8-Carbamoyl-2-(2,3-disubstituted pyridin-6-yl)-1,2,3,4-tetrafluoroethylene as an apoptosis-inducing agent for the treatment of cancer and immune and autoimmune diseases Hydroisoquinoline Derivatives

A pyridyl and substituent technology, applied in the field of diseases expressing anti-apoptotic Bcl-xL protein during the treatment of diseases, can solve problems such as weak binding only

Active Publication Date: 2016-08-24
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-disubstituted pyridin-6-yl)-1,2,3,4-tetrafluoroethylene as an apoptosis-inducing agent for the treatment of cancer and immune and autoimmune diseases Hydroisoquinoline Derivatives
  • 8-Carbamoyl-2-(2,3-disubstituted pyridin-6-yl)-1,2,3,4-tetrafluoroethylene as an apoptosis-inducing agent for the treatment of cancer and immune and autoimmune diseases Hydroisoquinoline Derivatives
  • 8-Carbamoyl-2-(2,3-disubstituted pyridin-6-yl)-1,2,3,4-tetrafluoroethylene as an apoptosis-inducing agent for the treatment of cancer and immune and autoimmune diseases Hydroisoquinoline Derivatives

Examples

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preparation example Construction

[0945] After preparation as described in Scheme 1, a compound of formula (6) can be combined with a boronic acid (or boronate equivalent) of formula (8) or wherein Y 1 , L 1 and Y 2 Organotin or organozinc halides of formula (8a) as described herein and M is tributyltin or zinc halide are reacted under Suzuki, Stille or Negishi coupling conditions known to those skilled in the art and readily available in the literature to give Compounds of formula (I) are provided. Alternatively, compounds of formula (7), which can be prepared from compounds of formula (6) as described in Scheme 1, can be combined with 1 is a triflate or halide and Y 1 , L 1 and Y 2 Compounds of formula (9) as described herein are reacted under Suzuki coupling conditions known to those skilled in the art and readily available in the literature to provide compounds of formula (I).

[0946]

[0947] As shown in Scheme 3, where R x1 is hydrogen or Y as described herein 1 The pyrazole of the formula (1...

Embodiment 1

[0963] 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

[0965] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-1H-pyrazole

[0966] 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.

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Abstract

Disclosed are a compound of formula (I) that inhibits the activity of an anti-apoptotic Bcl-xL protein, a composition containing the compound and a method for treating a disease that expresses a Bcl-xL protein during a disease, such as cancer; X is a heteroaryl group; Y1 is phenylene or heteroarylene; L1 is a linking group; Y2 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; Z1 is C(O)OR9, C(O)N10R11, 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 Patents(China)
IPC IPC(8): C07D417/14C07D513/04C07D471/04C07D487/04A61K31/4725A61P35/00
CPCC07D417/14C07D471/04C07D487/04C07D513/04C07D493/08A61K31/4725A61K31/4985A61K31/5025A61K31/5377A61K31/541C07D401/04A61P35/00A61P35/02
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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