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A class of 4-pyrimidinediamine small molecule organic compounds and derivatives thereof, and applications thereof

An organic compound, ‐pyrimidinediamine technology, applied in the field of 4‐pyrimidinediamine small molecule organic compounds, can solve the problems of limited research and development, high cost, poor affinity, etc., and achieve the goal of inhibiting proliferation, promoting apoptosis, and improving activity Effect

Active Publication Date: 2018-12-11
EAST CHINA NORMAL UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The BCL6 peptide inhibitor (BPI) can reactivate the target gene of BCL6 by binding to the N-terminal BTB / POZ domain of BCL6 competitively with co-repressor SMRT, etc., and can kill BCL6 in vivo and in vitro. Expressed DLBCL, but BPI has problems such as low oral bioavailability and high cost, thus limiting its further clinical application
79-6 is the first small-molecule inhibitor of BCL6 reported in the literature, but it has poor affinity to BCL6 (IC50=212μM) (Cancer Cell 17, 400–411, April 13, 2010)
However, FX1 still has a big disadvantage, and FX1 still has poor inhibitory activity on tumor cell proliferation, which limits their further clinical research and development.

Method used

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  • A class of 4-pyrimidinediamine small molecule organic compounds and derivatives thereof, and applications thereof
  • A class of 4-pyrimidinediamine small molecule organic compounds and derivatives thereof, and applications thereof
  • A class of 4-pyrimidinediamine small molecule organic compounds and derivatives thereof, and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0136] Embodiment 1: Preparation of 4-pyrimidinediamine small molecule organic compound

[0137] Example 1-01, N 2 ‐Ethylamino‐N 4 Preparation of -(3‐chloro‐4‐methoxyphenyl)‐5‐fluoro‐2,4‐pyrimidinediamine (WH‐001)

[0138] Take 3‐chloro‐4‐methoxyaniline (1.567g, 10.0mmol) in absolute ethanol (30mL), add 5‐fluoro‐2,4‐dichloropyrimidine (1.837g, 11.0mmol) and 5.2mL of DIEA, heated to 40°C and stirred overnight. Post-processing: remove most of the organic solvent under reduced pressure, extract three times with dichloromethane and water, combine the organic phases and dry with anhydrous sodium sulfate, remove dichloromethane under reduced pressure, and obtain intermediate 2-chloro ‐5‐fluoro‐N‐(3‐chloro‐4‐methoxyphenyl)pyrimidin‐4‐amine (2.707 g, 94%).

[0139] Put 2‐chloro‐5‐fluoro‐N‐(3‐chloro‐4‐methoxyphenyl)pyrimidine‐4‐amine (144.06 mg, 0.5 mmol) in 5 mL of n-butanol, add 2 mL of ethylamine and 0.26mL of DIEA was heated to 120°C and stirred overnight. Post-processing: re...

Embodiment 1-07

[0145] Example 1-07, N 2 ‐((3S,5R)‐3,5‐dimethylpiperazinyl)‐N 4 Preparation of ‐(4‐(6‐bromo‐2‐pyridylamido)phenyl)‐5‐fluoro‐2,4‐pyrimidinediamine (WH‐007)

[0146] Take 4‐nitroaniline (276.26mg, 2.0mmol) in anhydrous DMF (2mL), add 5‐fluoro‐2,4‐dichloropyrimidine (400.7mg, 2.4mmol) and cesium carbonate (2.0g, 6.0mmol ) were reacted overnight at room temperature. Post-processing: extract three times with dichloromethane and water, combine the organic phases and add anhydrous sodium sulfate to dry, remove dichloromethane under reduced pressure, and obtain the intermediate 2‐chloro‐5‐fluoro‐N‐(4‐ Nitrophenyl)pyrimidin‐4‐amine (227 mg, 42.3%).

[0147] Dissolve 2‐chloro‐5‐fluoro‐N‐(4‐nitrophenyl)pyrimidine‐4‐amine (227 mg, 0.85 mmol) in 5 mL of n-butanol, add cis‐2,6‐dimethylpiperene Hazine (289mg, 2.54mmol) and DIEA (0.44mL, 2.54mmol) were heated to reflux at 120°C overnight. Post-processing: most of the solvent was removed under reduced pressure, and after routine processin...

Embodiment 2

[0169] Example 2: Homogeneous time-resolved fluorescence technique (HTRF) detects the compound of the present invention inhibits the interaction between BCL6 fragment protein and its co-repressor factor SMRT

[0170] Technical method:

[0171] Homogeneous time-resolved fluorescence (HTRF) is a method for detecting analytes in pure liquid phase systems that combines two techniques, fluorescence resonance energy transfer (FRET) and time-resolved fluorescence (TRF). In this system, the selected energy donor of the present invention is GST-Tb, and the acceptor is 6His-XL665 (Cisbio). Correspondingly, the expressed and purified proteins of the present invention also bear GST and His tags respectively, namely BCL6-GST and 6His-SMRT. The transcriptional repression active domain BTBdomain of BCL6 is a domain that binds to the transcription co-repressor SMRT (polypeptide SMRT). The BTB / POZ domain sequence at the N-terminal of the BCL6 protein required in the present invention is ADSC...

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PUM

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Abstract

The present invention discloses a class of 4-pyrimidinediamine small molecule organic compounds or related analogs or pharmaceutically acceptable salts thereof, wherein the structure is represented byformulas (I)-(VI). The present invention further discloses uses of the 4-pyrimidinediamine small molecule organic compounds or a pharmaceutical composition thereof in preparation of drugs for preventing and / or treating various malignant tumors, autoimmune diseases, inflammation and the like, and uses as B cell lymphokine 6 (BCL6) inhibitors in preparation of drugs for preventing and / or treating BCL6 mediated diseases.

Description

technical field [0001] The invention relates to a class of 4-pyrimidinediamine small molecular organic compounds and derivatives thereof and applications thereof. The compound or the pharmaceutical composition containing the compound can be used for the preparation of antitumor drugs, for the treatment of various malignant tumors, including related diseases such as tumor metastasis, as a B cell lymphokine 6 (BCL6) inhibitor can be used for the prevention of And / or treat BCL6-mediated diseases (such as autoimmune diseases, allergies and inflammation). Background technique [0002] Cancer is a general term for malignant tumor cells that can proliferate indefinitely beyond the control of the organism. In the current society, cancer has become the second leading cause of death in humans after cardiovascular disease. According to the latest "Global Cancer Report 2014" released by the World Health Organization (WHO), the number of cancer patients worldwide is currently growing r...

Claims

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Application Information

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IPC IPC(8): C07D239/48C07D401/14C07D403/04C07D409/14C07D405/14C07D403/14C07D413/14A61K31/505A61K31/5377A61K31/506A61P35/00A61P35/02A61P37/06A61P37/08A61P29/00A61P17/00A61P19/02A61P3/10A61P7/06A61P7/04A61P7/00A61P1/04A61P1/00A61P13/12A61P11/00
CPCC07D239/48C07D401/14C07D403/04C07D403/14C07D405/14C07D409/14C07D413/14A61K31/505A61K31/506A61K31/5377A61P1/00A61P1/04A61P3/10A61P7/00A61P7/04A61P7/06A61P11/00A61P13/12A61P17/00A61P19/02A61P29/00A61P35/00A61P35/02A61P37/06A61P37/08
Inventor 陈益华刘明耀郭伟凯邢雅婧黄懂霞易正芳杜冰张乾森
Owner EAST CHINA NORMAL UNIVERSITY
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