Sulfamate serving as indoleamine-2, 3-dioxygenase inhibitor and preparation method and application thereof

A C3-C10, C6-C20 technology applied in the field of medicinal chemistry

Active Publication Date: 2016-06-08
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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  • Sulfamate serving as indoleamine-2, 3-dioxygenase inhibitor and preparation method and application thereof
  • Sulfamate serving as indoleamine-2, 3-dioxygenase inhibitor and preparation method and application thereof
  • Sulfamate serving as indoleamine-2, 3-dioxygenase inhibitor and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0202] (Z)-2-((4-(nitrogen-(3-bromo-4-fluorophenyl)-N'-hydroxyimine-1,2,5-oxadiazole-3)amino)ethoxy Sulfonamide;

[0203]

[0204] The first step: the preparation of 4-amino-nitrogen'-hydroxyl-1,2,5-oxadiazole-3-carboxamidine (compound D)

[0205]

[0206] Dissolve malondicyanide (32.0g, 485mmol) in 600mL water and heat until completely dissolved. Under cooling in an ice-water bath, sodium nitrite (38.0 g, 533 mmol) and 6N hydrochloric acid (5.5 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 50% aqueous solution of hydroxylamine hydrochloride (99.0 g, 1500 mmol) was added dropwise to the reaction solution. After stirring for half an hour, it was raised to room temperature for 1 hour of reaction. Heat to reflux for 2 hours. After the reaction is complete, adjust the pH to 7.0 with 80 mL of 6N hydrochloric acid in an ...

Embodiment 2

[0248] (Z)-2-((4-(nitrogen-(3-bromo-4-fluorophenyl)-N'-hydroxyimine-1,2,5-oxadiazole-3)amino)ethoxy Methylsulfonamide;

[0249]

[0250] According to the preparation method of Example 1, compound K (50mg, 0.13mmol) was dissolved in 1mLDMA, methylaminosulfonyl chloride (34mg, 0.26mmol) was added dropwise under ice cooling, and reacted at room temperature for 3 hours, and then the reaction mixture was poured into 3mL of water , the precipitated solid was collected by filtration to obtain 60 mg of an intermediate as a white solid, and then the intermediate was treated under the same conditions as in the tenth step of Example 1 to obtain 20 mg of Example 2 as a white solid.

[0251] 1 HNMR (400MHz, CDCl 3 ):δ7.46(s,1H),7.24(dd,1H),7.07(t,1H),6.95(m,1H),6.92(s,1H),6.15(t,1H),4.53(d, 1H), 4.38(t, 2H), 3.71(q, 3H), 2.81(d, 3H);

[0252] MSESI: m / z=452.6, [M+H] + .

Embodiment 3

[0254] (Z)-2-((4-(nitrogen-(3-bromo-4-fluorophenyl)-N'-hydroxyimine-1,2,5-oxadiazole-3)amino)ethoxy Ethylsulfonamide;

[0255]

[0256] According to the preparation method of Example 2, compound K (50 mg, 0.13 mmol) was reacted with ethylsulfonyl chloride, and then hydrolyzed to obtain Example 3 as a white solid.

[0257] 1 HNMR (400MHz, CDCl 3):δ7.55(s,1H),7.26(dd,1H),7.03(t,1H),6.93(m,1H),6.92(s,1H),6.14(t,1H),4.58(t, 1H), 4.38(t,2H), 3.72(m,2H), 3.21(m,2H), 1.20(t,3H);

[0258] MSESI: m / z=466.6, [M+H] + .

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Abstract

The invention provides sulfamate serving as an indoleamine-2, 3-dioxygenase inhibitor and a preparation method and application thereof. The structure of the inhibitor is shown in the general formula I, wherein definitions of X, R1, R2, R3, R4, R5 and n are shown in the description and the claim. The invention further discloses the preparation method of the inhibitor. The compound shown in the general formula I can serve as the indoleamine-2, 3-dioxygenase inhibitor and is used for preparing medicine for preventing and/or treating indoleamine-2, 3-dioxygenase mediated diseases. The general formula I is shown in the description.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a sulfamic acid ester as an indoleamine-2,3-dioxygenase inhibitor and its preparation method and application, more specifically to a sulfamic acid ester containing and IDO inhibitors with 1,2,5-oxadiazole structures, their preparation methods and applications. Background technique [0002] Indoleamine-2,3-dioxygenase (Indoleamine-2,3-dioxygenase, IDO) is a monomeric enzyme containing heme first discovered in cells by the Hayaishi group in 1967. The cDNA-encoded protein is composed of Composed of 403 amino acids, the molecular weight is 45kDa, it is the rate-limiting enzyme of the catabolism of the tryptophan-kynurenine pathway, and it is widely expressed in the tissues of various mammals (HayaishiO.etalScience, 1969,164,389-396 ). In the cells of tumor patients, IDO often plays an important physiological role in inducing immune tolerance in the tumor mic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D271/08A61P29/00A61P35/00A61P25/28A61P27/02A61P25/24A61P25/22A61P37/02
CPCA61K31/4245C07D271/08
Inventor 王召印朱继东
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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