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3-Cyano-6-cyclopropylpyridine type IDO1 inhibitor and application thereof

A methyl compound technology, applied in the field of medicinal chemistry, to achieve the effect of novel structure and high activity

Active Publication Date: 2019-04-05
药大制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

IDO1 inhibitors have broad development prospects as drugs, but so far no suitable IDO1 inhibitors have been marketed as drugs, so finding new and efficient IDO1 inhibitors has important theoretical significance and application value

Method used

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  • 3-Cyano-6-cyclopropylpyridine type IDO1 inhibitor and application thereof
  • 3-Cyano-6-cyclopropylpyridine type IDO1 inhibitor and application thereof
  • 3-Cyano-6-cyclopropylpyridine type IDO1 inhibitor and application thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0024] Preparation of Intermediate I-2

[0025]

[0026] In 30 mL of In 10% dilute sulfuric acid, stirred at room temperature for 30 min, slowly added an aqueous solution of ammonium persulfate (9.9 g, 43.4 mmol, 2 eq) dropwise, reacted overnight at room temperature, and TLC detected that the reaction was complete. Post-processing: adjust the pH to 8-9 with ammonia water, filter with suction, extract the filtrate with ethyl acetate three times, wash the organic phase with saturated brine once, evaporate the ethyl acetate under reduced pressure to obtain I-2 (3.5 g, harvested rate 90%).

[0027] Preparation of intermediate 1-3

[0028]

[0029] Dissolve thioglycolic acid (1.1g, 12mmol, 1.2eq) in DMSO, stir at room temperature for 10min, slowly add K 2 CO 3 (6.9g, 50mmol, 5eq) continued to stir at room temperature for 30min, then added dropwise the DMSO diluent of II-1 (1.8g, 10mmol, 1eq) and slowly warmed up to 60°C, reacted for 4h, and the reaction was complete by TL...

Embodiment 1

[0031] Preparation of 2-((3-cyano-6-cyclopropylpyridin-2-yl)thio)-N-phenylacetamide (1)

[0032] Dissolve II-2 (0.46g, 2mmol, 1eq), EDCI (0.50g, 2.6mmol, 1.3eq) and HOBT (0.08g, 0.6mmol, 0.3eq) in DMF, react at no more than 10°C for 30min, add After aniline (0.20g, 2.2mmol, 1.1eq), the color of the reaction solution became darker, and the reaction was carried out overnight at room temperature, and the reaction was complete as detected by TLC. Post-processing: Pour the reaction solution into water, filter with suction, and obtain the crude product by column chromatography on the filter cake, which is recrystallized with petroleum ether-ethyl acetate system to obtain 1 (140 mg, yield 57%). m.p.223-225℃.HRMS m / z[M+H] + calculated for C 17 h 15 N 3 OS:310.1009,found:310.1019. 1 H NMR (300MHz, DMSO-d 6 )δ:9.31(s,1H,-NH-),8.32(d,J=8.4Hz,1H,-ArH),7.67(d,J=8.0Hz,2H,-ArH),7.36-7.29(m, 5H,-ArH,-S-CH 2 -C=O-), 7.07(t, J=7.2Hz, 1H, -ArH), 2.25-2.19(m, 1H, -CH(CH 2 ) 2 -),1.07-1....

Embodiment 2

[0034] Preparation of Compound 2

[0035] Preparation of 2-((3-cyano-6-cyclopropylpyridin-2-yl)thio)-N-(4-fluorophenyl)acetamide

[0036]Dissolve I-3 (0.46g, 2mmol, 1eq), EDCI (0.50g, 2.6mmol, 1.3eq) and HOBT (0.08g, 0.6mmol, 0.3eq) in DMF, react at no more than 10°C for 30min, add After aniline (0.24g, 2.2mmol, 1.1eq), the color of the reaction solution became darker, and the reaction was carried out overnight at room temperature, and the reaction was complete as detected by TLC. Post-processing: Pour the reaction solution into water, filter with suction, and obtain a crude product by column chromatography of the filter cake, which is recrystallized with petroleum ether-ethyl acetate system to obtain 2 (160 mg, yield 61%). m.p.198-200℃.HRMS m / z[M+H] + calculated for C 17 h 14 FN 3 OS:328.0914,found:328.0926. 1 H NMR (300MHz, DMSO-d 6 )δ:9.42(s,1H,-NH-),8.33(d,J=8.4Hz,1H,-ArH),7.69(dd,J=7.9,5.1Hz,2H,-ArH),7.36(m, 3H,-ArH,-S-CH 2 -C=O-), 7.16(t, J=8.9Hz, 2H, -ArH), 2.2...

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Abstract

The invention relates to a 3-cyano-6-cyclopropylpyridine type IDO1 inhibitor and application thereof. The 3-cyano-6-cyclopropylpyridine type IDO1 inhibitor is compound of general formula I or its pharmaceutically acceptable salt; n represents 1-4, R represents hydrogen, halogen, methyl group, C1-C4 alkoxy group, cyano group, nitro group, and C-C4 alkyl group. The 3-cyano-6-cyclopropylpyridine typeIDO1 inhibitor is novel in structure and high in activity, has low side effects and good drug metabolism, may act as an antitumor candidate compound. These compounds are used alone or used with otherantitumor drugs, so that efficacy of existing antitumor drugs is improved and their dosage and toxicity are decreased.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor with a benzo nitrogen-containing heterocyclic structure and its application. Background technique [0002] Indoleamine-2,3-dioxygenase 1 (IDO1) plays an important role in immune tolerance and is becoming a new target for tumor immunotherapy. IDO1 is a key rate-limiting enzyme in the metabolism of the essential amino acid tryptophan (Trp) in the human body. It exists widely in various tissues in the human body and is overexpressed in a variety of tumor tissues. The overexpression of IDO1 in tumor tissue leads to the depletion of Trp in the tumor microenvironment, thereby inhibiting the proliferation and differentiation of T cells, thereby inhibiting the immune system's immune response to tumors. Studies have shown that combined use of IDO1 inhibitors can not only enhance the efficacy of conventional chemotherapy, but also produc...

Claims

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Application Information

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IPC IPC(8): C07D213/85A61P35/00A61P37/02A61P25/28A61P25/18A61K31/4418
CPCA61P25/18A61P25/28A61P35/00A61P37/02C07D213/85
Inventor 卞金磊赵璐璐王举波马樱赫李志裕
Owner 药大制药有限公司
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