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Mutant IDH1 inhibitors useful for treating cancer

A C1-C6, alkyl technology, applied in the field of mutant IDH1 inhibitors that can be used in the treatment of cancer, can solve problems such as increased risk of brain tumors

Active Publication Date: 2017-12-01
UNITED STATES OF AMERICA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Elevated levels of 2HG have been shown to lead to increased risk of brain tumors in humans

Method used

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  • Mutant IDH1 inhibitors useful for treating cancer
  • Mutant IDH1 inhibitors useful for treating cancer
  • Mutant IDH1 inhibitors useful for treating cancer

Examples

Experimental program
Comparison scheme
Effect test

example

[0209] abbreviation

[0210] AcOH acetic acid

[0211] BOC tert-butoxycarbonyl

[0212] BSA bovine serum albumin

[0213] CBZ benzyloxycarbonyl

[0214] DCM dichloromethane

[0215] DIPEA Diisopropylethylamine

[0216] DMAP 4-(N,N-Dimethylamino)pyridine

[0217] DMF Dimethylformamide

[0218] DMF-DMA dimethylformamide dimethyl acetal

[0219] DMSO Dimethyl Sulfoxide

[0220] EtOAc ethyl acetate

[0221] LCMS liquid chromatography / mass spectrometry

[0222] LiHMDS lithium bis-(trimethylsilyl)amide

[0223] MP SPE Large Pore Solid Phase Extraction

[0224] NADPH reduced nicotinamide adenine dinucleotide phosphate

[0225] NaHMDS sodium bis-(trimethylsilyl)amide

[0226] NBS N-Bromosuccinimide

[0227] NCS N-chlorosuccinimide

[0228] NMR nuclear magnetic resonance

[0229] PEG polyethylene glycol

[0230] RPMI Roseville Parker Memorial Institute Medium (Cell Culture Medium)

[0231] p-TsOH p-toluenesulfonic acid

[0232] THF Tetrahydrofuran

[0233] TFA trifl...

Embodiment 1

[0237] Example 1. Synthesis of selected compounds

[0238]

[0239] Method 1 - Nitrile 1:

[0240] To a solution of 2-bromo-1-(4-chlorophenyl)ethanone (2.33 g, 10 mmol) in ethanol (25 mL) was added 2-cyanothioacetamide (1 g, 10 mmol). The reaction mixture was heated at reflux for 15.5 h. The reaction mixture was cooled to 0 °C. A precipitate formed and was removed by washing with filtration using hexane and then drying under vacuum. The product, 2-(4-(4-chlorophenyl)thiazol-2-yl)acetonitrile (nitrile N1) was a brown powder; LCMS: m / z (M+H) + = 235.0; 1 H NMR (400MHz, CDCl 3 )δ7.88–7.77(m,2H), 7.48(s,1H), 7.44–7.35(m,2H), 4.17(s,2H).

[0241]

[0242] Nitrile 2: synthesized by method 1, substituting 2-bromo-1-phenylethanone as starting material. After reaction, the mixture was concentrated and purified by silica gel chromatography (0% to 30% EtOAc / Hexane). The product was an orange-red solid (1.53 g, 77%); LCMS: m / z (M+H) + = 201.1.

[0243]

[0244] Nitrile ...

Embodiment 2

[0552] Example 2. Enzyme Assay

[0553] Assays were performed in 1536-well black solid bottom plates in a final assay volume of 9 μL. Depletion of the cofactor NADPH is coupled to the second enzyme diaphorase and its corresponding substrate resazurin by mutating the IDH1 enzyme.

[0554] Specifically, for IDH1R132H, 3 μL of enzyme (4 mM β-ME, 0.0005 mg / mL IDH1R132H, 150 mM NaCl, 20 mM Tris pH 7.5, 10 mM MgCl 2 , 0.05% BSA) were added to the plate, followed by the addition of 23 nL of test compound in DMSO. Cover the plate and incubate at room temperature for 30 minutes, at which time 3 μL of substrate (0.016 mM NADPH, 2 mM α-KG, 150 mM NaCl, 20 mM Tris pH 7.5, 10 mM MgCl 2 , 0.05% BSA). The reaction was incubated at room temperature for 60 minutes at which time the assay mix (0.06 mg / mL diaphorase, 0.036 mM resazurin, 150 mM NaCl, 20 mM Tris pH 7.5, 10 mM MgCl 2 , 0.05% BSA). After a 5 min incubation, fluorescence generated by conversion of resazurin to resorufin (excitatio...

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PUM

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Abstract

Compounds of Formula I and Formula II and the pharmaceutically acceptable salts thereof are disclosed. The variables A, B, Y, Z, X1, X2, R1-4 and R13-18 are disclosed herein. The compounds are useful for treating cancer disorders, especially those involving mutant IDH1 enzymes. Pharmaceutical compositions containing the compounds of the Formula I or Formula II and methods of treatment comprising administering the compounds of Formula I and Formula II are also disclosed.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application No. 62 / 095322, filed December 22, 2014, which is hereby incorporated by reference in its entirety. [0003] Statement of Government Funding [0004] This invention was made in part with government support from the National Institutes of Health. The government has certain rights in this invention. Background technique [0005] Isocitrate dehydrogenase 1 (IDH1, protein accession number NP_005887.2) is an enzyme that normally functions to convert isocitrate to alpha-ketoglutarate. Mutated forms of this enzyme, most commonly IDH1 (R132H) in which arginine 132 is mutated to histidine, are common in various cancers, including glioma, cholangiocarcinoma, chondrosarcoma, and AML. IDH1 (R132H, R132C, R132S) mutations and similar IDH1 mutations are gain-of-function mutations that result in the ability of the enzyme to acquire the dependent reduction of alpha-ketoglu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/22C07D401/04C07D417/04C07D417/14C07D471/04A61K31/47A61P35/00
CPCC07D215/22C07D401/04C07D417/04C07D417/14C07D471/04C07D401/14C07D215/54C07D413/04C07D471/14C07D487/08C07D487/10C07D491/052C07D491/107A61P35/00A61K31/435A61K31/437A61K31/4375A61K31/4439A61K31/4545A61K31/46A61K31/4704A61K31/4709A61K31/496A61K31/499A61K31/506A61K31/5377A61K31/551C07D213/82C07D215/227C07D413/14C07D451/02C07D491/048
Inventor 马修·布莱恩·博克瑟杰森·马修·罗德拉詹·普拉加尼刘莉曼迪·伊雷妮·艾米丽·戴维斯凯勒·瑞恩·布里马科姆沈敏安东·西梅奥诺夫苏伦德拉·卡拉瓦迪丹尼尔·詹森·乌尔班阿吉特·贾达夫王晓东安德鲁·路易斯·麦基弗
Owner UNITED STATES OF AMERICA
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