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Compound with TDO and IDO1 dual inhibitory activity, and application of compound in preparation of drugs for treating neurodegenerative diseases

A compound and pharmaceutical technology, applied in the field of chemical medicine, can solve problems such as inhibition of killing, stagnation, and reduction of tryptophan concentration

Pending Publication Date: 2020-09-22
XIHUA UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Under normal circumstances, TDO and IDO1 are expressed at low levels in the body, but most tumor cells will form high-expression TDO and IDO1, which converts L-tryptophan into N-formylkynurenine and reduces the cellular microbiome. The concentration of tryptophan in the environment makes the synthesis of tryptophan-dependent T cells stagnate in the G1 phase, and the proliferation of T cells is inhibited, thereby inhibiting the killing effect of the body's immune system on tumor tissue

Method used

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  • Compound with TDO and IDO1 dual inhibitory activity, and application of compound in preparation of drugs for treating neurodegenerative diseases
  • Compound with TDO and IDO1 dual inhibitory activity, and application of compound in preparation of drugs for treating neurodegenerative diseases
  • Compound with TDO and IDO1 dual inhibitory activity, and application of compound in preparation of drugs for treating neurodegenerative diseases

Examples

Experimental program
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Effect test

preparation example Construction

[0087] 1 Preparation of Intermediate A2

[0088] Compound A1 (5.0g, 22.1mmol) was dissolved in 30mL of toluene, DPPA (7.9g, 28.7mmol), Et3N (6.2mL, 44.2mmol) was added under stirring, benzyl alcohol (6.9mL, 66.2mmol) was added after stirring for 10min . After the addition was completed, the temperature was raised to 110°C for reflux. After 3 hours, the reaction was complete, the reaction liquid was concentrated under reduced pressure to remove the reaction solution, the residue was diluted with water, extracted three times with EA, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain light yellow solid A2 (6.22g, 18.8mmol), with a yield of 85%.

[0089] 2 Preparation of Intermediate A3

[0090] A2 (100mg, 0.3mmol) was dissolved in a mixed solvent (methanol:dioxane=1:1), iron powder (51mg, 0.9mmol) and 10N conc...

Embodiment 1

[0150] Example 1, Compounds TA-1, TA-14, TA-15, TA-16, TA-16-a, TA-16-b, TA-16-c, TA-17, TB-1, TB-4 , TB-6, TB-35, TB-36 synthesis

[0151]

[0152] Among them, the structure of TA-16 is: The structure of TA-16-a is: The structure of TA-16-b is: The structure of TA-16-c is:

[0153] Dissolve amines (1.0 equivalents) and different substituted aldehydes (1.2-2.0 equivalents) in dichloromethane (DCM), add dihydropyridine (1.4 equivalents) and an appropriate amount of 4A molecular sieves, drop trifluoroacetic acid (TFA , 0.5 times equivalent), reflux at 40°C for 12 hours. Refer to the method of patent CN108689936A reductive amination for synthesis. Yield: 20%-80%.

Embodiment 2

[0154] Example 2 Compounds TA-4, TA-5, TB-17, TB-26, TB-28, TB-29, TB-30, TB-31, TB-32, TB-33, TB-34, TB- Synthesis of 37

[0155]

[0156] Synthesized with reference to Example 1, the synthetic yield: 17%-88%.

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PUM

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Abstract

The present invention provides a compound represented by a formula I, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which can selectively inhibit TDO and IDO1, and has an obvious inhibition effect on TDO and / or IDO1. Besides, the compound prepared by the invention has an obvious anti-tumor effect, also has a certain treatment effect on Parkinson's disease and Alzheimer's disease, and has a good application prospect in the field of medicine preparation.

Description

technical field [0001] The invention belongs to the field of chemical medicine, and in particular relates to an indazole derivative with dual inhibitory activities of TDO and IDO1 and its application for preparing medicine for neurodegenerative diseases. Background technique [0002] Indoleamine 2,3-dioxygenase 1 (Indoleamine 2,3-dioxygenase 1, IDO1) and tryptophan 2,3-dioxygenase (tryptophan 2,3-dioxygenase, TDO) are catalytic tryptophan It is the rate-limiting enzyme for the epoxidation and cleavage of indole in other indoleamine molecules, making it catabolize by the kynuric acid pathway. [0003] TDO and IDO1 play an important role in tumor immune immunity and tumorigenesis. Under normal circumstances, TDO and IDO1 are expressed at low levels in the body, but most tumor cells will form high-expression TDO and IDO1, which converts L-tryptophan into N-formylkynurenine and reduces the cellular microbiome. The concentration of tryptophan in the environment makes the synthe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/56C07D261/20C07D209/46C07D401/12C07D209/48C07D403/12A61P25/28A61P35/00A61P25/16A61P25/24A61P37/02A61P31/00
CPCC07D231/56C07D261/20C07D209/46C07D401/12C07D209/48C07D403/12A61P25/28A61P35/00A61P25/16A61P25/24A61P37/02A61P31/00
Inventor 钱珊曹治兴徐世军李玉芝王周玉李国菠杨羚羚
Owner XIHUA UNIV
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