Substituted tricyclic pyrazole derivatives with protein kinase activity

Abstract

Chemical compounds that are derivatives of 2H[1]-benzothiepino[5,4-c]pyrazole, 2H[1]-benzoxepino[5,4-c]pyrazole, 1-benzothiopyrano[4,3-c]pyrazole, 1-benzopyrano[4,3-c]pyrazole, 4,5-dihydro-2h-furano[2,3-g]indazole and 4,5-dihydro-2h-thieno[2,3-g]indazole derivatives 2H[1]-benzothiepino[5,4-c]pyrazole, [1]-benzothiopyrano[4,3-c]pyrazole, 4,5-dihydro-2H-furano[2,3-g]indazole and 4,5-dihydro-2H-thieno[2,3-g]indazole derivatives are inhibitors of protein kinase activity. Several of the protein kinases, whose activity is inhibited by these chemical compounds, are involved in angiogenic and / or edematous processes. Thus, these chemical compounds can ameliorate disease states where angiogenesis, edema or endothelial cell hyperproliferation or hyperpermeability is a factor. Like cancer, artritis, atherosclerosis, psoriasis, hemangioma, myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis, corneal disease, rubeosis, neovascular glaucoma, macular degeneration, wound healing, peptic ulcer Helicobacter related diseases, fractures, diabetic retinopathy, and cat scratch fever.

Description

Background of the invention [0001] At least 400 enzymes have been identified as protein kinases. These enzymes catalyze the phosphorylation of target protein substrates. Phosphorylation is generally a transfer reaction in which a phosphate group is transferred from ATP to a protein substrate. The specific structure of the target substrate to which the phosphate group is transferred is a tyrosine, serine or threonine residue. Since these amino acid residues are the target structures for phosphoryl transfer, these protein kinases are often referred to as tyrosine kinases or serine / threonine kinases. [0002] Phosphorylation and resistance phosphatase reactions on tyrosine, serine and threonine residues are involved in a myriad of cellular processes that become responsive to different intracellular signals (usually mediated through cellular receptors) Fundamental to responding, regulating cellular function, and activating or inactivating cellular processes. Protein kinase cas...

AI Technical Summary

Problems solved by technology

To date, no direct evidence has been published for the critical role of KDR in VEGF-mediated vascular hyperpermeability