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Apoptosis-inducing agents

A compound, independent technology, applied in the disease field of Bcl-xL protein, can solve only weak binding, cytotoxicity and other problems

Active Publication Date: 2015-06-24
ABBVIE INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] We have developed a class of small molecule BH3-only protein mimics, namely ， ABT-737 and ABT-263, which strongly bind a subgroup of anti-apoptotic Bcl-2 proteins including Bcl-2, Bcl-w, and Bcl-xL, but only weakly bind Mcl-1 and A1, and show Mechanism-Based Cytotoxicity

Method used

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  • Apoptosis-inducing agents
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  • Apoptosis-inducing agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1074] N-(1,3-Benzothiazol-2-yl)-2-(4-{[(4-{[(2R)-4-(dimethylamino)-1-(phenylsulfanyl) But-2-yl]amino}-3-nitrophenyl)sulfonyl]carbamoyl}-1,3-thiazol-2-yl)-1,2,3,4-tetrahydroisoquinoline-8 - Formamide.

Embodiment 1A

[1076] 2-(8-(Benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylic acid

[1077] To 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid (6.8 g) and benzo[d]thiazol-2-amine (5.52 g) in di To a solution in methyl chloride (80 mL), add 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (9.4 g) and 4-(dimethyl amino)pyridine (6 g). The mixture was stirred overnight, diluted with dichloromethane (400 mL), and washed with 5% aqueous HCl and brine. The organic layer was washed with Na 2 SO 4 Drying and concentration afforded the title product.

Embodiment 1B

[1079] (R)-4-(4-(Dimethylamino)-1-(phenylsulfanyl)butan-2-ylamino)-3-nitrobenzenesulfonamide

[1080] To a solution of Example 1A (8.5 g) in dichloromethane (80 mL) was added 2N HCl in ether (80 mL). The reaction mixture was stirred overnight and concentrated to give the title product.

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Abstract

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.

Description

technical field [0001] The present invention relates to compounds that inhibit the activity of Bcl-xL anti-apoptotic proteins, compositions containing these compounds, and methods of treating diseases in which anti-apoptotic Bcl-xL proteins are expressed. Background technique [0002] Apoptosis is considered a fundamental biological process of tissue homeostasis in all living species. In mammals in particular, it has been shown to regulate early embryonic development. In later stages of life, cell death is the default mechanism for removing potentially dangerous cells, such as cells carrying cancerous defects. Several apoptotic pathways have been revealed, and one of the most important involves proteins of the Bcl-2 family, which are key regulators of the mitochondrial (also called "intrinsic") pathway of apoptosis. See, Danial, N.N. and Korsmeyer, S.J. Cell (2004) 116, 205-219. Structural homology domains BH1, BH2, BH3 and BH4 are characteristic of proteins of this fa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4725A61P35/00C07D401/04
CPCC07D401/04C07D417/14C07D513/04C07D471/04C07D487/04A61P35/00A61P35/02A61K31/4725A61K45/06A61K31/5377A61K31/4985A61K31/5025
Inventor A.S.朱德A.J.索尔斯陶志福
Owner ABBVIE INC