-2,4-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine derivatives

“…The synthesis of target [1,2,4]triazolo [4,3-b]pyridazine compounds 14-17 is depicted in Scheme 3. The key intermediate 2-hydroxymethylbenzo[b] [1,4]oxazine derivative 9 was prepared as described, from 2-amino-5-nitrophenol 6 in three steps via i) cyclization affording ethyl 2,4-dimethyl-7-nitro-3-oxo-3,4-dihydro-2H-benzo[b] [1,4]oxazine-2-carboxylate 7, ii) its Nmethylation to 8 10 and iii) subsequent borane reduction 1b of 8 (Scheme 2).…”

“…The key intermediate 2-hydroxymethylbenzo[b] [1,4]oxazine derivative 9 was prepared as described, from 2-amino-5-nitrophenol 6 in three steps via i) cyclization affording ethyl 2,4-dimethyl-7-nitro-3-oxo-3,4-dihydro-2H-benzo[b] [1,4]oxazine-2-carboxylate 7, ii) its Nmethylation to 8 10 and iii) subsequent borane reduction 1b of 8 (Scheme 2). 6-Chloro- [1,2,4]triazolo [4,3-b]pyridazine 4 was also obtained by a literature procedure, involving cyclization of 3-chloro-6-hydrazinylpyridazine 3 with diethyl ethoxymethylenemalonate, 11 and cyclization of 3 with triethyl orthoacetate afforded 6-chloro-3-methyl- [1,2,4]triazolo [4,3-b]pyridazine 5 12 (Scheme 1).…”

“…Recently we have described a new series of potential antithrombotic compounds 1 based on a 2,4-dimethyl-3,4-dihydro-2H-benzo[b] [1,4]oxazine scaffold possessing both thrombin inhibitory and fibrinogen receptor antagonistic activities. 1 In an attempt to study structure-activity relationships and improve both their thrombin inhibitory activity and fibrinogen receptor binding affinity, we systematically introduced fluorine into different positions of the P3 benzyl group and replaced the basic benzamidino group present in 1 with [1,2,4]triazolo [4,3-b]pyridazine-6-yl moiety that could mimic the benzamidino part of the molecule (Figure 1).…”

“…1 In an attempt to study structure-activity relationships and improve both their thrombin inhibitory activity and fibrinogen receptor binding affinity, we systematically introduced fluorine into different positions of the P3 benzyl group and replaced the basic benzamidino group present in 1 with [1,2,4]triazolo [4,3-b]pyridazine-6-yl moiety that could mimic the benzamidino part of the molecule (Figure 1). It is well documented that aromatic carbon-bound fluorine can participate in hydrogen bonding and electrostatic interactions 2 thus contributing to the binding of drug molecules to their targets.…”

“…It is well documented that aromatic carbon-bound fluorine can participate in hydrogen bonding and electrostatic interactions 2 thus contributing to the binding of drug molecules to their targets. 3 Since many potent thrombin inhibitors possessing a highly basic benzamidine moiety lack oral whereas replacement of the benzamidine functionality in 1 by [1,2,4]triazolo [4,3-b]pyridazine-6-yl group to obtain analogues 14-17, had a detrimental effect on thrombin inhibition and platelet fibrinogen receptor binding. On the contrary, the antiproliferative activity of compounds 1 studied on two endothelial (HMEC-1, BAEC) and two cancer (HELA, MCF-7) cell lines in connection with their antiangiogenic potential related to their thrombin inhibitory and fibrinogen receptor antagonistic activity, remained preserved in [1,2,4]triazolo [4,3-b]pyridazine compounds 14-17.…”