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IDO restrainer containing (E)-4-(beta-bromo vinyl)benzoyloxy structure

A technology of phenoxyacyl and vinyl bromide, applied in organic chemistry, active ingredients of heterocyclic compounds, drug combinations, etc., can solve problems such as reducing the utilization of free serum tryptophan

Active Publication Date: 2009-05-13
SHANGHAI TIANCI BIOLOGICAL VALLEY BIOLOGICAL ENG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

IDO reduces free serum tryptophan availability during sustained cremation stimulated by high levels of interferon gamma

Method used

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  • IDO restrainer containing (E)-4-(beta-bromo vinyl)benzoyloxy structure
  • IDO restrainer containing (E)-4-(beta-bromo vinyl)benzoyloxy structure
  • IDO restrainer containing (E)-4-(beta-bromo vinyl)benzoyloxy structure

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1: the preparation of (E)-4-(beta-bromovinyl)phenol

[0027] The synthetic route is as follows:

[0028]

[0029] The first step: the preparation of 4-hydroxyacrylic acid

[0030] In a 50mL three-neck flask equipped with a reflux condenser and a thermometer, add 0.611g (5mmol) of 4-hydroxybenzaldehyde, 1.040g (10mmol) of malonic acid, 10mL of pyridine, and 3 drops of piperidine, and heat up to 80°C. The reaction was stirred for 6 to 8 hours, followed by TLC detection (ethyl acetate / n-hexane / acetic acid=10 / 20 / 1 as developing solvent). After the reaction, cool to room temperature, neutralize to pH=2 with 6M cold hydrochloric acid, filter, wash with ice water and ethyl acetate, P 2 o 5 Vacuum drying gave 0.700 g of light yellow powder, namely (E)-4-(β-bromovinyl)phenol, with a yield of 92%.

[0031] The second step: the preparation of (E)-3-(4-acetylphenyl)acrylic acid

[0032] In a 25mL egg-shaped bottle equipped with a calcium chloride drying tube, add...

Embodiment 2

[0037] Embodiment 2: Preparation of (E)-4-(β-bromovinyl)phenol 2-pyrrole ester (compound 1)

[0038] Add 10 mL (110 mmol) of benzene, 199 mg (1 mmol) of (E)-4-(β-bromovinyl) phenol, 117 mg (1.05 mmol) of 2-pyrrolic acid, 12 mg (0.1 mmol) of a 25 mL dry round bottom flask For p-dimethylaminopyridine (DMAP), stir magnetically at room temperature for 8 minutes, then add 206 mg (1 mmol) of N, N'-dicyclohexylcarbodiimide (DCC), and complete the reaction at room temperature for 24 hours. The solvent was evaporated under reduced pressure, and the residue was separated and purified by column chromatography using ethyl acetate:petroleum ether=1:5-1:9 as the eluent to obtain (E)-4-(β-bromovinyl)phenol 2 - pyrrole ester 285 mg, the yield is 98%. The reaction and product characterization data are as follows:

[0039]

[0040] Light yellow solid; mp130.6-132.7℃.

[0041] IR (KBr): 1719, 935, 751cm -1 .

[0042] 1 H NMR (300MHz, CDCl 3 ): δ=6.36-6.37 (1H, m), 6.75 (1H, d, 14.4Hz),...

Embodiment 3

[0044] Embodiment 3: Preparation of (E)-4-(β-bromovinyl)phenol 2-furanoic acid ester (compound 2)

[0045] Add 12mL (130mmol) of benzene, 199mg (1mmol) of (E)-4-(β-bromovinyl)phenol, 123mg (1.1mmol) of 2-furanoic acid, 61mg (0.5mmol) For p-dimethylaminopyridine (DMAP), 227 mg (1.1 mmol) of N, N'-dicyclohexylcarbodiimide (DCC) was added after magnetic stirring at room temperature for 10 minutes, and the reaction was completed at room temperature for 22 hours. The solvent was evaporated under reduced pressure, and the residue was separated and purified by column chromatography using ethyl acetate:petroleum ether=1:6-1:10 as the eluent to obtain (E)-4-(β-bromovinyl)phenol 2 - Furanate 270mg, the yield is 92%. The reaction and product characterization data are as follows:

[0046]

[0047] White solid; mp100.6-100.8℃.

[0048] IR (KBr): 1734, 930, 762cm -1 .

[0049] 1 H NMR (300MHz, CDCl 3 ): δ = 6.60-6.61 (1H, m), 6.76 (1H, d, J = 14.1Hz), 7.11 (1H, d, J = 14.1Hz), 7.1...

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Abstract

The invention belongs to the technical field of new drug synthesis, and in particular relates to an IDO inhibitor containing (E)-4-(beta-bromovinyl)phenoxy acyl structure, as well as a preparation method thereof. The preparation method comprises the following steps: solvent benzene, (E)-4-(beta-bromovinyl) phenol, carboxylic acid and p-dimethylaminopyridine are added to a flask respectively and magnetically stirred for 5 to 20 minutes at room temperature; then N, N'-dicyclohexylcarbodiimide is added and reacts for 2 to 24 hours at room temperature; after the reaction is completed, the solvent benzene is steamed off after decompression; residue is subjected to column chromatography separation and purification by taking ethyl acetate / petroleum ether as leacheate, and then a needed product can be obtained, wherein the molar ratio of the solvent benzene to the (E)-4-(beta-bromovinyl) phenol is 50-200:1; the molar ratio of the carboxylic acid to the (E)-4-(beta-bromovinyl) phenol is 1-1.5:1; the molar ratio of the p-dimethylaminopyridine to the (E)-4-(beta-bromovinyl) phenol is 0.1-1.5:1; and the molar ratio of the N, N'-dicyclohexylcarbodiimide to the (E)-4-(beta-bromovinyl) phenol is 1-1.2:1. The method takes the (E)-4-(beta-bromovinyl) phenol as a synthesis building block and obtains a series of the novel IDO inhibitors containing the (E)-4-(beta-bromovinyl)phenoxy acyl structure through esterification reaction, and the IDO inhibitors can be used for treating the diseases with the pathological features of IDO mediated tryptophan metabolic pathway.

Description

technical field [0001] The invention belongs to the technical field of new drug synthesis, and in particular relates to an IDO inhibitor containing (E)-4-(β-bromovinyl)phenoxyacyl structure and a preparation method thereof. Background technique [0002] Indoleamine-2,3-dioxygenase (IDO; MW 48,000; EC 1.13.11.42) is a heme-containing enzyme that is the first and rate-limiting enzyme in mammalian tryptophan metabolism . IDO catalyzes the oxidation of the essential amino acid tryptophan to N-formylkynurenine via dioxygen and is responsible for the disposal of tryptophan in the human body. General inhibitors of heme-containing enzymes are known to inhibit IDO in a non-specific manner. In addition, certain tryptophan (substrate) analogs such as 1-methyl-L-tryptophan (1MT) and β-(3-benzofuryl)-DL-alanine are competitive for IDO Inhibitors (Cady, S.G. and Sono, M. Arch. Biochem. Biophys. 1991 291, 326). [0003] Interferon gamma is one of several potential inducers of IDO expre...

Claims

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Application Information

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IPC IPC(8): C07D207/34C07D307/68C07D213/78A61K31/34A61K31/40A61K31/44A61P43/00
Inventor 匡春香杨青江玉波
Owner SHANGHAI TIANCI BIOLOGICAL VALLEY BIOLOGICAL ENG
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