Indoleamine-2,3-dioxygenase inhibitor containing sulfoximine subjected to nitrogen alkylation and arylation

A technology of alkyl and aryl, applied in the field of medicinal chemistry

Active Publication Date: 2017-09-19
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In 1937, Kotake et al. purified the protein from rabbit intestines and discovered for the first time that TDO was mainly expressed in the liver of mammals. It has not been found that he is closely related to the immune system.

Method used

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  • Indoleamine-2,3-dioxygenase inhibitor containing sulfoximine subjected to nitrogen alkylation and arylation
  • Indoleamine-2,3-dioxygenase inhibitor containing sulfoximine subjected to nitrogen alkylation and arylation
  • Indoleamine-2,3-dioxygenase inhibitor containing sulfoximine subjected to nitrogen alkylation and arylation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0252] (±)(Z)-nitrogen-(3-bromo-4-fluorophenyl)-nitrogen'-hydroxy-4-((2-(nitrogen, sulfur-dimethylsulfoximine)ethyl)amino) -1,2,5-oxadiazole-3-carboxamidine

[0253]

[0254] The first step: 4-Amino-nitrogen’-hydroxy-1,2,5-oxadiazole-3-carboxamidine

[0255]

[0256] Dissolve malondicyanide (3.2g, 48.5mmol) in 70mL of water and heat to completely dissolve. Under ice-water bath cooling, sodium nitrite (3.8 g, 55 mmol) and 6N hydrochloric acid (0.6 mL) were added. After reacting in an ice bath for 0.5 hours, the temperature was raised to room temperature and reacted for 2 hours. The reaction solution was continued to be cooled in an ice bath, and a 50% hydroxylamine hydrochloride aqueous solution (9.9 g, 150 mmol) was added dropwise to the reaction solution. After stirring for half an hour, it was raised to room temperature and reacted for 1 hour. The reaction was heated under reflux for 2 hours. After the reaction was completed, the pH was adjusted to 7.0 with 8 mL of 6N hydrochl...

Embodiment 2

[0301] (±)(Z)-nitrogen-(3-bromo-4-fluorophenyl)-nitrogen'-hydroxy-4-((3-(sulfur-methyl-nitroethylsulfoximine)ethyl)amino )-1,2,5-oxadiazole-3-carboxamidine

[0302]

[0303] According to the preparation method of Example 1, the reagent of the tenth step was replaced with triethyloxonium tetrafluoroborate, and the conditions of the eleventh step were used to obtain the target compound.

[0304] 1 H NMR: (400MHz, acetone-d 6 ): δ10.85(s,1H), 8.12(s,1H), 7.28-7.26(m,1H), 7.17-7.13(m,1H), 7.02-6.98(m,1H), 6.64(s,1H) ), 3.81 (s, 2H), 3.57 (s, 1H), 3.43-3.40 (m, 1H), 3.31-3.06 (m, 5H), 1.11-1.05 (m, 3H).

[0305] MS(ESI):[M+H] + m / z=449.0

Embodiment 3

[0307] (±)(Z)-nitrogen-(3-bromo-4-fluorophenyl)-nitrogen'-hydroxy-4-(2-(sulfur-methyl-nitrogen-phenylsulfoximine)ethyl)amino )-1,2,5-oxadiazole-3-carboxamidine

[0308]

[0309] The first step: (±)4-(3-bromo-4-fluorophenyl)3-4-(((2-(methylsulfoxidephenylimine)ethyl)tert-butoxycarbonylamino)-1 ,2,5-oxadiazol-3-yl)-1,2,4-oxadiazolone

[0310]

[0311] The product of the ninth step of Example 1 (20mg, 0.037mmol) was dissolved in dichloromethane (2ml), phenylboronic acid (8mg, 0.055mmol) was added, and copper acetate (5mg) was stirred at room temperature for 2 hours. TLC showed that the reaction was complete. Add water (10ml) and ethyl acetate (10mL) to the reaction solution, then extract with ethyl acetate (2x10mL) and combine the organic phases, then wash with water (10mL), saturated brine (10mL), and dry with sodium sulfate. After concentration, column chromatography is separated and purified to obtain the target compound (15mg, 66% yield)

[0312] 1 HNMR(400MHz, acetone-d 6 ): δ 7...

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Abstract

The invention discloses an indoleamine-2,3-dioxygenase inhibitor containing sulfoximine subjected to nitrogen alkylation and arylation and a preparation method thereof. The inhibitor disclosed by the invention has a structure shown in a general formula (I), wherein the definitions of X, R1, R2, R3, R4, R7, R8, R9, n and m are shown in a description and claims. The invention also discloses a preparation method of the inhibitor. According to the indoleamine-2,3-dioxygenase inhibitor disclosed by the invention, a compound shown in the general formula (I) can be used as the indoleamine-2,3-dioxygenase inhibitor and can be used for preparing medicines for preventing and / or treating indoleamine-2,3-dioxygenase-mediated diseases. The formula (1) is shown in the description.

Description

Technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to an IDO inhibitor containing nitrogen alkylation, arylation and acylation sulfoximine and 1,2,5-oxadiazole structures and a preparation method thereof. Background technique [0002] Indoleamine-2,3-dioxygenase (IDO) is a monomeric enzyme containing heme that was first discovered in cells by Hayaishi’s group in 1967. The cDNA encoded protein is It is composed of 403 amino acids and has a molecular weight of 45kDa. It is the rate-limiting enzyme in the catabolism of the chromatin-kynurenine pathway and is widely expressed in a variety of mammalian tissues (Hayaishi O. et al Science, 1969, 164,389-396). In the cells of tumor patients, IDO is often used as an important physiological role in inducing tumor microenvironmental immune tolerance, and its mediated tryptophan (Trp)-kynurenine (Kynurenine, Kyn) metabolic pathway is involved in tumors. Immune escape, and ID...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D271/08A61K31/4245A61P29/00A61P35/00A61P25/00A61P27/02A61P25/24A61P25/22A61P25/28A61P37/06
CPCC07D271/08A61K31/4245
Inventor 王召印郭巍朱继东胡新波
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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