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Application of azatryptanthrin derivatives as IDO1 (indoleamine 2,3-dioxygenase) and/or TDO (tryptophan 2,3-dioxygenase) inhibitors

A technology of zatryptanthin and its derivatives, which is applied in the field of use of azatryptanthin derivatives as IDO1 and/or TDO inhibitors, and can solve problems such as not being involved and showing no activity

Active Publication Date: 2017-10-20
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this patent does not involve IDO1 and TDO targets, and the research results also show that the introduction of nitrogen atoms in the benzene ring has no direct relationship with the activity, and 8-nitro-1-azapyptanthin has no effect when the concentration is as high as 20 μM. show activity

Method used

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  • Application of azatryptanthrin derivatives as IDO1 (indoleamine 2,3-dioxygenase) and/or TDO (tryptophan 2,3-dioxygenase) inhibitors
  • Application of azatryptanthrin derivatives as IDO1 (indoleamine 2,3-dioxygenase) and/or TDO (tryptophan 2,3-dioxygenase) inhibitors
  • Application of azatryptanthrin derivatives as IDO1 (indoleamine 2,3-dioxygenase) and/or TDO (tryptophan 2,3-dioxygenase) inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0155] Compound CY-1-1: Pyrido[2',3':4,5]pyrimido[1,2-α]indole-5,11-dione

[0156]

[0157] Isatin (0.9mmol) and DBU (2mmol) were dissolved in DMF (3ml) and stirred at room temperature for ten minutes. Dissolve 2-aminonicotinic acid (1mmol), N-methylmorpholine (1.8mmol), and HBTU (1mmol) in DMF (3ml), and add the reacted isatin and DBU solution dropwise into the solution. Stir for 20 h, monitor by TLC. After the reaction is complete, evaporate the solvent to dryness, and separate by column chromatography (dichloromethane:methanol=80:1) to obtain an orange-yellow solid with a yield of 59%. 1 H NMR (400MHz, DMSO-d 6 )δ9.08(dd, J=4.6,2.0Hz,1H),8.71(dd,J=7.9,2.0Hz,1H),8.45(d,J=8.0Hz,1H),7.90(t,J=7.9 , 4.4Hz, 2H), 7.75 (dd, J = 7.9, 4.6Hz, 1H), 7.51 (t, J = 7.6, 0.7Hz, 1H). 13 C NMR (101MHz, DMSO-d 6 )δ 182.28, 158.08, 157.20, 156.11, 147.63, 145.70, 137.90, 136.30, 127.23, 124.92, 124.70, 122.14, 119.17, 116.89.

Embodiment 2

[0159] Compound CY-1-2: 9-fluoropyrido[2',3':4,5]pyrimido[1,2-α]indole-5,11-dione

[0160]

[0161] Using 5-fluoroisatin instead of isatin, the preparation method is the same as that of CY-1-1 in Example 1. The product was a yellow solid with a yield of 51%. 1 H NMR (400MHz, DMSO-d 6 )δ9.07(s,1H),8.69(d,J=6.4Hz,1H),8.44(d,J=4.7Hz,1H),7.83(d,J=4.5Hz,1H),7.75(d, J=7.5Hz, 2H). 13 C NMR (101MHz, DMSO-d 6 )δ 181.85, 160.13, 158.53, 157.46, 156.72, 142.41, 136.83, 125.34, 124.62, 124.34, 119.54, 119.23, 112.48, 112.18.

Embodiment 3

[0163] Compound CY-1-3: 9-(trifluoromethoxy)pyrido[2',3':4,5]pyrimido[1,2-α]indole-5,11-dione

[0164]

[0165] Using 5-trifluoromethoxy isatin instead of isatin, the preparation method is the same as that of CY-1-1 in Example 1. The product was a light yellow solid with a yield of 29%. 1 H NMR (400MHz, DMSO-d 6 )δ9.09(d, J=3.7Hz, 1H), 8.71(d, J=7.7Hz, 1H), 8.54(d, J=8.7Hz, 1H), 7.97(s, 1H), 7.92(d, J=8.7Hz, 1H), 7.77 (dd, J=7.7, 4.6Hz, 1H). 13 C NMR (101MHz, DMSO-d 6 )δ 181.56, 158.48, 157.55, 156.84, 148.22, 146.96, 144.61, 136.89, 130.69, 125.40, 124.39, 121.75, 119.46, 119.19, 119.06, 118.38.

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Abstract

The invention discloses an application of azatryptanthrin derivatives as IDO1 (indoleamine 2,3-dioxygenase) and / or TDO (tryptophan 2,3-dioxygenase) inhibitors. The structure of the derivatives is shown as the general formula (I) in the description, wherein substituents are defined in detail in the description. The compounds shown as the general formula (I) have an inhibition effect on IDO1 and / or TDO and can be used for treating diseases having pathological characteristics of IDO1 and / or TDO mediated tryptophan metabolism, and the diseases include but are not limited to tumors, autoimmune diseases, infectious diseases, Alzheimer disease, depression and anxiety disorder.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, and more specifically relates to the use of an azatryptophan derivative as an inhibitor of tryptophan metabolism key enzymes along the kynuric acid pathway—IDO1 and / or TDO, for the treatment of IDO1 and / or TDO. Diseases with pathological features of TDO-mediated tryptophan metabolism, including but not limited to tumors, autoimmune diseases, infectious diseases, Alzheimer's disease, depression, anxiety. Background technique [0002] As an essential amino acid in the human body, tryptophan can only be ingested through diet, and the content in the body is relatively small. The concentration of tryptophan in adult plasma is about 40-80μM, and about 95% of tryptophan is metabolized through the kynuric acid pathway[ Armstrong, M.D. and Stave, U. Metabolism. 1973, 22, 561–569.]. Metabolites of this pathway are immunosuppressive and play a key role in tumor immune escape. The first tryptopha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/519A61P35/00A61P31/00A61P37/06A61P25/28A61P25/24A61P25/22C07D471/14C07D471/22
CPCA61K31/519C07D471/14C07D471/22A61P35/00
Inventor 孟祥豹陈宇李中军张美琪
Owner PEKING UNIV
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