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Enhancer of Zeste homolog 2 inhibitors

A compound, C2-C8 technology, applied in the field of compounds, can solve problems such as the loss of function of tumor suppressors

Inactive Publication Date: 2016-03-30
GLAXOSMITHKLINE INTELLECTUAL PROPERTY (NO 2) LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the exact mechanism by which aberrant EZH2 activity leads to cancer progression is unknown, many EZH2 target genes are tumor suppressors, implying that loss of tumor suppressor function is a key mechanism

Method used

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  • Enhancer of Zeste homolog 2 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0436] Example 1: (E)-10-((trans-4-aminocyclohexyl)oxy)-12-chloro-3-methyl-5,6,15,16-tetrahydrobenzo[c]pyrido [4,3-j][1]Azacyclododecanentaene-1,14(2H,9H)-dione hydrochloride

[0437] (a) 4-(but-3-en-1-yl)-2-methoxy-6-methylnicotinonitrile

[0438]

[0439] To a solution of 2-methoxy-4,6-dimethylnicotinonitrile (1.5 g, 9.25 mmol) in THF (40 mL) was added LiHMDS (10.17 mL, 10.17 mmol) at -78°C, and the mixture was placed in - Stir at 78°C for 1 hour. 3-Bromoprop-1-ene (0.880 mL, 10.17 mmol) was added, and the mixture was stirred at -78°C for 1 hour and warmed to 0°C over 1 hour. The mixture was then stirred at 0°C for 3 hours. The reaction was saturated with NH 4 Quenched with aqueous Cl and extracted with EtOAc (3x). The combined organics were subjected to Na 2 SO 4 Dried and concentrated. The residue was subjected to reverse phase HPLC (using Trilution software, with phenomenonex Gemini5uC18(2) 100A, AXIA30x100mm5 micron, 10-minute run (30mL / min, 40% CH 3 CN / H 2 ...

Embodiment 2

[0477] Example 2: (E)-12-chloro-10-((trans-4-(dimethylamino)cyclohexyl)oxy)-3-methyl-5,6,15,16-tetrahydrobenzo [c]pyrido[4,3-j][1]azacyclododecapentaene-1,14(2H,9H)-dione

[0478]

[0479] To (E)-10-((trans-4-aminocyclohexyl)oxy)-12-chloro-3-methyl-5,6,15,16-tetrahydrobenzo[c]pyrido[4, 3-j][1]Azacyclododecenepentaene-1,14(2H,9H)-dione hydrochloride (230mg, 0.467mmol) in MeOH (8mL) slurry was added formaldehyde (0.278mL ,3.74mmol), NaBH 3 CN (147 mg, 2.335 mmol), then AcOH (0.027 mL, 0.467 mmol) was added. The resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and MeOH was added. The resulting suspension was filtered to give a residue and a filtrate containing both product. The residue was subjected to reverse phase HPLC ( Instrument, Trilution software, WatersSunFirePrepC18OBD5uM, 19x50mm column, using 10-50% CH containing 0.1% TFA 3 CN aqueous solution) purification. The resulting fractions were concentrated in vacuo ...

Embodiment 3

[0480] Example 3: 12-chloro-10-((trans-4-(dimethylamino)cyclohexyl)oxy)-3-methyl-6,7,8,9,15,16-hexahydrobenzo [c]pyrido[4,3-j][1]azacyclododecapentaene-1,14(2H,5H)-dione

[0481]

[0482] (E)-12-chloro-10-((trans-4-(dimethylamino)cyclohexyl)oxy)-3-methyl-5,6,15,16-tetrahydrobenzo[c] Pyrido[4,3-j][1]azacyclododecapentaene-1,14(2H,9H)-dione (26 mg, 0.054 mmol) in EtOAc (2 mL) and MeOH (10 mL) The solution was degassed with nitrogen for 5 min, then platinum (10 wt% on charcoal, 10 mg) was added and the solution was purged with nitrogen for an additional 5 min. The reaction mixture was stirred under a hydrogen atmosphere (balloon) for 8 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 12-chloro-10-((trans-4-(dimethylamino)cyclohexyl)oxy)-3-methyl-6,7,8,9, 15,16-Hexahydrobenzo[c]pyrido[4,3-j][1]azacyclododecapentaene-1,14(2H,5H)-dione (20 mg, 77%), It is a white solid. LC-MS(ES) m / z=244(main product), 486[M+H] + (secondary product...

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PUM

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Abstract

This invention relates to novel compounds according to Formula (I) which are inhibitors of Enhancer of Zeste Homolog 2 (EZH2), to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy for the treatment of cancers.

Description

technical field [0001] The present invention relates to compounds which inhibit enhancer of Zeste homolog 2 (EZH2) and are therefore useful for inhibiting proliferation and / or inducing apoptosis in cancer cells. Background technique [0002] Epigenetic modifications play an important role in the regulation of many cellular processes, including cell proliferation, differentiation, and cell survival. Global epigenetic modifications are common in cancer and include global changes in DNA and / or histone methylation, dysregulation of noncoding RNAs, and Nucleosome remodeling. However, unlike genetic mutations that occur in cancer, these epigenetic changes can be reversed by selectively inhibiting the enzymes involved. Multiple methylases known to be involved in histone or DNA methylation are dysregulated in cancer. Therefore, selective inhibitors of specific methylases would be useful in the treatment of proliferative diseases, such as cancer. [0003] EZH2 (human EZH2 gene: C...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/4353A61P35/00
CPCA61P1/04A61P1/16A61P1/18A61P11/00A61P13/08A61P13/10A61P13/12A61P15/00A61P17/00A61P19/00A61P21/00A61P25/00A61P35/00A61P35/02A61P43/00C07D471/04C07D471/14C07D498/04
Inventor S.D.奈特L.V.拉弗朗斯三世K.C.麦克纳尔蒂S.P.罗默里尔M.A.西费尔德D.T.福斯本纳B.W.金李玫
Owner GLAXOSMITHKLINE INTELLECTUAL PROPERTY (NO 2) LTD
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