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Indoleamine2,3-dioxygenase inhibitor, as well as preparation method and application thereof

A technology selected from, alkyl, and applied in the field of drug development, which can solve the problems of limited improvement, unfavorable clinical development, and poor exposure.

Active Publication Date: 2017-10-31
SHANGHAI HANSOH BIOMEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Patent WO2016041489A1 discloses a series of sulfonylimino compounds, which have good inhibitory activity on indoleamine 2,3-dioxygenase (IDO), but the best compound 6 disclosed in this patent is relative to INCB-24360 The increase in exposure (AUC) is limited, and T 1 / 2 Very short, not conducive to clinical development; although compound 13 (compound 6 prodrug) prolongs T 1 / 2 , but its exposure (AUC) is not as good as INCB-24360, therefore, further development of T with suitable clinical administration 1 / 2 , At the same time, compounds with higher exposure (AUC) have attracted many scientists around the world to continue their efforts

Method used

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  • Indoleamine2,3-dioxygenase inhibitor, as well as preparation method and application thereof
  • Indoleamine2,3-dioxygenase inhibitor, as well as preparation method and application thereof
  • Indoleamine2,3-dioxygenase inhibitor, as well as preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0169] (Z)-N 1 -(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarbimidate)-1,2,5-oxadiazole- 3-yl)amino)ethyl)oxalamide (1)

[0170]

[0171] Step 1: N 1 -(2-((4-(4-(3-Bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3- (Base)-1,2,5-oxadiazol-3-yl)amino)ethyl)oxalamide 1m.

[0172] Put 3-(4-((2-aminoethyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl) in a 100mL single-neck bottle -1,2,4-oxadiazole-5(4H)-one 1l (300mg, 0.78mmol), oxalamide (138mg, 1.56mmol) dissolved in N,N-dimethylformamide (8mL), add O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate (375.6mg, 1.17mmol), then add N,N-diisopropylethylamine (0.5mL, 2.34 mmol), react at room temperature for 2 hours, add water (50mL), solid precipitate, filter, dry solid to obtain N 1 -(2-((4-(4-(3-Bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1 ,2,5-oxadiazol-3-yl)amino)ethyl)oxalamide 1m (105mg), the yield is 32.0%.

[0173] MS m / z (ESI): 456.0, 458.0 (M, M+2).

[0174] Step 2:...

Embodiment 2

[0179] (Z)-N 1 -(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarbimidate)-1,2,5-oxadiazole- 3-yl)amino)ethyl)-N 2 -Methyloxalamide (2)

[0180]

[0181] Step 1: Methyl 2-((2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole - 3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)amino)-2-carbonyl acetate 2b.

[0182] Put 3-(4-((2-aminoethyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl) in a 100mL single-neck bottle -1,2,4-oxadiazole-5(4H)-one 1l (385mg, 1.0mmol), dimethyl oxalate (141.6mg, 1.2mmol) dissolved in methanol (15mL), add sodium methoxide (130mg, 2.4 mmol), react at room temperature overnight, LC-MS monitors the complete conversion of the raw materials, and stop the reaction. Saturated ammonium chloride solution (30mL) was added, extracted with ethyl acetate (50mL x 2), the combined organic phases were washed with saturated sodium chloride (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain methyl 2- (...

Embodiment 3

[0189] (Z)-N 1 -(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarbimidate)-1,2,5-oxadiazole- 3-yl)amino)ethyl)-N 2 -Ethyloxalamide (3)

[0190]

[0191] Step 1: N 1 -(2-((4-(4-(3-Bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3- (Yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)-N 2 -Ethyloxalamide 3b.

[0192] Methyl 2-((2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4- Oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)amino)-2-carbonyl acetate (240mg, 0.51mmol) dissolved in methanol (15mL), 1M ethylamine solution (2 mL) was added to the above solution, and reacted at room temperature for 3 hours. LC-MS monitored the complete conversion of the raw materials, the reaction was stopped, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate Concentrate, get N 1 -(2-((4-(4-(3-Bromo-4-fluorop...

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Abstract

The invention relates to an indoleamine2,3-dioxygenase inhibitor having a structure as shown in a formula (I), as well as a preparation method and application thereof. The IDO inhibitor is (Z)-N'-hydroxyl-N-benzoate derivative, has high inhibiting activity for IDO, can be used for effectively inhibiting the IDO activity and inhibiting immunosuppression of patients, can be widely applied to treatment or prevention of cancer or tumors, virus infection, depression, neural degeneration disease, trauma, age related cataract, organ transplant rejection or autoimmune disease, and is expected to be developed into a new generation of immunosuppressors.

Description

Technical field [0001] The invention belongs to the field of drug development, and specifically relates to an indoleamine 2,3-dioxygenase inhibitor and a preparation method and application thereof. Background technique [0002] Indoleamine 2,3-dioxygenase (IDO) is a protease related to tryptophan metabolism. Tryptophan is one of the eight essential amino acids. Tryptophan can be used to synthesize proteins in the body. Tryptophan can also be used as a precursor substrate to synthesize serotonin and melatonin (N- Acetyl-5-methoxytryptamine). Serotonin and melatonin are neurotransmitters and neuroendocrine hormones, which are involved in the regulation of various nerve and physiological processes in the body. In addition, tryptophan can also produce kynurenine and other metabolites through the kynurenine metabolic pathway. The first step of the kynurenine metabolic pathway is under the catalysis of indoleamine 2,3-dioxygenase or tryptophan 2,3-dioxygenase (TDO), tryptophan L-try...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D271/08A61K31/4245A61K31/5377A61P35/00A61P31/12A61P25/24A61P25/28A61P27/12A61P37/06A61P37/02A61P35/02
CPCC07D271/08A61K9/0019A61K47/40C07D413/04A61K45/06A61K31/5377A61P35/00A61K31/4245
Inventor 吴盛华李凯龙包如迪
Owner SHANGHAI HANSOH BIOMEDICAL
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