Preparation method of IDO inhibitor

An alkyl and amino technology, applied in the field of preparation of IDO inhibitors, can solve the problems of limited clinical activity, high toxicity, poor biological activity of NLG919, etc.

Active Publication Date: 2020-07-31
XIAMEN BIOTIME BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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 IDO inhibitor
  • Preparation method of IDO inhibitor
  • Preparation method of IDO 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

[0094] N-(4-chlorophenyl)-6-(6-fluoroquinolin-4-yl)spiro[2.5]octane-1-carboxamide

[0095]

[0096]The first step: Dissolve 1,4-cyclohexanedione monoethylene glycol ketal (10.0g, 64.03mmol) in 250mL 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 con...

Embodiment 20

[0105] N-(4-chlorophenyl)-6-(6-fluoroquinolin-4-yl)-1-azaspiro[2.5]octane-1-carboxamide

[0106] N-(4-chlorophenyl)-6-(6-fluoroquinolin-4-yl)-1-azaspiro[2.5]octane-1-carboxamide

[0107]

[0108] The synthesis of compound 20 starts from the intermediate 1e in Example 1 and is prepared via the following steps:

[0109] The first step: Dissolve compound 1e (500mg, 2.06mmol) in 20mL ultra-dry THF, add tetraethoxytitanium (2.81g, 12.36mmol) under nitrogen, and then add tert-butylsulfinamide (747mg, 6.18mmol),. The reaction mixture was reacted at 60°C for 4 hours. The reaction was cooled to room temperature, the mixture was poured into an equal volume of saturated brine and stirred, the resulting suspension was filtered through celite, and the filter cake was washed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by a fast column machine to obtain compound 20a (51...

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Abstract

The invention relates to a preparation method of a compound shown as a formula I shown in the specification. 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 a class of IDO inhibitors. Background technique [0004] Tryptophan (TRP) is an α-amino acid used in pr...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07D215/18
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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