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IDO inhibitor, preparation method, pharmaceutical composition and application

A technology of inhibitors and compositions, applied in the direction of drug combinations, antipyretics, anti-inflammatory agents, etc., can solve the problems of low selectivity and weak IDO2 inhibitory activity, and achieve a simple preparation method, wide application, and easy operation Effect

Active Publication Date: 2022-05-27
CHINA PHARM UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Purpose of the invention: Aiming at the weak inhibitory activity of existing compounds on IDO2 and the lack of high selectivity, the present invention aims to provide a class of IDO inhibitors with excellent anti-inflammatory activity, preparation methods, pharmaceutical compositions and applications

Method used

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  • IDO inhibitor, preparation method, pharmaceutical composition and application
  • IDO inhibitor, preparation method, pharmaceutical composition and application
  • IDO inhibitor, preparation method, pharmaceutical composition and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1: (Z)-N-((1-(2-((4-(N-(3-bromobenzyl)-N'-hydroxyformamidine)-1,2,5-oxadiazole- Synthesis of 3-yl)amino)ethyl)-1H-1,2,3-triazol-4-yl)methyl)picolinamide (I-1)

[0051] Synthesis of (Z)-4-amino-N-(3-bromobenzyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboxamidine (IV-1)

[0052] Into the 2L three-necked flask was sequentially added raw material (Z)-4-amino-N'-hydroxy-1,2,5-oxadiazole-3-carbimidoyl chloride (II-1, 21.0g, 129.7mmol), 3-Bromobenzylamine (III-1, 20.0 g, 108.1 mmol) and 95% ethanol (500 mL) were stirred, and 200 mL of Na was added to the reaction solution. 2 CO 3 The solution (17.2 g, 162.0 mmol) was heated to 60° C. with heating and stirring for 5 hours, and the TLC monitoring (petroleum ether: ethyl acetate=5: 1) was completed; the reaction solution was transferred to a 2L eggplant-shaped bottle, and evaporated under reduced pressure. Ethanol, then add 500 mL of water, stir at 25 ° C for 1 hour, suction filter, wash the filter cake with water (100 × 3 mL),...

Embodiment 2

[0065] Example 2: (Z)-N-((1-(2-((4-(N-(3-bromobenzyl)-N'-hydroxyformamidine)-1,2,5-oxadiazole- Synthesis of 3-yl)amino)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-1H-pyrrole-2-carboxamide (I-2)

[0066] With compound X-1 (0.10 g, 0.26 mmol), N-(propyl-2-yn-1-yl)-1H-pyrrole-2-carboxamide (XI-2, 45 mg, 0.31 mmol) and copper sulfate (8 mg, 0.05 mmol) / sodium ascorbate (20 mg, 0.10 mmol) as raw materials, the same operation as I-1, 60 mg of white solid I-2 was obtained, the yield was 43.8%, m.p. 156.0-158.0 ℃. 1 H-NMR (300MHz, DMSO-d 6), δ(ppm): 11.46(s, 1H), 10.85(s, 1H), 8.52(s, 1H), 7.96(s, 1H), 7.49–7.38(m, 2H), 7.28(t, J= 7.6Hz, 1H), 7.21(d, J=7.8Hz, 1H), 7.08(t, J=7.1Hz, 1H), 6.88–6.81(m, 2H), 6.43(s, 1H), 6.10(s, 1H), 4.66–4.53 (m, 4H), 4.48 (d, J=5.7Hz, 2H), 3.68 (d, J=6.1Hz, 2H).

Embodiment 3

[0067] Example 3: (Z)-N-((1-(2-((4-(N-(3-chlorobenzyl)-N'-hydroxyformamidine)-1,2,5-oxadiazole- Synthesis of 3-yl)amino)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-1H-pyrrole-2-carboxamide (I-3)

[0068] Synthesis of (Z)-4-amino-N-(3-chlorobenzyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboxamidine (IV-2)

[0069] With compound II-1 (6.9 g, 42.5 mol), 3-chlorobenzylamine (III-2, 5.0 g, 35.4 mmol) and Na 2 CO 3 (5.6g, 53.1mmol) was used as raw material, and the operation was the same as IV-1 to obtain 4.8g of off-white solid IV-2, yield 50.7%, m.p.106.0-108.0℃. 1 H-NMR (400MHz, DMSO-d 6 ), δ(ppm): 10.84(s, 1H, ), 7.31(t, J=7.7Hz, 1H), 7.29–7.23(m, 2H), 7.15(d, J=7.6Hz, 1H), 7.04( t, J=7.2Hz, 1H), 6.29(s, 2H), 4.62(d, J=7.2Hz, 2H).

[0070] 3-(4-Amino-1,2,5-oxadiazol-3-yl)-4-(3-chlorobenzyl)-1,2,4-oxadiazol-5(4H)-one (V -2) Synthesis

[0071] Using compound IV-2 (4.5 g, 16.8 mmol) and CDI (4.0 g, 25.2 mol) as raw materials, and operating the same as V-1, 4.0 g of white solid V-2 was obt...

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Abstract

The invention discloses an IDO inhibitor, a preparation method, a pharmaceutical composition and application. The structure of the inhibitor is as shown in a formula (I), and the inhibitor comprises isomers, pharmaceutically acceptable salts or a mixture of the isomers and the pharmaceutically acceptable salts. The IDO inhibitor and the pharmaceutical composition thereof have an efficient inhibition effect on IDO, and can be used as a medicine for treating inflammatory diseases such as rheumatoid arthritis and the like; the prepared medicine can exert efficacy at the molecular level and the animal level, the anti-inflammatory activity is superior to that of naproxen, and the compound is simple and convenient in synthesis method and easy to operate.

Description

technical field [0001] The invention relates to a class of IDO inhibitors, preparation methods, pharmaceutical compositions and applications, in particular to a class of IDO inhibitors, preparation methods, pharmaceutical compositions and applications that can be prepared as drugs for treating inflammatory diseases such as rheumatoid arthritis. Background technique [0002] Rheumatoid Arthritis (RA) is a chronic autoimmune disease dominated by inflammatory synovitis. Its clinical manifestations are non-specific inflammation of peripheral joints. Progressive destruction, synovitis occurs repeatedly for a long time, causing the destruction of intra-articular bone and cartilage, which in turn leads to joint dysfunction and even loss of function. And it shows an upward trend with the intensification of aging. Among them, the elderly group (age > 65 years old) has the highest prevalence rate, and the incidence rate of females is higher than that of males. Bone destruction is ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14A61P29/00A61P19/02A61K31/4439A61K31/4245
CPCC07D413/14A61P29/00A61P19/02Y02P20/55
Inventor 徐云根朱启华何光超沈慧孙泽人陈琳雅鲍紫荆张杉吴蕴泽万晟程铭
Owner CHINA PHARM UNIV
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