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Application of 1H-indazole-4-amine compounds as IDO (indoleamine 2,3-dioxygenase) inhibitor

A compound and solvate technology, applied in the field of IDO inhibitors, can solve the problems of reducing tryptophan concentration, inhibiting killing effect, and stagnant synthesis.

Active Publication Date: 2017-08-11
XIHUA UNIV
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  • Abstract
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  • Application Information

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Problems solved by technology

Under normal circumstances, IDO is expressed at a low level in the body, but most tumor cells will form a high expression of IDO, which converts L-tryptophan into N-formylkynurenine, reducing the color of the cell microenvironment. The concentration of tryptophan 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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  • Application of 1H-indazole-4-amine compounds as IDO (indoleamine 2,3-dioxygenase) inhibitor
  • Application of 1H-indazole-4-amine compounds as IDO (indoleamine 2,3-dioxygenase) inhibitor
  • Application of 1H-indazole-4-amine compounds as IDO (indoleamine 2,3-dioxygenase) inhibitor

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] The synthesis of embodiment 1 intermediate raw material

[0091] (1) Synthesis of 6a and 6b

[0092]

[0093] The raw material 4-nitro-1H-indazole 5a (CAS: 2942-40-7, 1.4g, 8.26mmol, purchased from Anaiji Chemical Reagent Co., Ltd.) or 6-bromo-4-nitro-1H-indazole Azole 5b (CAS: 885518-46-7, 2.0g, 8.26mmol, purchased from Jiangsu Nantong Biotechnology Co., Ltd.) was dissolved in a mixed solvent of ethanol (20mL) and water (10mL), and ammonium chloride (221.5mg, 4.13mmol), a part of iron powder (1.3g, 23.46mmol) was first added thereto, heated to 80°C and stirred for 5 minutes, then the remaining iron powder (1.0g, 17.86mmol) was added, and stirred for 20 minutes. After the reaction of the raw materials was detected by TLC, the reaction solution was filtered while it was hot, and the filter residue was washed with ethanol (10 mL). Ethanol was spun off under reduced pressure, and the aqueous layer was extracted three times with ethyl acetate (20 mL). The organic phas...

Embodiment 2

[0104] Synthesis of Embodiment 2 Compounds of the present invention 3a, 3b and 3c

[0105]

[0106]Synthesis of ethyl 2-(6-bromo-1H-indazole-4-amino)acetate (11)

[0107] 6-Bromo-1H-indazol-4-amino 6b (212.0 mg, 1.00 mmol) was dissolved in DMF (5 mL), and potassium carbonate (345.0 mg, 2.50 mmol) and potassium iodide (14.9 mg, 0.09 mmol) were added. Under the protection of argon, ethyl bromoacetate (167.0 μL, 1.50 mmol) was added and reacted at 65° C. overnight. After the complete reaction of the raw material (6b) was detected by TLC, a large amount of DMF was pumped away with an oil pump, ethyl acetate (25 mL) was added, and washed with water (20 mL) three times. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and spin-dried to pass through the column (PE:EA=15:1). 206.9mg of light yellow solid was obtained, the yield was 70%.

[0108] Synthesis of 2-(6-bromo-1H-indazole-4-amino)acetic acid (12)

[0109] Dissolve ethyl 2...

Embodiment 3

[0118] Embodiment 3 Synthesis of compounds of the present invention 1a, 1c-j and 1p

[0119]

[0120] Amine 6b (0.28mmol) and benzaldehyde 16 (0.24mmol) were dissolved in dichloromethane (DCM, 3mL), dihydropyridine (DHP, 83.5mg, 0.33mmol) and appropriate amount of 4A molecular sieves (840.2mg) were added dropwise Add trifluoroacetic acid (TFA, 17.6 μL, 0.24 mmol), reflux at 40°C for 12 hours, filter the reaction solution, spin dry, and pass through the column to obtain compound 1a.

[0121] 4-((6-Bromo-1H-indazol-4-amino)methyl)benzoic acid (1a). Yield 64%; brown solid; 1 H-NMR (400MHz, d 6 -DMSO,ppm):δ12.80(br,2H,COOH and indazole-NH),8.22(s,1H,indazole-H3),7.91(d,2H,J=8.3Hz,Ar-H2and Ar-H6) ,7.49(d,2H,J=8.3Hz,Ar-H3and Ar-H5),6.64(s,1H,indazole-H7),6.01(s,1H,indazole-H5),4.53(s,2H,benzyl- CH 2 ). 13 C-NMR (100MHz, d 6 -DMSO, ppm): δ167.7, 145.3, 143.0, 142.2, 132.5, 130.0, 129.9, 127.5, 121.7, 112.6, 101.2, 100.6, 46.2. ESI-MS: 344.0035[M-H].

[0122] Select the corr...

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Abstract

The invention discloses 1H-indazole-4-amine compounds and further discloses a preparation method of the 1H-indazole-4-amine compounds and an application of the 1H-indazole-4-amine compounds as an IDO (indoleamine 2,3-dioxygenase) inhibitor. The 1H-indazole-4-amine compounds can be used for preventing and / or treating various diseases such as Alzheimer's disease, cataract, cellular immune activation associated infection, autoimmune disease, acquired immune deficiency syndrome, cancer, depression or tryptophan metabolic disorder.

Description

technical field [0001] The present invention relates to 1H-indazol-4-amine compound, and also relates to its preparation method and application as IDO inhibitor. Background technique [0002] Indoleamine 2,3-dioxygenase (Indoleamine 2,3-dioxygenase, IDO) catalyzes the epoxidation and cleavage of indole in indoleamine molecules such as tryptophan, making it catabolized by the kynuric acid pathway. fast enzyme. [0003] IDO plays an important role in tumor immune immunity and tumorigenesis. Under normal circumstances, IDO is expressed at a low level in the body, but most tumor cells will form a high expression of IDO, which converts L-tryptophan into N-formylkynurenine, reducing the color of the cell microenvironment. The concentration of tryptophan 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 tissues. At the same time, t...

Claims

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Application Information

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IPC IPC(8): C07D231/56A61K31/416A61P25/28A61P27/12A61P31/00A61P37/02A61P31/18A61P35/00A61P25/24A61P3/00
CPCC07D231/56
Inventor 钱珊李国菠王周玉杨羚羚张曼何彦颖王伟何涛陈泉龙
Owner XIHUA UNIV
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