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Benzonitrogen-containing heterocyclic indoleamine-2,3-dioxygenase 1 inhibitors and uses thereof

A technology of -NH2, nitrogen atom, applied in the field of indoleamine-2,3-dioxygenase 1 inhibitor and its preparation

Active Publication Date: 2019-10-22
CHINA PHARM UNIV
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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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  • Benzonitrogen-containing heterocyclic indoleamine-2,3-dioxygenase 1 inhibitors and uses thereof
  • Benzonitrogen-containing heterocyclic indoleamine-2,3-dioxygenase 1 inhibitors and uses thereof
  • Benzonitrogen-containing heterocyclic indoleamine-2,3-dioxygenase 1 inhibitors and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Preparation of 4-amino-3-(N'-hydroxyamidino)-1,2,5-oxadiazole(III)

[0057] Add sodium nitrite (20.7g, 300mmol) and 40mL water into a 500mL reaction flask, stir to dissolve, slowly add malononitrile (9.9g, 150mmol) hydrochloric acid (2N) solution dropwise at room temperature, stir overnight at room temperature, and cool to 0°C, add dropwise an aqueous solution of hydroxylamine hydrochloride (23g, 340mmol), stir for 30min, adjust the pH to 10 with 10N sodium hydroxide below 20°C, rise to 35°C for 2h, and then heat to reflux for 2h. Cool to room temperature, extract the reaction solution with 20 mL of ethyl acetate, distill off the solvent under reduced pressure to obtain a white solid, place the water layer overnight, precipitate a solid, filter with suction, wash with water, combine the filter cake with the white solid obtained by distillation under reduced pressure and dry to obtain a white powder like solid (14.9 g, 69.5%). 1 H NMR (300MHz, DMSO-d 6 )δ: 10.46(s,1H,-...

Embodiment 2

[0061] Preparation of compound CPUL-I101

[0062] Preparation of 4-amino-3-(N-methyl-N'-hydroxyamidino)-1,2,5-oxadiazole (V-1)

[0063] Add IV (1.0g, 6.2mmol) and 40mL ethanol into a 100mL reaction flask, stir, and slowly add 40% methylamine ethanol solution (0.48g, 6.2mmol) and triethylamine (1.25g, 12.4 mmol), stirred at room temperature for 3 h, evaporated the solvent under reduced pressure, added ethyl acetate and stirred, filtered with suction, washed the filtrate once with water and saturated aqueous sodium chloride solution, dried the organic layer with anhydrous sodium sulfate, evaporated the solvent under reduced pressure to obtain yellow Oil (0.68g, 70.1%). HRMS m / z[M+H] + calculated for C 4 h 7 N 5 o 2 :157.0602,found:157.0600.

[0064] Preparation of 4-methylamino-3-(N'-hydroxyamidino)-1,2,5-oxadiazole (VI-1)

[0065] V-1 (0.68g, 4.3mmol) and 9mL of water were added to a 50mL reaction flask, and a 3mL aqueous solution of potassium hydroxide (0.73g, 13mmol) ...

Embodiment 3

[0071] Preparation of Compound CPUL-I102

[0072] Compound CPUL-I102 (38.9 mg, 15%) was synthesized in the same manner as compound CPUL-I101 except that ethylamine (0.95 mmol) was used instead of methylamine. m.p.187-188℃, 1 H NMR (300MHz, DMSO-d6)δ:10.99(s,1H,-OH),7.08-7.14(m,4H,-ArH),6.08-6.22(m,1H,-NH-),4.55(s, 2H,-CH 2 -),3.55(t,J=5.6Hz,2H,-CH 2 -),3.19-3.23(m,2H,-CH 2 -),2.88(t,J=5.6Hz,2H,-CH 2 -), 1.18(t, J=5.1Hz, 3H, -CH 3 )ppm.HRMS m / z[M+H]+calculated for C 14 h 17 N 5 o 2 :287.1380,found:287.1382.

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Abstract

The invention relates to the field of pharmaceutical chemistry and particularly relates to an iodoleamine-2,3-dioxygenase 1 inhibitor (I), represented by a formula (I) shown in the description, with a nitrogen-containing benzoheterocyclic structure, wherein X, R, n and m are as defined in the description. Proven by pharmacodynamic tests, the compound disclosed by the invention can be used for treating diseases with IDO1 mediated pathological features of a tryptophan metabolism pathway such as malignant tumors, autoimmune diseases, Alzheimer's disease and schizophrenia.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an indoleamine-2,3-dioxygenase 1 inhibitor with a benzo nitrogen-containing heterocyclic structure and a preparation method thereof Background technique [0002] Indoleamine 2,3-dioxygenase (IDO) is a metabolic enzyme containing heme in cells, which is the key rate-limiting enzyme mediating tryptophan metabolism , is an important component of the kynurenine pathway. Since IDO was discovered in 2003, it has been extensively studied by the academic and pharmaceutical circles as an important target for drug development. [0003] The first step in the degradation of tryptophan is the oxidation of tryptophan to N-formyl-L-kynurenine, which is produced by IDO and tryptophan-2,3-dioxygenase (tryptophan 2,3- Dioxygenase, TDO) is mediated by one of the two heme-dependent dioxygenases. Among the two dioxygenases, IDO is considered to be a checkpoint that regulates the oxidation reacti...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/06C07D413/14A61K31/4725A61K31/4245A61K31/4709A61P35/00A61P37/00A61P25/28A61P25/18
Inventor 吴照球李志裕鲁凯强卞金磊张轶惟
Owner CHINA PHARM UNIV
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