Targeted indoleamine-2,3-dioxygenase 1 nitrogen mustard inhibitor as well as preparation method and application thereof

A compound and amino technology, applied in the field of medicine, can solve the problems of unreported research on multi-target inhibitors, achieve good IDO1 inhibitory activity, delay tumor growth, and broad-spectrum anti-tumor activity in vitro

Inactive Publication Date: 2018-05-04
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] At present, there are few reports on the research of IDO-based multi-target inhibitors

Method used

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  • Targeted indoleamine-2,3-dioxygenase 1 nitrogen mustard inhibitor as well as preparation method and application thereof
  • Targeted indoleamine-2,3-dioxygenase 1 nitrogen mustard inhibitor as well as preparation method and application thereof
  • Targeted indoleamine-2,3-dioxygenase 1 nitrogen mustard inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1: 3-(bis(2-chloroethyl)amino)-N-(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarboxamidino) Synthesis of -1,2,5-oxadiazole-3-methyl)amino)ethyl)benzamide

[0053] A, 3-(bis(2-chloroethyl)amino)-N-(2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro -1,2,4-oxadiazole-3-methyl)-1,2,5-oxadiazole-3-methyl)amino)ethyl)benzamide

[0054] Compound 3-(4-((2-aminoethyl))amino-1,2,5-oxadiazole-3-methyl)-4-(3-bromo-4-fluorophenyl)-1,2 , 4-oxadiazol-5(4H)-ketone hydroiodide (0.20g, 0.4mmol) and 3-(bis(2-chloroethyl)amino)benzoic acid (0.11g, 0.4mmol) were dissolved in DMF HATU (0.15g, 0.4mmol) and DIPEA (0.18mL, 1mmol) were added, and after stirring overnight at room temperature, the reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by silica gel column chromatography (eluent: dichloromethane / methanol=120:1...

Embodiment 2

[0057] Example 2: 2-(3-(bis(2-chloroethyl)amino)phenyl)-N-(2-((4-(N-(3-bromo-4-fluorophenyl)-N' Synthesis of -Hydroxyformamido)-1,2,5-oxadiazole-3-methyl)amino)ethyl)acetamide

[0058] According to the method of Example 1, in step A, replace 3-(bis(2-chloroethyl)amino)benzoic acid with 2-(3-(bis(2-chloroethyl)amino)phenyl)acetic acid, in In Step B, 2-(3-(bis(2-chloroethyl)amino)phenyl)-N-(2-((4-(4-(3-bromo-4-fluorophenyl)-5- Carbonyl-4,5-dihydro-1,2,4-oxadiazole-3-methyl)-1,2,5-oxadiazole-3-methyl)amino)ethyl)acetamide instead of 3- (Bis(2-chloroethyl)amino)-N-(2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2 , 4-oxadiazole-3-methyl)-1,2,5-oxadiazole-3-methyl)amino)ethyl)benzamide to obtain 2-(3-(bis(2-chloroethyl )amino)-N-(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarboxamidino)-1,2,5-oxadiazole-3-form Base) amino) ethyl) acetamide 0.12g, yield 77%.

Embodiment 3

[0059] Example 3: 3-(3-(bis(2-chloroethyl)amino)phenyl)-N-(2-((4-(N-(3-bromo-4-fluorophenyl)-N' Synthesis of -Hydroxyformamido)-1,2,5-oxadiazole-3-methyl)amino)ethyl)propionamide

[0060] According to the method of Example 1, in step A, replace 3-(bis(2-chloroethyl)amino)benzoic acid with 3-(3-(bis(2-chloroethyl)amino)phenyl)propionic acid, In step B with 3-(3-(bis(2-chloroethyl)amino)phenyl)-N-(2-((4-(4-(3-bromo-4-fluorophenyl)-5 -carbonyl-4,5-dihydro-1,2,4-oxadiazole-3-methyl)-1,2,5-oxadiazole-3-methyl)amino)ethyl)propionamide instead of 3 -(bis(2-chloroethyl)amino)-N-(2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1, 2,4-oxadiazole-3-methyl)-1,2,5-oxadiazole-3-methyl)amino)ethyl)benzamide gives 3-(3-(bis(2-chloroethyl Base)amino)phenyl)-N-(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarboxamidino)-1,2,5-oxadiazole -3-methyl)amino)ethyl)propionamide 0.23g, yield 85%.

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Abstract

The invention discloses a targeted indoleamine-2,3-dioxygenase 1 nitrogen mustard inhibitor as well as a preparation method and application thereof. A structure of the inhibitor is shown as a generalformula I, wherein definition of R is as shown in the claims and specification. Pharmacological experiments prove that the compound disclosed by the invention has excellent IDO1 inhibitory activity and has broad-spectrum in-vitro antitumor activity. In-vivo experiments prove that the compound disclosed by the invention can achieve effects of down-regulating the in-vivo IDO1 activity and obviouslydelaying tumor growth, and can be applied to preparing IDO1-mediated medicines for tumor diseases with pathological features in a tryptophan metabolism pathway. The structural formula is as shown in the specification.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a nitrogen mustard inhibitor targeting indoleamine-2,3-dioxygenase 1 and its preparation method and application. Background technique [0002] Nitrogen mustards are still an important class of antineoplastic drugs in clinical application, such as Chlorambucil and Melphalan. [0003] [0004] The mechanism of action of this type of antitumor drug is that it can form electron-deficient ethyleneimine ions in the body, and then co-exist with electron-rich groups in biomacromolecules (such as DNA, RNA, or some important enzymes). Valence binding, inactivation or DNA molecule breakage, so as to achieve anti-tumor effect. Nitrogen mustard drugs have the advantages of broad anti-tumor spectrum and strong lethality to tumor cells, but they also have disadvantages such as low therapeutic efficiency, poor selectivity, and large toxic and side effects. [0005] Indoleamine 2,3-dioxygen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D271/08C07D413/12A61K31/4245A61P35/00
CPCC07D271/08C07D413/12
Inventor 方堃王卫盛春泉张永强
Owner EAST CHINA UNIV OF SCI & TECH
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