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Indoline compound as well as derivative, preparation method, pharmaceutical composition and application thereof

A compound, indoline technology, applied in the field of indoline compounds and their derivatives, can solve the problems of low activity and insufficient druggability, and achieve the effects of simple preparation method, excellent curative effect and easy operation

Pending Publication Date: 2022-03-22
CHINA PHARM UNIV +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Purpose of the invention: In view of the low activity and insufficient druggability of existing holo-IDO1 inhibitors, the present invention aims to provide a class of indoline compounds with high apo-IDO1 inhibitory activity and excellent druggability and Its derivatives, preparation methods, pharmaceutical compositions and applications

Method used

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  • Indoline compound as well as derivative, preparation method, pharmaceutical composition and application thereof
  • Indoline compound as well as derivative, preparation method, pharmaceutical composition and application thereof
  • Indoline compound as well as derivative, preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Embodiment 1: (R)-N-(1-(1-(cyclohexanecarbonyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-fluorobenzamide ( 1) synthesis

[0069]

[0070] Synthesis of N-acetylindoline (1A)

[0071] 2,3-Dihydro-1H-indole (10.00g, 83.91mmol) and triethylamine (25.47g, 251.73mmol) were dissolved in 40mL of anhydrous dichloromethane, and acetyl chloride (9.88 g, 125.87mmol) in anhydrous dichloromethane (10mL), react overnight at room temperature, concentrate under reduced pressure, add 100mL of water, extract with dichloromethane (3×80mL), combine the organic phases, wash with saturated brine, and anhydrous sulfuric acid Dry over magnesium, filter with suction, concentrate under reduced pressure, and separate and purify by column chromatography to obtain 11.78 g of white solid with a yield of 87.1%. MS(ESI)m / z:160.1[M-H] - ; 1 H NMR (300MHz, DMSO-d 6 )δ (ppm) 8.05 (d, J = 8.1Hz, 1H), 7.21 (d, J = 7.2Hz, 1H), 7.14 (t, J = 7.5Hz, 1H), 6.97 (t, J = 7.5Hz, 1H), 4.05(t, J=7.8Hz, 2H), 3.12(t,...

Embodiment 2

[0086] Embodiment 2: (R)-N-(1-(1-(cyclohexanecarbonyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-chlorobenzamide ( 2) synthesis

[0087]

[0088] Dissolve 1G (0.080g, 0.29mmol) and triethylamine (0.088g, 0.87mmol) in 3mL of anhydrous dichloromethane, slowly add 4-chlorobenzoyl chloride (0.061g, 0.35mmol) dropwise at 0°C Anhydrous dichloromethane (1 mL) solution, reacted at room temperature for 3 h, concentrated under reduced pressure, added 30 mL of water, extracted with dichloromethane (3×20 mL), combined organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered. Concentrate under reduced pressure, and separate and purify by column chromatography to obtain 0.10 g (99.1% ee) of white solid with a yield of 83.3%. MS(ESI)m / z:409.2[M-H] - ; 1 H NMR (300MHz, DMSO-d 6 )δ (ppm) 8.82 (d, J = 8.1Hz, 1H), 8.01 (d, J = 8.1Hz, 1H), 7.90 (d, J = 8.4Hz, 2H), 7.54 (d, J = 8.7Hz, 2H), 7.24(s, 1H), 7.14(d, J=8.4Hz, 1H), 5.12-5.08(m, 1H), 4.14(t...

Embodiment 3

[0089] Example 3: (R)-N-(1-(1-(cyclohexanecarbonyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-cyanobenzamide (3) synthesis

[0090]

[0091] 1G (0.13g, 0.48mmol) and triethylamine (0.14g, 1.43mmol) were dissolved in 3mL of anhydrous dichloromethane, and 4-cyanobenzoyl chloride (0.080g, 0.48mmol) was slowly added dropwise at 0°C Anhydrous dichloromethane (2mL) solution, reacted at room temperature for 3h, concentrated under reduced pressure, added 30mL of water, extracted with dichloromethane (3×20mL), combined organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered , concentrated under reduced pressure, and separated and purified by column chromatography to obtain 0.17 g (99.5% ee) of a white solid, with a yield of 89.5%. MS(ESI)m / z:400.2[M-H] - ; 1 H NMR (300MHz, DMSO-d 6 )δ (ppm) 9.00 (d, J = 7.8Hz, 1H), 8.04-7.95 (m, 5H), 7.25 (s, 1H), 7.15 (d, J = 8.7Hz, 1H), 5.15-5.06 (m ,1H),4.14(t,J=8.4Hz,2H),3.11(t,J=8.1Hz,2H),1.79-1.6...

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Abstract

The invention discloses an indoline compound and a derivative, a preparation method, a pharmaceutical composition and application thereof. The structure of the indoline compound is shown in a formula (I). Derivatives of the indoline compound relate to stereoisomers, tautomers, metabolites, metabolic precursors, prodrugs, solvates, salts of the solvates, crystals, pharmaceutically acceptable salts or mixtures of the stereoisomers, the tautomers, the metabolites, the metabolic precursors, the prodrugs and the solvates of the indoline compound. The indoline compound and the derivative thereof have a remarkable inhibition effect on the activity of indoleamine 2, 3-dioxygenase 1, can be used for preparing a medicine for treating indoleamine 2, 3-dioxygenase 1 mediated immunosuppression related diseases, and exerts antitumor activity by activating host immune response.

Description

technical field [0001] The present invention relates to a class of indoline compounds and their derivatives, preparation methods, pharmaceutical compositions and applications, in particular to an indoline compound that can be prepared as an indoleamine 2,3-dioxygenase 1 inhibitor drug And derivatives thereof, preparation method, pharmaceutical composition and application. Background technique [0002] Indoleamine 2,3-dioxygenase 1 (IDO1) is the rate-limiting enzyme that catalyzes the oxidative metabolism of L-tryptophan in humans. IDO1 can catalyze the metabolism of L-tryptophan to produce kynurenine and its downstream metabolites with immunosuppressive effects, so IDO1 plays an important role in maintaining the body's immune homeostasis and tolerance. Furthermore, like cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed death receptor 1 (PD-1) and its ligand PD-L1, IDO1 plays an important role in tumor immune evasion. Studies have shown that IDO1 is overexpre...

Claims

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Application Information

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IPC IPC(8): C07D209/08C07D401/06C07D401/12C07D401/14A61K31/4045A61K31/4439A61K31/444A61P37/02A61P35/00A61P31/12A61P25/00A61P35/02A61P31/18A61P31/20A61P31/16A61P31/14A61P25/28A61P25/16A61P25/14A61P19/02A61P17/00A61P9/10A61P27/12A61P37/06A61P21/04A61P17/06
CPCC07D209/08C07D401/06C07D401/12C07D401/14A61P37/02A61P35/00A61P31/12A61P25/00A61P35/02A61P31/18A61P31/20A61P31/16A61P31/14A61P25/28A61P25/16A61P25/14A61P19/02A61P17/00A61P9/10A61P27/12A61P37/06A61P21/04A61P17/06
Inventor 赖宜生胡碧云马雪薇葛书山郭文洁徐强钟海清余龙波
Owner CHINA PHARM UNIV
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