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8-carbamoyl-2-(2,3-di substituted pyrid-6-yl)-1,2,3,4-tetrahydroisoquinoline derivatives as apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases

A technology of selecting and compounding, applied in the direction of drug combination, organic active ingredients, medical preparations containing active ingredients, etc., can solve problems such as only weak binding

Active Publication Date: 2014-08-13
ABBVIE INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] We have developed a class of small molecule BH3-only protein mimics, ABT-737 and ABT-263 - which interact with a subset of anti-apoptotic Bcl-2 proteins (including Bcl-2, Bcl-w and Bcl-xL ) strongly binds, but only weakly binds to Mcl-1 and A1, and exhibits mechanism-based cytotoxicity

Method used

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  • 8-carbamoyl-2-(2,3-di substituted pyrid-6-yl)-1,2,3,4-tetrahydroisoquinoline derivatives as apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases
  • 8-carbamoyl-2-(2,3-di substituted pyrid-6-yl)-1,2,3,4-tetrahydroisoquinoline derivatives as apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases
  • 8-carbamoyl-2-(2,3-di substituted pyrid-6-yl)-1,2,3,4-tetrahydroisoquinoline derivatives as apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases

Examples

Experimental program
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Effect test

Embodiment 1

[0964] 6-[8-(1,3-Benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[tricyclo[3.3 .1.1 3,7 ]dec-1-ylmethyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic acid

Embodiment 1A

[0966] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-1 H -pyrazole

[0967] 1-(Bromomethyl)adamantane (0.458 g) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- A mixture of 1H-pyrazole (0.377g) in N,N-dimethylformamide (5ml) was cooled to 0°C. To this solution was added 60% sodium hydride (0.096 g). The solution was heated at 70°C overnight. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with brine, washed with MgSO 4 Dry, filter and concentrate. The residue was purified by flash column chromatography on silica gel eluting with 25% ethyl acetate / hexanes to provide the title compound.

Embodiment 1B

[0969] 8-(Benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester

[0970] To 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid (6.8 g) and benzo[ d To a solution of ]thiazol-2-amine (5.52 g) in dichloromethane (80 ml) was added 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (9.4 g) and 4-dimethylaminopyridine (6 g). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane (400 mL), washed with 5% aqueous HCl, water and brine and washed with Na 2 SO 4 dry. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide the title compound.

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Abstract

Disclosed are compounds of formula (I) which inhibit the activity of anti-apoptotic Bcl-xL proteins, compositions containing the compounds and methods of treating diseases during which Bcl-xL proteins are expressed, eg cancer. X is heteroaryl; Y1 is phenylene or heteroarylene; L1 is a linker; Y2 is cycloalkyi, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; Z1 is C(O)OR9, C(O)NR10R11, C(O)R11, NR10C(O)R11, etc.

Description

[0001] This application claims priority to U.S. Provisional Application Serial No. 61 / 547162, filed October 14, 2011, which is incorporated herein by reference in its entirety. field of invention [0002] The present invention relates to compounds that inhibit the activity of Bcl-xL anti-apoptotic proteins, compositions containing the compounds and methods of treating diseases during which anti-apoptotic Bcl-xL proteins are expressed. Background of the invention [0003] Apoptosis is considered a fundamental biological process in tissue homeostasis in all living species. In mammals in particular, it has been shown to regulate early embryonic development. Later in life, cell death is the default mechanism to remove potentially dangerous cells, such as cells with cancerous defects. Several apoptotic pathways have been revealed, the most important one involving the Bcl-2 family of proteins, which are key regulators of the mitochondrial (also called "intrinsic") pathway of apop...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/14C07D513/04C07D471/04C07D487/04A61K31/4725A61P35/00
CPCC07D417/14C07D471/04C07D493/08C07D513/04C07D487/04C07D401/04A61K31/4725A61K31/4985A61K31/5025A61K31/5377A61K31/541A61P35/00A61P35/02
Inventor L.王G.多赫蒂X.王Z-F.陶M.布伦科A.R.昆策尔M.D.温德特X.宋R.弗里T.M.汉森G.M.萨利文A.朱德A.索尔斯
Owner ABBVIE INC
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