2,2,2-Trifluoroethyl-thiadiazines: a patent evaluation of WO2016023927

Abstract

The Alzheimer's disease (AD) is acknowledged as the most common type of dementia in aging adults. It is characterized by the formation of intracellular neurofibrillary tangles and extracellular amyloid plaques. The latter insoluble deposits mainly consist of β-amyloid peptides (Aβ), which are the derivatives of the amyloid precursor protein (APP). The formation of neurotoxic Aβ-peptides involves the cleavage of APP with beta-secretase enzyme (beta-site APP cleaving enzyme 1, BACE1) so the potential of BACE1 inhibitors as therapeutic agents for AD is now drawing much attention. The patent application WO2016023927 reports the preparation of new 1,2,4-thiadiazine inhibitors of BACE1 activity and their use as therapeutically active substances. Some of the new compounds are claimed to be good inhibitors with the IC values in the 0.000292-0.134165 μM range. Several pharmaceutical preparations based on these compounds are proposed for possible treatment and prevention of AD. Expert opinion: In light of the novelty from the chemical point of view and improved biological activity, the reported 2,2,2-trifluoroethylthiadiazines could be considered as promising BACE1 inhibitors. However, the available data are insufficient to make a recommendation if these compounds can be considered as drug candidates. Further studies with a larger number of compounds are required. The compounds described in the patent have to be characterized more thoroughly from the chemical viewpoint (e.g., by means of IR, H andC NMR spectroscopy, X-ray crystallography), especially as regards stereochemical details.

1,2,6-Thiadiazine 1-Oxides: Unsaturated Three-Dimensional S,N-Heterocycles from Sulfonimidamides

“…Moreover, the construction of annulated ring systems is possible (Figure , top). Surprisingly, to date only a few cyclic sulfonimidamides have been reported . For example, research at Hoffmann-La Roche investigated six- and seven-membered cyclic or bicyclic sulfonimidamides as BACE1 inhibitors for potential treatment of Alzheimeŕs disease (Figure A). − BASF Agrochemicals developed cyclic sulfonimidamide derivatives of the marketed insecticide sulfoxaflor with the aim to improve physicochemical properties and reduce toxicity in a series of pesticides (Figure B). , Further cyclic sulfonimidamides have been reported as bioisosters of carboxylic acids or sultams (Figure C).…”

Recent advances in the chemistry of thieno[2,3-b]pyridines 1. Methods of synthesis of thieno[2,3-b]pyridines

“…[156][157][158][159][160][161] The search for new compounds in this series is due to the fact that tacrine, being one of the few drugs effi cient in the treatment and therapy of Alzheimer´s disease, has a pronounced hepatotoxic eff ect. 162 The reaction of ketones with 2-amino-3-cyanothiophenes is usually catalyzed by acids: TsOH and AlCl 3 , The Friedländer reaction takes place under a wide variety of conditions. Thus, thiophene 86 can react with The reaction of Gewald´s 2-aminothiophenes with ethyl acetoacetate is less unambiguous.…”

2,3-Dihydro-1,2,6-thiadiazine 1-Oxides by Biginelli-Type Reactions with Sulfonimidamides under Mechanochemical Conditions

“… Consequently, several programs have started focusing on devising new preparative approaches to such compounds and identifying new targets for unprecedented applications in various fields of research . Cyclic derivatives of sulfonimidamides have been recognized as three-dimensional heterocycles, contrasting their achiral sulfonamide-based analogues by the potential to obtain and apply single stereoisomers with stereogenic sulfur atoms. ,− The industrial interest in such compounds is revealed by the significant number of recent patents from pharmaceutical and crop protection companies Figure shows representative examples from our group with compound B being an acyclic N -acyl sulfonimidamide (and analogue of the anticancer agent tasisulam) and cyclic derivatives C and D with either one endo- and one exocyclic nitrogen substituent or two endocyclic nitrogens, respectively …”