Novel 1,1-dioxo-1,2-benzisothiazole derivatives and their pharmaceutical uses

Novel saccharin-based antithrombotic compounds that prevent platelet aggregation by targeting the talin-GPIIIa binding pathway

This technology features novel compounds or their salts—based on a 1,1-dioxo-1,2-benzisothiazole scaffold with various substituted aromatic rings attached at the 3-position via linkers such as oxygen, amine, hydrazine, or piperazine—as active ingredients in pharmaceutical compositions for inhibiting platelet aggregation and preventing or treating thrombotic diseases. It also includes food compositions containing the same compounds.

Platelet aggregation is a primary cause of cardiovascular diseases such as stroke, coronary artery disease, and pulmonary embolism. However, existing GPIIb/IIIa inhibitors, which work by competitively blocking fibrinogen binding, are associated with serious side effects like intracranial hemorrhage, retroperitoneal hemorrhage, and thrombocytopenia. Many elderly patients are often unable to be prescribed antiplatelet agents due to diagnostic uncertainty, creating a need for a new, effective, and safer antiplatelet mechanism.

This technology focuses on the process where the cytoskeletal protein talin binds to the GPIIIa tail to activate GPIIb/IIIa. By using benzisothiazole derivatives as bioisostere scaffolds to inhibit this activation, it prevents platelet aggregation. Substituents include methyl, t-butyl, trifluoromethyl, methoxy, bromo, chloro, and fluoro groups, with over 30 specific compounds presented, including phenoxy, benzylamino, and thiazolidinedione derivatives. Applicable to acute coronary syndrome treatments, stroke and deep vein thrombosis prevention, and blood circulation health supplements, this technology offers a new antiplatelet drug candidate that reduces the risk of bleeding side effects by blocking aggregation at the activation signaling stage, unlike existing drugs that directly block fibrinogen binding.

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Key Features:

• A pharmaceutical composition for inhibiting platelet aggregation comprising a 1,1-dioxo-1,2-benzisothiazole derivative of Formula 1, where X is O, NR4, NR5CH2, or NR6NR7, as an active ingredient
• Compounds where R1 through R3 are each hydrogen, halogen, nitro, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, aryl, or heteroaryl
• A pharmaceutical composition for the prevention or treatment of thrombotic diseases such as arterial thrombosis, venous thrombosis, coronary thrombosis, and cerebral infarction
• A food composition for inhibiting platelet aggregation comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient

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This invention was developed with support from the Ministry of Science and ICT for the discovery and efficacy validation of a new mechanism-based antiplatelet agent targeting Glycoprotein IIb/IIIa inside-out signaling.

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