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Oxadiazole derivative containing heterocyclic side chain, synthesis method and application thereof

A compound and solvate technology, applied in the field of oxadiazole derivatives, can solve the problems of low oral bioavailability, large polar surface area and the like

Active Publication Date: 2019-08-20
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The enzyme and cell activity of the compound are good, and the animal level also has excellent performance, but it has certain disadvantages such as low oral bioavailability due to glucuronidation and excessive polar surface area (PSA), etc.

Method used

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  • Oxadiazole derivative containing heterocyclic side chain, synthesis method and application thereof
  • Oxadiazole derivative containing heterocyclic side chain, synthesis method and application thereof
  • Oxadiazole derivative containing heterocyclic side chain, synthesis method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] The preparation of embodiment 1 compound S1

[0074]

[0075] For the synthesis of compound 1-1, refer to CN 104042611.

[0076] Synthesis of compound 1-2:

[0077] Compound 1-1 (3g, 6.5mmol), triethylamine (1.96g, 19.4mmol), 4-dimethylaminopyridine (160mg, 1.3mmol) were dissolved in 40ml of dichloromethane, and dicarbonic acid was added under ice bath Di-tert-butyl ester (2.8 g, 13 mmol), stirred for 20 min, and removed the ice bath. After stirring at room temperature for 2 h, TLC detected that the reaction was complete and extracted with water. The organic layer was washed with water and saturated brine in sequence, and dried over anhydrous sodium sulfate. After suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 2.8 g of white solid with a yield of 76%.

[0078] 1 H NMR (300MHz, DMSO) δ7.98(d, J=5.8Hz, 1H), 7.54-7.62(m, 2H), 4.38(t, J=5.2Hz, 2H), 3.95(t, J=4.4Hz ,2H),...

Embodiment 2

[0087] The preparation of embodiment 2 compound S2

[0088]

[0089] Synthesis of compound 2-1:

[0090] Compound 1-2 (140mg, 0.248mmol), 2-methyl-1,2,5-thiadiazoline-1,1-dioxide (51mg, 0.372mmol), cesium carbonate (243mg, 0.744mmol) Dissolve in 3ml of N,N-dimethylformamide (DMF), stir at room temperature for 4h, add water to extract after TLC detection, the organic layer is washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 62 mg of oil, with a yield of 41%.

[0091] 1 H NMR (300MHz, DMSO) δ7.96 (d, J = 7.8Hz, 1H), 7.65–7.53 (m, 2H), 3.78 (t, J = 6.8Hz, 2H), 3.29–3.13 (m, 6H) ,2.54(s,3H),1.41(s,9H).

[0092] Synthesis of compound 2-2:

[0093] Compound 2-1 (60mg, 0.1mmol) was dissolved in 2ml of dichloromethane, stirred at room temperature for 2h, after the reaction was detected by TL...

Embodiment 3

[0097] The preparation of embodiment 3 compound S3

[0098]

[0099] For the synthesis of compound 3-1, refer to CN 104042611.

[0100] Synthesis of Compound 3-2:

[0101] Compound 3-1 (2g, 5.85mmol) was placed in a round-bottomed flask, added with 23ml of trifluoroacetic acid and 15ml of 30% hydrogen peroxide solution, and reacted at 45°C for 2 days. After the reaction was detected by TLC, 50 ml of saturated aqueous sodium thiosulfate solution and 25 ml of ethyl acetate were added, and stirred for 20 min. Water was added for extraction, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 1.12 g of product with a yield of 46%.

[0102] 1 H NMR (300MHz, DMSO) δ8.05 (dd, J=6.1, 2.4Hz, 1H), 7.73–7.63 (m, 1H), 7.57 (t, J=8.7Hz, 1H).

[0103] Synthesis of Comp...

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PUM

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Abstract

The invention discloses an oxadiazole derivative containing a heterocyclic side chain, a synthesis method and an application thereof. The structure of the oxadiazole derivative is represented by a general formula I, wherein each substituent is as defined in the specification and the claims. The compound has relatively strong IDO inhibitory activity, has relatively good drug absorption potential, and has good development prospect.

Description

technical field [0001] The invention relates to an oxadiazole derivative containing a heterocyclic side chain, a synthesis method and an application thereof. Background technique [0002] Indoleamine 2,3-dioxygenase (IDO, Indoleamine 2,3-dioxygenase) is an intracellular heme-containing enzyme that was first discovered in 1967. It consists of 403 amino acids, with a molecular weight of about 45KD, forming an α-helical domain with one large and one small folds. [0003] Tryptophan is one of the essential amino acids for humans, and IDO is closely related to it. Part of the tryptophan absorbed by the human body from the outside world is used to synthesize proteins, serotonin and melatonin, and the other part is metabolized by the kynurenine pathway. IDO and TDO are the first and rate-limiting catalytic enzymes in the kynurenine pathway, which can promote the oxidative cleavage of the 2,3-double bond of the indole ring in tryptophan to generate N-formyl kynurenine , and furth...

Claims

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Application Information

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IPC IPC(8): C07D417/12C07D413/12A61K31/5377A61K31/433A61K31/4245A61K31/427A61K31/549A61K31/428A61P35/00A61P25/28A61P37/02A61P31/18A61P27/12A61P25/24
CPCC07D417/12C07D413/12
Inventor 张翱蒙凌华丁健陈树伦丁春勇郭伟
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI