Use of naphthoquinone derivative as inhibitor for IDO1 and/or TDO

A technology of IDO1 and derivatives, which is applied in the field of application of naphthoquinone derivatives as IDO1 and/or TDO inhibitors, and can solve the problems of T cells being difficult to reactivate, unable to pass through, and depleted of the substrate tryptophan

Active Publication Date: 2020-01-14
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The overexpression of IDO1 can cause the depletion of the substrate tryptophan, so that the proliferation of T cells that are extremely sensitive to tryptophan deficiency stays in the G1 phase and can

Method used

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  • Use of naphthoquinone derivative as inhibitor for IDO1 and/or TDO
  • Use of naphthoquinone derivative as inhibitor for IDO1 and/or TDO
  • Use of naphthoquinone derivative as inhibitor for IDO1 and/or TDO

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] Synthesis of 2-(2-chlorophenyl)-1H-naphthalene[2,3-d]imidazole-4,9-dione (NQ-1-1)

[0105]

[0106] The compound 2,3-diamine-1,4-naphthoquinone (1mmol) was dissolved in DMF (10ml), and 2-chlorobenzaldehyde (1mmol) and sodium metabisulfite (1mmol) were added sequentially, and the reaction solution was stirred at 120°C for 8h After the completion of the reaction detected by TLC, the solvent was distilled off under reduced pressure to obtain a yellow viscous substance. After stirring and mixing the sample through silica gel, the silica gel column chromatography (dichloromethane: methanol = 60:1) separated to obtain a yellow solid. The yield was 82. %. 1 H NMR(400MHz,DMSO-d6)δ14.37(s,1H), 8.10(dd,J=6.1,3.0Hz,2H), 7.85 (dd,J=6.1,3.0Hz,2H), 7.79(d, J=7.5Hz, 1H), 7.67(d, J=7.5Hz, 1H), 7.59(t, J=7.5Hz 1H), 7.53(t, J=7.5Hz, 1H); 13 C NMR (101MHz, DMSO) δ 150.83, 134.39, 133.17, 132.65, 132.56, 132.37, 130.72, 129.09, 127.85, 126.80. HR-ESI-MS: C 17 H 9 ClN 2 O 2 Theoretical value: ...

Embodiment 2

[0108] Synthesis of 2-(3-chlorophenyl)-1H-naphthalene[2,3-d]imidazole-4,9-dione (NQ-1-2)

[0109]

[0110] Using 3-chlorobenzaldehyde instead of 2-chlorobenzaldehyde, the preparation method is the same as NQ-1-1. Brown solid, yield 86%. 1 HNMR(400MHz,DMSO-d6)δ14.52(s,1H), 8.32(dd,J=1.7Hz,1.2Hz, 1H), 8.21(ddd,J=5.0,3.5,1.7Hz,1H),8.13( dd, J = 5.7, 3.3 Hz, 2H), 7.87 (dd, J = 5.7, 3.3 Hz, 2H), 7.63-7.58 (m, 2H); 13 C NMR (101MHz, DMSO) δ151.18, 134.32, 134.24, 133.15, 131.36, 130.92, 130.65, 126.78, 126.73, 125.78. HR-ESI-MS: C 17 H 9 ClN 2 O 2 Theoretical value: 309.0425[M+H] + , Measured value: 309.0411.

Embodiment 3

[0112] Synthesis of 2-(4-chlorophenyl)-1H-naphthalene[2,3-d]o-4,9-dione (NQ-1-3)

[0113]

[0114] Use 4-chlorobenzaldehyde instead of 2-chlorobenzaldehyde, and the preparation method is the same as NQ-1-1. Yellow solid, the yield is 80%. 1 HNMR(400MHz,DMSO-d6)δ14.45(s,1H), 8.23(d,J=8.3Hz,2H), 8.09(dd,J=5.7,3.3Hz,2H),7.84(dd,J=5.8 ,3.3Hz,2H),7.62(d,J=8.4Hz, 2H).

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PUM

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Abstract

The invention discloses a use of a naphthoquinone derivative as an inhibitor for IDO1 and/or TDO. The derivative is shown as a general formula (I), and the definition of each substituent is detailed in the specification. The compound represented by the general formula (I) has an inhibitory effect on indoleamine-2,3-dioxygenase 1 (IDO1) and/or tryptophan-2,3-dioxygenase (TDO), and can be used for treating diseases with IDO1- and/or TDO-mediated tryptophan metabolism as pathological features, including but not limited to tumors, autoimmune diseases, infectious diseases, Alzheimer's disease, depression, and anxiety disorder.

Description

Technical field [0001] The present invention relates to the field of medicinal chemistry, and more specifically to the use of a naphthoquinone derivative as a key enzyme in the metabolism of tryptophan along the kynuric acid pathway—IDO1 and / or TDO, to treat IDO1 and / or TDO-mediated Tryptophan metabolism is pathologically characterized diseases, including but not limited to tumors, autoimmune diseases, allergic diseases, infectious diseases, Alzheimer's disease, Parkinson's disease, schizophrenia, epilepsy, depression, Anxiety disorders, cataracts. Background technique [0002] Indoleamine-2,3-dioxygenase 1 (IDO1 for short) is an immunomodulatory enzyme located in the cytoplasm. It was first discovered in the small intestine of rabbits in 1967 [Yamamoto S, The Journal of Biological Chemistry, 1967, 242(22):5260-5266], widely distributed in various tissues and cells other than the liver of mammals, mainly found in the thymic medulla and secondary lymphoid organs, and scattered in...

Claims

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Application Information

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IPC IPC(8): A61K31/4184A61K31/4439A61K31/427A61K31/4709A61K31/506A61K31/437A61K31/343C07D235/02C07D401/04C07D417/04C07D403/04C07D409/04C07D277/84C07D471/04C07D513/04C07D417/14C07D307/92A61P35/00A61P37/06A61P37/08A61P31/04A61P31/12A61P25/28A61P25/16A61P25/18A61P25/22A61P25/24A61P25/08A61P27/12
CPCA61K31/4184A61K31/4439A61K31/427A61K31/4709A61K31/506A61K31/437A61K31/343C07D235/02C07D401/04C07D417/04C07D403/04C07D409/04C07D277/84C07D471/04C07D513/04C07D417/14C07D307/92A61P35/00A61P37/06A61P37/08A61P31/04A61P31/12A61P25/28A61P25/16A61P25/18A61P25/22A61P25/24A61P25/08A61P27/12
Inventor 孟祥豹潘良坤郑强陈宇李中军
Owner PEKING UNIV
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