Tryptanthrin derivatives and application thereof

A compound and mixture technology, applied in the field of medicine, can solve problems such as T-cell activation signal transduction blockage, achieve good therapeutic effect, broad application prospects, and inhibit cell proliferation

Inactive Publication Date: 2019-07-02
SHANGHAI SHENGYUE PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, a large number of studies have shown that IDO is highly expressed in leukemia cells, which inhibits the proliferation of local T cells, inhibits the immune response mediated by T-cells, and blocks the transduction of T-cell activation signals, thereby mediating the escape of tumor cells from the immune system. attack

Method used

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  • Tryptanthrin derivatives and application thereof
  • Tryptanthrin derivatives and application thereof
  • Tryptanthrin derivatives and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1 Synthesis of 8-nitropyrido[3',2':4,5]pyrimido[1,2-a]indole-6,12-dione

[0041]

[0042] 5-Nitroindole-2,3-dione (192mg, 1mmol) and 1,8-diazabicycloundec-7-ene (304mg, 2mmol) were dissolved in N,N-dimethyl Formamide (1 mL), stirred at room temperature for ten minutes. Dissolve 3-aminopyridine-2-carboxylic acid (138mg, 1mmol), N-methylmorpholine (202mg, 2mmol), O-benzotriazole-tetramethyluronium hexafluorophosphate (380mg, 1mmol) in In N,N-dimethylformamide (2 mL), the reacted solution of isatin and DBU was added dropwise to the solution, and stirred at room temperature for 20 hours. The solvent was evaporated to dryness and separated by column chromatography (dichloromethane:methanol=80:1) to obtain an orange-yellow solid (400mg, 67%) which was 8-nitropyrido[3',2':4,5]pyrimido [1,2-a]indole-6,12-dione (Compound 3).

[0043] LC-MS: 295[M+H] +

Embodiment 2

[0044] Example 2 Synthesis of 8-nitropyrimido[5',4':4,5]pyrimido[1,2-a]indole-6,12-dione

[0045]

[0046] 5-Nitroindole-2,3-dione (192mg, 1mmol) and 1,8-diazabicycloundec-7-ene (304mg, 2mmol) were dissolved in N,N-dimethyl Formamide (1 mL), stirred at room temperature for ten minutes. Dissolve 5-aminopyrimidine-4-carboxylic acid (138mg, 1mmol), N-methylmorpholine (202mg, 2mmol), O-benzotriazole-tetramethyluronium hexafluorophosphate (380mg, 1mmol) in In N,N-dimethylformamide (2 mL), the reacted solution of isatin and DBU was added dropwise to the solution, and stirred at room temperature for 20 hours. The solvent was evaporated to dryness and separated by column chromatography (dichloromethane:methanol=80:1) to obtain an orange-yellow solid (403mg, 67%) which was 8-nitropyrimido[5',4':4,5]pyrimido [1,2-a]indole-6,12-dione (Compound 5).

[0047] LC-MS: 296[M+H] +

Embodiment 3

[0048] Example 3 Synthesis of 8-nitroindole [2,1-b] pteridine-6,12-dione

[0049]

[0050] 5-Nitroindole-2,3-dione (192mg, 1mmol) and 1,8-diazabicycloundec-7-ene (304mg, 2mmol) were dissolved in N,N-dimethyl Formamide (1 mL), stirred at room temperature for ten minutes. Dissolve 3-aminopyrazine-2-carboxylic acid (139mg, 1mmol), N-methylmorpholine (202mg, 2mmol), O-benzotriazole-tetramethyluronium hexafluorophosphate (380mg, 1mmol) In N,N-dimethylformamide (2 mL), the reacted solution of isatin and DBU was added dropwise to the solution, and stirred at room temperature for 20 hours. The solvent was evaporated to dryness and separated by column chromatography (dichloromethane:methanol=80:1) to obtain an orange-yellow solid (412mg, 69%) which was 8-nitroindole[2,1-b]pteridine-6,12 - diketones (compound 7).

[0051] LC-MS: 296[M+H] +

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Abstract

The invention discloses compounds represented by a general formula (I) shown in the description, wherein in the formula (I), A and B are respectively a six-membered cyclic compound containing D1, D2,D3 and D4 and a six-membered cyclic compound containing D5, D6, D7 and D8. The invention also disclose an indoleamine-2,3-dioxygenase and/or tryptophan-2,3-dioxygenase inhibitor containing the above compounds and the application of the compounds in preparation of medicaments for treating cancers. The compounds provided by the invention can effectively inhibit cell proliferation, and have good therapeutic effects on various diseases such as the cancers, significant therapeutic effects on breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer,brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumors, ovarian tumors, peritoneal tumors, stage IV melanoma, glioma, neuroblastoma, hepatocellular carcinoma, mastoid renal tumors, head and neck tumors, leukemia, lymphoma, myeloma and non-small cell lung cancers, and very broad application prospects.

Description

technical field [0001] The present invention relates to the technical field of medicine, in particular to an indoleamine-2,3-dioxygenase (IDO) inhibitor and / or tryptophan-2,3-dioxygenase (TDO) inhibitor Tryptanthrin derivatives and uses thereof. Background technique [0002] Tryptophan is an essential amino acid for the human body and is metabolized through the kynurenic acid pathway. Its metabolites are immunosuppressive and play a key role in tumor suppression escape. The study found that indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) are the rate-limiting enzymes in this metabolic process. [0003] Indoleamine-2,3-dioxygenase (Indoleamine-2,3-dioxygenase, ID0) was first discovered in cells by the Hayaishi group in 1967. It is a monomeric enzyme containing heme, cDNA encoding protein Composed of 403 amino acids, including IDO1, IDO2. Munn and Mellor first proposed in Science in 1998 that IDO1 plays an immunomodulatory protective role in infants ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/14C07D487/14C07D487/04C07D471/22A61K31/519A61K31/5377A61P35/00A61P25/28A61P37/02A61P35/02A61P25/22A61P25/24A61P27/12A61P31/18A61P25/00
CPCC07D471/14C07D487/14C07D487/04C07D471/22
Inventor 孙芳占有妮
Owner SHANGHAI SHENGYUE PHARM TECH CO LTD
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