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Small molecule compound having an IDO1/TDO double target, preparation method and applications thereof

A small molecule compound, IDO1 technology, applied in the fields of medical preparations containing active ingredients, organic chemistry, organic active ingredients, etc., can solve the problem of no relevant articles reported, no IDO1/TDO dual target small molecule compounds have been found, etc. Achieve the effect of reducing immune evasion, good application prospects, and low energy consumption

Active Publication Date: 2019-02-01
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are no relevant reports on small molecule compounds with dual targets of IDO1 and TDO. Therefore, there is an urgent need for a small molecule compound that can simultaneously inhibit the activity of IDO1 and TDO to reduce the immune evasion of tumor cells, and then through immunotherapy to achieve Curing of Tumor Diseases
[0006] IDO1 / TDO dual-target small molecule compounds have good application prospects as drugs in the pharmaceutical industry, but so far no good IDO1 / TDO dual-target small molecule compounds have been found as marketed drugs

Method used

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  • Small molecule compound having an IDO1/TDO double target, preparation method and applications thereof
  • Small molecule compound having an IDO1/TDO double target, preparation method and applications thereof
  • Small molecule compound having an IDO1/TDO double target, preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Compound 1: 1-Phenyl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione

[0050] Use raw material A as (raw material A1), raw material B is (raw material B1).

[0051] The synthetic route is as follows:

[0052]

[0053] The specific synthesis method is:

[0054] (1) Add raw material A1 (1 g, 6.85 mmol) and strong base potassium tert-butoxide (3.84 g, 34.25 mmol) into 12 mL of anhydrous tert-butanol solvent, then stir for 2 h at room temperature under an oxygen atmosphere of 1 atm. After the reaction, dilute hydrochloric acid was added to the reaction system to adjust the pH to 1-2, a yellow solid precipitated in the reaction system, and the intermediate I was obtained by suction filtration 1 , the reaction yield was 50%. Intermediate I 1 It can be directly used in the next reaction without further purification.

[0055] (2) Add raw material B1 (1g, 10.75mmol) and 20mL of acetonitrile into a 100mL round bottom flask and stir to dissolve at 0°C, then add t-BuONO (2.9...

Embodiment 2

[0060] In this embodiment, on the basis of the above-mentioned compounds, the raw material B was replaced, as follows:

[0061] Compound 2:

[0062] Use raw material A as (raw material A1), raw material B is (raw material B2)

[0063] The synthetic route is as follows:

[0064]

[0065] The specific preparation method is the same as the above-mentioned embodiment, and will not be repeated here.

[0066] The yield of compound 2 was 88%.

[0067] That 1 H NMR data are as follows:

[0068] 1 H NMR (400MHz, DMSO-d 6 )δ8.25(dd, J=7.3,1.6Hz,1H),8.13(dd,J=7.3,1.7Hz,1H),8.01–7.92(m,2H),7.92–7.85(m,2H),7.54 (t,J=8.8Hz,2H).ESI-MS m / z:296.08[M+H] + .

Embodiment 3

[0070]In this embodiment, on the basis of the above-mentioned compounds, the raw material B was replaced, as follows:

[0071] Compound 3:

[0072] Use raw material A as (raw material A1), raw material B is (Raw material B3)

[0073] The synthetic route is as follows:

[0074]

[0075] The specific preparation method is the same as the above-mentioned embodiment, and will not be repeated here.

[0076] The yield of compound 3 was 86%.

[0077] That 1 H NMR data are as follows:

[0078] 1 H NMR (400MHz, DMSO-d 6 )δ8.25(dd, J=7.3,1.7Hz,1H),8.15(dd,J=7.2,1.7Hz,1H),8.03–7.93(m,3H),7.86–7.76(m,2H),7.73 (dd,J=17.8,9.9Hz,1H).ESI-MS m / z:312.05[M+H]+.

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Abstract

The invention belongs to the field of chemical medicine, and particularly relates to a small molecule compound having an IDO1 / TDO double target, wherein the general formula is defined in the specification. According to the present invention, the embodiment schemes prove that the small molecule compound can simultaneously inhibit two enzymes IDO1 and TDO so as to reduce the immune evasion of tumorcells, achieve self-cure of tumor diseases, achieve good medicinal potential and provides new potential choice for clinical medication; the preparation method has characteristics of simpleness, mild reaction condition, convenient operation, convenient control, low energy consumption, high yield and low cost, and is suitable for industrial production; and the prepared compound has advantages of high biological activity, strong selectivity to tumor cells, remarkable drug-like properties, and good application prospects in the pharmaceutical industry.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis of medicines, specifically a small molecular compound with IDO1 / TDO dual targets and its preparation method and application. Background technique [0002] Tumor immunotherapy is an important research direction today, including some clinically successful immune checkpoint compounds, such as Keytrude (PD-1) (Cancer, 2015,3,36.), Opdivo (PD-1 / PD -L1)(NEngl J Med.,2012,366,2455–2465.; N Engl J Med.,2012,366,2443–2454.) and Yervoy(CTLA-4)(J Clin Oncol.,2010,28, 3167–3175.), etc. With the in-depth study of tumor diseases, studies have found that there are other immune checkpoints in the tumor microenvironment. By adjusting the functions of these immune checkpoints, the tumor microenvironment can be improved accordingly, and then the immunotherapy of tumors can be realized. [0003] Tryptophan is an amino acid that is essential to the human body and cannot be synthesized in the human body. I...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/16C07D401/04C07D403/04C07D403/10A61K31/4192A61K31/4439A61K31/4725A61K31/496A61P35/00
CPCA61P35/00C07D249/16C07D401/04C07D403/04C07D403/10
Inventor 杨胜勇李琳丽
Owner SICHUAN UNIV
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