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Novel Substituted-1,1-dioxo-benzo[1,2,4]thiadizin-3-ones
Korea Health Industry Development Institute (KHIDI) South Korea flag South Korea
Abstract ID:
Recent advances in pharmacology, molecular biology, and genetics on the serotonin system hold out the promise of the development of improved pharmacological treatment for some aspects of neurological diseases....
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Excellent binding affinity to the 5-HT6 receptor, ?Effect on apomorphine(2 D/D, i.p.)-induced disruption of prepulse inhibition (PPI) in rats.

Technology Overview

Technology Platform

The core technology of KRICT is to provide novel substituted-1,1-dioxo-benzo[1,2,4]thiadizin-3-ones or formula 1, which have excellent binding affinity to the 5-HT6 receptor, excellent selectivity to the 5-HT6 receptor over other receptors, inhibition of the serotonin(5-HT)-stimulated cAMP accumulation and an effect on apomorphine(2 D/D, i.p.)-induced disruption of prepulse inhibition (PPI) in rats. Also, the compounds of the present invention of effective dose don't show any rotarod deficits in mice.


Formula 1

Background and unmet needs: Although the function of serotonin (5-HT) in the central nervous system is still being clarified, various studies have indicated 5-HT has been implicated in the aetiology of many disease states and may be particularly important in mental illness, such as depression, anxiety, schizophrenia, eating disorders, obsessive compulsive disorder (OCD), migraine and panic disorder. During the last decade, multiple 5-HT receptor subtypes have been characterized. Initially, receptor subtypes were characterized using pharmacological tools only. Most recently, the 5-HT6 receptor has been cloned from rat cDNA based on its homology to previously cloned G-protein-coupled receptors

Until selective ligands were developed, exploration of 5-HT6 pharmacology was largely dependent on the use of nonselective agents. In the absence of selective ligands for the receptor, functional studies have been carried out using an antisense approach. 5-HT6 specific antisense produced a specific behavioural syndrome of yawning, stretching and chewing, but had no other discernable action in rats. The nonselective ligands were useful for investigating the pharmacology of 5-HT6 systems in preparations where other 5-HT receptors were absent (e.g., cAMP assays); however, owing to their lack of selectivity, they were of limited value for most other pharmacological studies.

Recent advent of selective agents has greatly benefited 5-HT6 studies, and this field of research has recently exploded. The development of more selective ligands may therefore lead to treatments with increased efficacy and reduced side effects. Alternatively, selective ligands may form completely novel therapies.  The bisaryl sulfonamides Ro 04-6790 , Ro 63-0563 were identified as very selective 5-HT6. Shortly thereafter, MS-245, SB-271046, SB-357134 were reported. The problems associated with these antagonists were their low penetration of the CNS or low bioavailability.

Discovery and Achievements:  The inventors made an effort to develop a 5-HT6 antagonist having excellent binding affinity and selectivity, and has completed the present invention by discovering that benzothiadiazine derivatives are 5-HT6 antagonists having very excellent binding strength and selectivity compared to sulfonamide or sulfonic structures disclosed in the prior art.

Fig. 1. Preparation of  1,1-dioxo-benzo[1,2,4]thiadizin-3-one


wherein,  R1 – R5 and Z are same as the aforementioned definition in Formula 1, and X is a fluorine, chlorine, bromine, iodine or trifluoroacetate, and Y is chlorine, bromine, iodine, methanesulfonate orp-toluenesulfonate

First, in the step (a), the intermediate I may be obtained by reaction of the compound 2 and a suitable amine in the presence of a base. The compound 2 used as starting material, 2-aminosulfonylchlorides may be commercially available or where they are not commercially available, may be prepared by the procedure described herein or by the analogous procedures for known compounds from the art of organic synthesis. The base is preferably triethylamine and, the reaction is conveniently conducted in an inert solvent, such as 1.4-dioxane or tetrahydrofuran, at the room temperature

                     In the step (b), the cyclization of the intermediates I prepared in the step (a) provides the corresponding intermediates II(l,l-dioxo-l,4-dihydro-benzo[ 1,2,4] thiadiazin-3-ones) with high yield. The cyclization is conducted by reaction of the intermediates I and phosgen(COCl), preferably, di-, tri-phosgen. The reaction is conveniently carried out in an inert solvent such as 1.4-dioxane or tetrahydrofuran under the refluxing condition. Then, in the step (c), the intermediate lll(2,4-substituted-benzo[l,2,4] thiadiazin-3-ones) is obtained by substitution on the intermediate II prepared in the above step (b) in the presence of a base.  In the step (d), substituted-l,l-dioxo-benzo[l,2,4]thiadiazin-3-ones represented by formula 1 is obtained by neucleophilic substitution reaction of the intermediate m prepared in the step (c) and a appropriate amine.

Fig. 2. Inhibitory effect of compounds according to the example of the present invention and methiothepin on cAMP accumulation mediated by 5-HT6 receptor of human HeLa cell.                       


Fig. 3. Inhibitory effect of compounds according to the example of the present invention (50 D/D, i.p.) on hyperactivity of a rat induced by apomorphine (2 D/D, i.p.).

Last Updated Jun 2016
Technology Type THERAPEUTIC
Phase of Development EARLY STAGE

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