- 6,7-DIHYDRO-5H-PYRIDO[2,3-C]PYRIDAZINE DERIVATIVES AND RELATED COMPOUNDS AS BCL-XL PROTEIN INHIBITORS AND PRO-APOPTOTIC AGENTS FOR TREATING CANCER
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The present invention discloses 6,7-dihydro-5H-pyrido[2,3- c]pyridazine, 1,2,3,4-tetrahydroquinoline, 1H-indole, 3,4- dihydro-2H-1,4-benzoxazine, 1H-pyrrolo[2,3-b]pyridin-1-yl, 7H- pyrrolo[2,3-c]pyridazine, 5H,6H,7H,8H,9H-pyridazino[3,4-b]azepine derivatives and related compounds of formula (I) as Bcl-xL protein inhibitors for use as pro-apoptotic agents for treating cancer, autoimmune diseases or immune system diseases. Formula (I). The description discloses the preparation of exemplary compounds (e.g. pages 113 to 354 examples 1 to 221) as well as pharmacological studies with relevant data (e.g. pages 355 to 367; examples A to E; tables 1 to 5). Exemplary compounds are e.g. 2-{6-[(1,3-benzothiazol-2-yl) amino]-1,2,3,4-tetrahydroquinolin-1-yl}-1,3-thiazole-4-carboxylic acid (example 1) or e.g. 3-{1-[(adamantan-1-yl)methyl]-5- methyl-1H-pyrazol-4-yl}-6-{3-[(1,3-benzothiazol-2-yl)amino]-4- methyl-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl]pyridine-2-carboxylic acid (example 24).
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Page/Page column 99-100
(2021/02/05)
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- ANTI-EGFR ANTIBODY DRUG CONJUGATES
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The invention relates to anti-Epidermal Growth Factor Receptor (EGFR) antibody drug conjugates (ADCs) which inhibit Bcl-xL, including compositions and methods of using said ADCs.
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Paragraph 0839; 0945
(2019/06/07)
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- Intramolecular C-H Amination Reaction Provides Direct Access to 1,2-Disubstituted Diamondoids
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We present a new approach to disubstituted diamondoids from corresponding carboxylic acids. A dirhodium-acetate-catalyzed (1 mol-%) nitrene insertion reaction of sulfamides was, for the first time, applied to intramolecular C-H functionalization reactions of rigid tricyclic frameworks. This straightforward approach enables the effective and regioselective synthesis of a variety of diamondoid-based cyclic sulfamidates, which are synthetically valuable building blocks. Reductive deprotection of the sulfamidate moiety leads to corresponding 1,3-amino alcohol derivatives. Oxidation of the sulfamidate moiety by KMnO4 provides access to 1,3-keto alcohols or imines. Finally, we report the synthesis of Vildagliptin analogues as new antidiabetic drug candidates (DPP-4 inhibitors). Intramolecular dirhodium-acetate-catalyzed (1 mol-%) nitrene insertion reactions provide direct access to 1,2-disubstituted diamondoids. This approach was applied to the synthesis of Vildagliptin (DPP-4 inhibitor) analogues.
- Hrdina, Radim,Metz, Fabian M.,Larrosa, Marta,Berndt, Jan-Philipp,Zhygadlo, Yevgeniya Y.,Becker, Sabine,Becker, Jonathan
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supporting information
p. 6231 - 6236
(2015/10/06)
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- APOPTOSIS-INDUCED AGENTS FOR THE TREATMENT OF CANCER AND IMMUNE AND AUTOIMMUNE DISEASES
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Disclosed are compounds which inhibit the activity of anti-apoptotic Bcl-xL proteins, compositions containing the compounds and methods of treating diseases during which is expressed anti-apoptotic Bcl-xL protein.
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Paragraph 0934
(2013/04/24)
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- Lipophilic isosteres of a π-π Stacking interaction: New inhibitors of the Bcl-2-Bak protein-protein interaction
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The discovery of new Bcl-2 protein-protein interaction antagonists is described. We replaced the northern fragment of ABT737 (π-π stacking interactions) with structurally simplified hydrophobic cage structures with much reduced conformational flexibility and rotational freedom. The binding mode of the compounds was elucidated by X-ray crystallography, and the compounds showed excellent oral bioavailability and clearance in rat PK studies.
- Yusuff, Naeem,Dore, Michael,Joud, Carol,Visser, Michael,Springer, Clayton,Xie, Xiaoling,Herlihy, Kara,Porter, Dale,Toure, B. Barry
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supporting information; experimental part
p. 579 - 583
(2012/09/08)
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