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Imidazole methylamine derivatives having activity of indoleamine-2, 3-dioxygenase (IDO) inhibitor, and synthesis method of imidazole methylamine derivatives

A solvate, compound technology, applied in the field of compound medicine, can solve problems such as adverse reactions

Active Publication Date: 2019-10-01
XIHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While these IDO1 inhibitors produce curative effect, they also lead to some adverse reactions

Method used

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  • Imidazole methylamine derivatives having activity of indoleamine-2, 3-dioxygenase (IDO) inhibitor, and synthesis method of imidazole methylamine derivatives
  • Imidazole methylamine derivatives having activity of indoleamine-2, 3-dioxygenase (IDO) inhibitor, and synthesis method of imidazole methylamine derivatives
  • Imidazole methylamine derivatives having activity of indoleamine-2, 3-dioxygenase (IDO) inhibitor, and synthesis method of imidazole methylamine derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0105] Embodiment 1, the synthesis of N-(1-(1H-imidazol-4-yl) propyl)-4-methoxyaniline (compound 1)

[0106]

[0107] (1) Synthesis of Intermediate 1b

[0108] First, 4-imidazole formaldehyde (1a, 960mg, 10mmol) was added to the reaction flask, placed under an ice-water bath, and after 10min, triethylamine (TEA) (278μl, 2.0mmol) was added to the reaction flask, and the mixture Stir for 5 min under ice-water bath. Then di-tert-butyl dicarbonate (2.4g, 1.0mmol) was added to the reaction flask, and the reaction was moved to room temperature for overnight reaction. After TLC detected that the reaction was complete, the solvent was spin-dried, and alumina column chromatography (PE:EA =2:1) ​​to obtain intermediate 1b.

[0109] (2) Synthesis of Intermediate 1c

[0110]Then intermediate 1b (980.4mg, 5.0mmol) was placed in a three-necked flask, ventilated with argon, added cooled redistilled tetrahydrofuran (20ml) and cooled at -78°C for 2h, then poured into the reaction flask w...

Embodiment 2

[0120] Embodiment 2, the synthesis of N-(1-(1H-imidazol-4-yl) allyl)-4-methoxyaniline (compound 2)

[0121]

[0122] First, 2b was synthesized by using the raw material intermediate 1b and vinylmagnesium bromide according to the synthesis method of 1c.

[0123] Using 2b and acetyl chloride, 2c was synthesized according to the synthesis method of 1d.

[0124] Finally, the target compound 2 (white solid) was synthesized according to the synthesis method of compound 1 using 2c and raw material p-aminoanisole, with a total yield of 21%.

[0125] Compound 2 1 H NMR and 13 The C NMR data are as follows:

[0126] 1 HNMR(400MHz,DMSO)δ11.92(brs,1H),7.58(s,1H),6.89(s,1H),6.69(d,J=9.00Hz,2H),6.62(d,J=9.04Hz, 2H),6.03-5.95(m,1H),5.36(brs,1H),5.22(d,J=17.12Hz,2H),5.09(d,J=22.16Hz,2H),4.89(s,1H), 3.63(s,3H).

[0127] 13 C NMR (100MHz, DMSO): 151.3, 142.6, 139.9, 135.4, 115.0, 114.8, 114.7. ESIHRMS exact mass calcd.for (C 13 h 15 N 3 O-H) - requires m / z 228.1142, found m / z 228...

Embodiment 3

[0128] Example 3, 1-(1H-imidazol-4-yl)-N-methyl-1-phenylmethanamine

[0129]

[0130] First, use intermediate 1b and phenylmagnesium bromide to synthesize 3b according to the synthesis method of 1c, then use 3b and acetyl chloride to synthesize 3c according to the synthesis method of 1d, and finally use 3c and raw material methylamine aqueous solution to synthesize the target according to the synthesis method of compound 1 Compound 3 (transparent viscous liquid), the total yield is 12%.

[0131] Compound 3 1 H NMR and 13 The C NMR data are as follows:

[0132] 1 H NMR (400MHz, CDCl 3 )δ7.49(s,1H),7.29(q,J=7.9Hz,1H),7.19(d,J=8.0Hz,1H),7.13(d,J=10.0Hz,1H),6.95(td, J=8.4,2.4Hz,1H),6.71(s,1H),5.20(s,1H),4.30(s,2H)ppm.

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Abstract

The invention discloses imidazole methylamine derivatives having the activity of an indoleamine-2, 3-dioxygenase (IDO) inhibitor, and a synthesis method of the imidazole methylamine derivatives. The invention in particular relates to the indoleamine-2, 3-dioxygenase (IDO) inhibitor with a novel structure, and application of the inhibitor in pharmacy, belonging to the field of compound medicines. The compounds provided by the invention are as shown in a formula I, have the novel structure, show the good IDO inhibitory activity, provide a new option for clinical treatment of diseases associatedwith abnormal IDO activity, and provide a potential medicine for prevention and / or treatment of diseases such as Alzheimer disease, cataracts, cellular immune activation-related infections, autoimmunediseases, AIDS, cancers, depression or abnormal metabolism of tryptophan.

Description

technical field [0001] The invention belongs to the field of compound drugs, and relates to an imidazole methylamine derivative with indoleamine-2,3-dioxygenase (IDO) inhibitor activity and a synthesis method thereof, in particular to an indole with a novel structure Amine-2,3-dioxygenase (IDO) inhibitors and their use in pharmaceuticals. Background technique [0002] The interaction between tumors and the host immune system is complex and variable. Many scientists are trying to elucidate the mechanism of interaction between the two, hoping to improve the status quo of tumor treatment. At the same time, tumor immunotherapy has become a hot research field in the pharmaceutical industry. As a member of many tumor immune cycle regulators, indoleamine 2,3-dioxygenase 1 (Indoleamine 2,3-dioxygenase 1, IDO-1) is recognized for its high expression in various tumor tissues. much attention. [0003] Indoleamine 2,3-dioxygenase 1 (Indoleamine 2,3-dioxy-genase1, IDO-1) is an immuno...

Claims

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Application Information

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IPC IPC(8): C07D233/64A61K31/4174A61P25/28A61P27/12A61P31/00A61P37/02A61P31/18A61P35/00A61P25/24A61P3/00
CPCC07D233/64
Inventor 王周玉钱珊杨羚羚李玲徐伟杨欢刘思言姚昊宴婕李超
Owner XIHUA UNIV
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