Synthesis of Eosinophil Infiltration Inhibitors with Antihistaminic Activity.

Abstract

A series of [1, 2, 4]triazolo[1, 5-b]pyridazines (5) and imidazo[1, 2-b]pyridazines (6) having cyclic amines was synthesized and evaluated for antihistaminic activity and inhibitory effect on eosinophil infiltration. When a piperidine or a piperazine containing a benzhydryl group and a suitable spacer was incorporated at the 6-position, the fused pyridazines were found to exhibit both antihistaminic activity and an inhibitory effect on eosinophil chemotaxis. Above all, 6a showed potent antihistaminic activity, but little blockade of central H(1) receptors in contrast with its complete blockade of peripheral H(1) receptors as determined by an ex vivo binding assay. Furthermore, 6a inhibited eosinophil infiltration of the skin caused by a topical antigen challenge in sensitized guinea pigs, while an antihistamine terfenadine was not effective. After the pharmacokinetic study, 6a was found to be rapidly hydrolyzed to 6o, which was also orally active. Compound 6o, 2-[6-[[3-[4-(diphenylmethoxy)piperidino]propyl]amino]imidazo[1, 2-b]pyridazin-2-yl]-2-methylpropionic acid dihydrate (TAK-427), having both antihistaminic and antiinflammatory activity, is currently undergoing clinical trials as a therapeutic agent for atopic dermatitis and allergic rhinitis.

Synthesis of Some Novel Norbornene‐Fused Pyridazines as Potent Inhibitors of Carbonic Anhydrase and Acetylcholinesterase

“…) . Several compounds derived from pyridazines scaffold have been reported to possess a wide spectrum of biological activity such as the antidepressant, dopaminergic drug, monoamine oxidase inhibitor, anticonvulsant, GABA antagonist, muscarinic M1 partial agonist, and acetylcholinesterase (AChE) inhibitor . The chemistry of pyridazines is also dominantly useful as a pioneer for the preparation of other heterocycles, pi‐conjugated organic materials, and self‐assembled supramolecular architectures .…”

Crystal structure of 2-(4-methylpiperazin-1-yl)quinoline-3-carbaldehyde

“…For biological activity of quinoline derivatives, see: Nasveld et al (2005); Eswaran et al (2009); Leatham et al (1983); Muruganantham et al (2004); Maguire et al (1994); Wilson et al (1992); Strekowski et al (1991). For photonic and electronic properties of poly-substituted quinolines, see: Gyoten et al (2003) Data collection: APEX2 (Bruker, 2009); cell refinement: APEX2 and SAINT-Plus (Bruker, 2009); data reduction: SAINT-Plus and XPREP (Bruker, 2009); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: Mercury (Macrae et al, 2008); software used to prepare material for publication: SHELXL97.…”

Regioselective one-pot, three component synthesis of ethyl 6-aryl-3-propylpyridazine-4-carboxylates in water

“…This can be realized from the vast number of articles and patents published in the synthesis, chemistry, and biological activities of pyridazines. [11][12][13][14] The pyridazines and their derivatives exhibit a broad range of biological activity, such as analgesic, 15 antibacterial, 16 anti-inflammatory, 11 antihypertensive 17 or antihistaminic 18 properties. The derivatives of pyridazines could also find application as ligands in metallic complexes which possess catalytic properties.…”