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Halogen-substituted isoindoline compound and application thereof

A compound and halogen technology, applied in the field of medicine, can solve the problem of halogen-substituted isoindoline compounds and the like

Pending Publication Date: 2022-08-02
CHENGDU FENDI PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, there are no protein-regulating drugs based on GSPT1 and other proteins on the market, and there are no reports of halogen-substituted isoindoline compounds as small molecules of protein regulators such as GSPT1 in the prior art

Method used

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  • Halogen-substituted isoindoline compound and application thereof
  • Halogen-substituted isoindoline compound and application thereof
  • Halogen-substituted isoindoline compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] Example 1: Synthesis of compound FDAB-1

[0089]

[0090] Synthesis of T1-1: Cuprous cyanide (5.28 g, 59.0 mmol) and tert-butyl nitrite (14 g, 136.1 mmol) were dissolved in 100 ml of dimethyl sulfoxide, and the temperature was raised and kept at 60 °C. After 30 minutes, a solution of 4-bromo-3-fluoro-2-methylaniline (10 g, 49.0 mmol) in dimethyl sulfoxide (20 mL) was slowly added dropwise for about 30 minutes. After stirring the reaction at 60°C for about 1 hour, LCMS showed that the starting material had disappeared. The reaction solution was cooled to room temperature, 6M hydrochloric acid solution was added dropwise to the reaction solution to quench the reaction, and then ethyl acetate (2×100 mL) was added for extraction and separation. The organic phases were combined and backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. After column chromat...

Embodiment 2

[0096] Example 2: Synthesis of compound FDAB-2

[0097] Dissolve FDAB-1 (5.7 g, 20.0 mmol) and di-tert-butyl dicarbonate (6.5 g, 30.0 mmol) in 60 mL of tetrahydrofuran / N,N-dimethylformamide=10:1 mixed solvent at room temperature Raney nickel (0.6 g) was added. The mixed system was replaced by hydrogen three times while maintaining a certain hydrogen pressure system. The temperature was raised to 40° C. and the reaction was stirred at this temperature for about 4 hours. LCMS detection showed that the reaction of FDAB-1 was complete. The reaction solution was cooled and filtered with suction, the filter cake was washed three times with 50 ml of dichloromethane / methanol (10 / 1), the filtrates were combined and concentrated under reduced pressure. Then, 100 mL of water was added to the concentrated solution, followed by extraction and separation with ethyl acetate (3×100 mL). The organic phases were combined and backwashed with saturated brine. The organic phase was dried over an...

Embodiment 3

[0098] Example 3: Synthesis of compound FDAB-3

[0099] The intermediate FDAB-2 (3.9 g, 10 mmol) was dissolved in 30 mL of dichloromethane, and a solution of hydrochloric acid in 1,4-dioxane (1 M, 5 mL) was added at room temperature and the temperature was raised to 40 °C for reaction. After about 1 hour of reaction, LCMS detection showed that the raw material FDAB-2 disappeared. Concentrate under reduced pressure to remove excess hydrochloric acid solution and solvent, adjust the concentration to dichloromethane and adjust the acidity to ~7 with ammonia water, concentrate again and perform column chromatography (methanol: dichloromethane=1 / 100-1 / 10) to obtain off-white solid product FDAB-3 is about 2.8 g, and the yield is about 86%.

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Abstract

The invention relates to a halogen-substituted isoindoline compound as shown in the following formula I and application of the halogen-substituted isoindoline compound. The compound provided by the invention has obviously more excellent anti-tumor activity, and can be prepared into an oral dosage form which is more convenient, safer and more economical for administration. Therefore, the utilization value is remarkably improved compared with that of the existing compound.

Description

technical field [0001] The invention belongs to the technical field of medicine, and particularly relates to halogen-substituted isoindoline compounds and applications thereof. Background technique [0002] Protein mutations, expression imbalances, allosteric and functional abnormalities can cause many diseases. Protein synthesis or degradation is a tightly regulated process in both space and time during cell growth and proliferation. Dysregulation of these processes may lead to uncontrolled cell growth, proliferation, and migration, leading to diseases such as cancer, aging, and viral infections. [0003] The translation termination factor GSPT1 (eRF3a) is closely related to diseases such as cancer, which mediates stop codon recognition and promotes the release of nascent peptides from ribosomes. In addition to its translation termination function, GSPT1 is involved in several other key cellular processes, such as cell cycle regulation, cytoskeletal organization and apopt...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07D401/14C07D405/14C07D417/14C07D409/14A61K31/4545A61K31/454A61P35/00A61P35/02
CPCC07D401/04C07D401/14C07D405/14C07D417/14C07D409/14A61P35/00A61P35/02C07D413/14C07F9/65583A61P31/12Y02P20/55
Inventor 胡伟王力强蔡鑫
Owner CHENGDU FENDI PHARM CO LTD
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