BCL-2-selective apoptosis-inducing agents for the treatment of cancer and immune diseases

A prodrug and compound technology, which is applied in the field of compounds that selectively inhibit the activity of anti-apoptotic Bcl-2 family proteins, and can solve problems such as side effects

Active Publication Date: 2012-01-04
ABBVIE INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Thus, the present inventors have found that although the compounds taught in the prior art have utility for the treatment of various cancers and immune diseases, they are not effective against the anti-apoptotic Bcl-X L The anti-apoptotic Bcl-2 protein of the protein is selective, and thus has a greater possibility of side effects, characterized by the inhibition of anti-apoptotic Bcl-X L protein, such as thrombocytopenia

Method used

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  • BCL-2-selective apoptosis-inducing agents for the treatment of cancer and immune diseases
  • BCL-2-selective apoptosis-inducing agents for the treatment of cancer and immune diseases
  • BCL-2-selective apoptosis-inducing agents for the treatment of cancer and immune diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[2183] 4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro -2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide

Embodiment 1A

[2185] Tert-Butyl 4-((4'-chlorobiphenyl-2-yl)methyl)piperazine-1-carboxylate

[2186] Combine 4'-chlorobiphenyl-2-carbaldehyde (Example 27C) (4.1g), tert-butyl piperazine-1-carboxylate (4.23g), and sodium triacetoxyborohydride (5.61g) / CH 2 Cl 2 (60ml) (and) Stir for 24 hours. The reaction was quenched with methanol and poured into ether. The solution was washed with water and brine, concentrated, and chromatographed on silica gel with 2-25% ethyl acetate / hexane.

Embodiment 1B

[2188] 1-((4'-Chlorobiphenyl-2-yl)methyl)piperazine

[2189] In CH 2 Cl 2 (30ml) and trifluoroacetic acid (30mL), stir Example 1A (3.0g) and triethylsilane (1ml) 2 Hours, and the reaction was concentrated, and then absorbed in ether and concentrated again. The product is used without further purification.

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Abstract

Disclosed are compounds which inhibit the activity of anti-apoptotic Bcl-2 or Bcl-xL proteins, compositions containing the compounds and methods of treating diseases during which are expressed anti-apoptotic Bcl-2 protein.

Description

[0001] This application claims the priority of US provisional application 61 / 120275 filed on December 5, 2008 and US provisional application 61 / 181180 filed on May 26, 2009, the entire contents of which are incorporated by reference. Technical field [0002] The present invention relates to a compound that selectively inhibits the activity of anti-apoptotic Bcl-2 family proteins, a composition containing the compound and a method for treating diseases during which the anti-apoptotic Bcl-2 protein is expressed. Background technique [0003] Anti-apoptotic Bcl-2 family proteins are related to many diseases and are being studied as potential therapeutic drug targets. These targets for interventional therapy include, for example, Bcl-2 family proteins Bcl-2, Bcl-X L And Bcl-w. Recently, inhibitors of Bcl-2 family proteins have been reported in jointly owned PCT / US / 2004 / 36770 published as WO 2005 / 049593 and PCT / US / 2004 / 367911 published as WO 2005 / 049594. Although the prior art teaches...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12A61K31/404A61P35/00C07D209/32C07D211/96C07D213/64C07D215/20C07D217/16C07D235/26C07D249/04C07D295/14C07D309/14C07D401/12C07D295/125
CPCC07D417/12C07D215/20C07D235/26C07D231/56C07D217/16C07D209/32C07D309/14C07D405/12C07D249/04C07D295/125C07D211/96C07D213/64C07D295/14C07D401/12C07D209/08C07D209/20C07D211/58C07D215/14C07D241/04C07D295/13C07D295/155C07D309/04C07D309/08C07D309/32C07D401/06C07D403/06C07D405/06C07D405/14C07D413/06C07D471/04C07D487/04A61P1/04A61P1/16A61P11/00A61P11/02A61P11/06A61P15/00A61P17/00A61P17/06A61P17/14A61P19/02A61P21/04A61P25/00A61P25/06A61P25/14A61P25/16A61P25/28A61P27/02A61P29/00A61P31/00A61P31/04A61P31/12A61P33/00A61P35/00A61P35/02A61P37/00A61P37/06A61P37/08A61P43/00A61P5/00A61P7/00A61P7/06A61P9/00A61P9/10A61P9/12A61K31/496A61K31/501C07D295/12A61K31/453A61K31/46A61K31/5377
Inventor M.布伦科H.丁G.A.多赫蒂S.W.埃尔莫尔L.哈斯沃尔德L.赫克萨默A.R.孔策尔R.A.曼泰W.J.麦克莱兰C.H.朴C.朴A.M.佩特罗斯X.宋A.J.索尔斯G.M.萨利文Z.陶G.T.王L.王X.王M.D.温德特
Owner ABBVIE INC
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