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Preparation method of indoleamine 2,3-dioxygenase inhibitor

An alkoxyl, C1-C6 technology, applied in the field of preparation of indoleamine 2,3-dioxygenase inhibitors, can solve the problems of clinical activity limitation, poor biological activity of NLG919, toxic and side effects, etc.

Inactive Publication Date: 2020-08-25
XIAMEN BIOTIME BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, due to the toxicity and side effects of INCB024360, the existing clinical research dose (50mg bid, or 100mg bid) is about 30% of the optimal dose (300mg bid, 600mg bid), and the clinical activity is greatly limited; at the same time, the toxicity of INCB024360 The group is also a pharmacophore, and INCB024360 and its derivatives have a problem of high toxicity
The safety of NLG919 is better, but the biological activity of NLG919 is poor

Method used

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  • Preparation method of indoleamine 2,3-dioxygenase inhibitor
  • Preparation method of indoleamine 2,3-dioxygenase inhibitor
  • Preparation method of indoleamine 2,3-dioxygenase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] N-(4-chlorophenyl)-6-(6-fluoroquinolin-4-yl)spiro[2.5]octane-1-carboxamide N-(4-chlorophenyl)-6-(6-fluoroquinolin-4-yl ) spiro[2.5]octane-1-carboxamide

[0094]

[0095]Step 1: Dissolve 1,4-cyclohexanedione monoethylene glycol ketal (10.0 g, 64.03 mmol) in 250 mL of methyl tert-butyl ether, add N-phenylbis(trifluoromethanesulfonyl ) imine (22.9 g, 64.03 mmol). The reaction solution was cooled to -78°C, and sodium bis(trimethylsilyl)amide (2 mol / L tetrahydrofuran solution) (32 mL, 64.03 mmol) was added dropwise to the reaction solution under a nitrogen atmosphere. After the dropwise addition, the reaction solution was stirred at this temperature for 60 minutes, then the reaction solution was raised to room temperature, and stirred overnight until TLC detected that the reaction raw materials were completely consumed. The reaction solution was quenched with 3 mL aqueous potassium bisulfate solution, the solid was removed by filtration, and the filtrate was concentrate...

Embodiment 2

[0104] N-(4-fluorophenyl)-6-(6-fluoroquinolin-4-yl)spiro[2.5]octane-1-carboxamide

[0105] N-(4-fluorophenyl)-6-(6-fluoroquinolin-4-yl)spiro[2.5]octane-1-carboxamide

[0106]

[0107] The synthesis of compound 2 is the same as that of compound 1, and 4-chloroaniline in Example 1 is replaced by 4-fluoroaniline. Compound 2 (16.97 mg) was obtained as a white solid with a yield of 22%. MS(ESI):m / z 393.3 (M+H) + . 1 H NMR (500MHz, d 6 -DMSO)δ10.28(s,1H),8.81(s,1H), 8.10–8.05(m,1H),8.03(d,J=11.0Hz,1H),7.69–7.60(m,3H),7.37 (s, 1H),7.13(t,J=8.0Hz,2H),3.49–3.40(m,1H),2.20(t,J=12.0Hz,1H), 1.98–1.85(m,4H),1.78( d, J=11.0Hz, 1H), 1.72(t, J=6.5Hz, 1H), 1.37–1.28(m, 1H), 1.17–1.07(m, 2H), 0.94–0.89(m, 1H).

Embodiment 3

[0109] N-(4-chlorobenzyl)-6-(6-fluoroquinolin-4-yl)spiro[2.5]octane-1-carboxamide

[0110]N-(4-chlorobenzyl)-6-(6-fluoroquinolin-4-yl)spiro[2.5]octane-1-carboxamide

[0111]

[0112] Synthesis of Compound 3 Starting from intermediate 1g in Example 1, it was prepared through the following steps:

[0113]

[0114] Step 1: Dissolve 1 g of compound (200 mg, 0.61 mmol) in 10 mL of ethanol, and add 4 mL of 2 mol / L sodium hydroxide solution. The reaction solution was heated to 50°C and reacted for 2 hours. After the reaction solution was cooled to room temperature, it was neutralized to pH=1 with 4 mol / L hydrochloric acid solution. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by preparative thin-layer chromatography to obtain compound 3a (150 mg) as a white solid with a yield of 83%. MS (ESI):m / z 300.0(M+H) + . 1 H NMR (500MHz, d 6 -DMSO) δ1...

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Abstract

The invention relates to a preparation method of a compound shown as a formula I. The compound prepared by the method disclosed by the invention has the activity of inhibiting indoleamine 2,3-dioxygenase.

Description

[0001] This application is a divisional application, the Chinese application number of its parent case is: 201880057640.2, the international application number is PCT / CN2018 / 124110, and the international application date is December 27, 2018. [0002] The present invention claims the priority of Chinese patent applications CN201711478307.2 and CN201810754253.6, and the contents recorded in the description, drawings and claims of the priority documents are fully incorporated into the description of the present invention and are taken as the original records of the description of the present invention part. The applicant further declares that the applicant has the right to amend the description and claims of the present invention based on the priority document. technical field [0003] The invention relates to the field of medicines, in particular to a preparation method of an indoleamine 2,3-dioxygenase inhibitor. Background technique [0004] Tryptophan (TRP) is an α-amino ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/18
CPCC07D215/18C07D401/04
Inventor 李磐温俏冬王骥甘泉路杨杨东晖
Owner XIAMEN BIOTIME BIOTECHNOLOGY CO LTD
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