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Antitumor compound, synthesis method and applications thereof

A synthetic method and compound technology, applied in the field of anti-tumor compounds and their synthesis, can solve the problems of poor activity and selectivity

Active Publication Date: 2020-04-10
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Reports on selective inhibitors of DYRK family members focus on DYRK1A, while the number of reports on DYRK2 is relatively small, and its activity and selectivity are also poor

Method used

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  • Antitumor compound, synthesis method and applications thereof
  • Antitumor compound, synthesis method and applications thereof
  • Antitumor compound, synthesis method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0136] The synthesis of embodiment 1 compound I-1, I-2, I-3, I-4

[0137] Synthesize I-1 according to the following steps:

[0138]

[0139] (1) Synthesis of compound 3:

[0140] To commercially available starting materials 1 (9.26 g, 40 mmol), 2 (6.90 g, 56 mmol) were added Cu (0..73 g, 11 mmol), Cu 2 O (0.82g, 5.7mmol), potassium carbonate (7.74g, 56mmol), DMF 100ml, stirred and reacted at 80°C overnight. The reaction solution was cooled to room temperature, and 2M dilute hydrochloric acid was added thereto until the system became acidic, and a large amount of solids precipitated out. The precipitated solid was suction-filtered, washed with water, and dried to obtain compound 3 (4.02 g, 37%), which was directly used in subsequent reactions without purification.

[0141] (2) Synthesis of compound 4:

[0142] Compound 3 (2.58 g, 9.45 mmol) was placed in a sealed tube, 30 ml of phosphorus oxychloride was added under the protection of argon, and reacted at 130° C. for 8 h...

Embodiment 2

[0156] The synthesis of embodiment 2 compound I-5, I-6

[0157] Synthesize I-5 according to the following steps:

[0158]

[0159] Under argon protection, 5ml of dry DMF was added to compound 4 (50mg, 0.183mmol) and 67% sodium hydrosulfide hydrate (22.9mg, 0.274mmol), and reacted at 50°C for 2h. Then tert-butyl 4-bromopiperidine-1-carboxylate (72.4 mg, 0.274 mmol) and potassium carbonate (50.5 mg, 0.365 mmol) were added thereto, and reacted at room temperature overnight. The reaction solution was spin-dried under reduced pressure, separated into water / dichloromethane, the organic phase was separated, dried over anhydrous sodium sulfate, and the solvent was spin-dried under reduced pressure. The obtained crude product was placed in 2 ml of dichloromethane solution containing 5% trifluoroacetic acid, reacted at room temperature for 2 h until no raw material remained, and the solvent was spin-dried under reduced pressure. Purified by HPLC / MS on Waters automatic purification ...

Embodiment 3

[0165] The synthesis of embodiment 3 compound I-7, I-8, I-9, I-10, I-11

[0166] Follow the steps below to synthesize I-10:

[0167]

[0168] (1) Synthesis of compounds 5 and 7:

[0169] Slowly add 30ml of boron tribromide to the suspension of compound 5 (1.65g, 6.05mmol) in 200ml of dry dichloromethane, and react at 0°C for 2h. Methanol was added to the reaction system to quench the reaction, and the solvent was spin-dried under reduced pressure. The crude product was separated and purified by silica gel column (dichloromethane / methanol=92 / 8) to obtain product 5 (0.22g, 14%) and reported compound 7 (0.80g, 56%), and recovered 0.70g of raw material.

[0170] The characterization information of compound 5 is specifically:

[0171] 1 H NMR (400MHz, MeOD) δ8.08(dd, J=9.4, 4.8Hz, 2H), 7.64(dd, J=7.6, 4.4Hz, 4H), 4.07(s, 3H).

[0172] (2) Synthesis of Compound 6:

[0173] Under the protection of argon, add dry DMF 10ml to compound 2 (94.5mg, 0.364mmol), potassium carbonate...

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Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to an antitumor compound, a synthesis method and applications thereof, wherein the compound has a structure represented by a general formula I or a general formula II, and shows good inhibitory activity on proteasome regulatory kinase DYRK2, so that antitumor activity can be achieved by inhibiting proteasome. The invention also relates to a synthesis method of the compound, wherein the method adopts a chemical total synthesis route, and the convergent synthesis route can be applied to chemical synthesis of compounds with similar structures and related derivatives, and develops a wide development space for novel antitumor drugs.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an antitumor compound and its synthesis method and application. Background technique [0002] Malignant tumor is the number one disease that threatens human health, ranking first among the three major causes of death in human diseases, accounting for a quarter of all disease deaths, and the number of morbidity and death is increasing year by year. The occurrence of tumor is caused by the interaction of many factors such as genetic factors, internal environment and external environment. The molecular mechanism involves abnormal changes in genomics, epigenetics and gene expression regulation. It is a multi-factor, multi-step, Intricate process. [0003] Among them, multiple myeloma (MM), as a common malignant tumor of the blood system, is characterized by the infinite clonal proliferation of malignant plasma cells in the bone marrow and the secretion of a single strain of immuno...

Claims

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Application Information

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IPC IPC(8): C07D219/06C07D401/12A61K31/473A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D219/06C07D401/12
Inventor 雷晓光肖俊宇王珏魏田田梁如琪
Owner PEKING UNIV
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