Novel pyrimidine-fused cyclic compounds as cytokine inhibitors

A compound, solvate technology, applied in a series of diseases, alleviating and controlling various diseases, treatment, prevention field, able to solve problems such as immune system errors

Active Publication Date: 2012-09-26
CHANGCHUN DISCOVERY SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the immune system may mistakenly launch an attack on its own body tissues for as yet unidentified triggers

Method used

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  • Novel pyrimidine-fused cyclic compounds as cytokine inhibitors
  • Novel pyrimidine-fused cyclic compounds as cytokine inhibitors
  • Novel pyrimidine-fused cyclic compounds as cytokine inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0289] Example 1: Pyrimido[4,5-b][1,4]benzothiazepine Synthesis of derivatives Synthesis experimental steps:

[0290]

[0291] The synthesis of precursor material 1 refers to published papers and patents (Bai, X. et, al. J. Org. Chem., 2005, 70, 10810. and PCT / US2006 / 006303).

[0292] pyrimido[4,5-b][1,4]benzothiazepine Synthesis of sulfoxide:

[0293]

[0294] 4-phenylthio-6-phenylpyrimido[4,5-b][1,4]benzothiazepine 1.0 (1.0mmol) dissolved in CH 2 Cl 2 (10mL), under magnetic stirring at room temperature, slowly drop m-CPBA (2.2mmol) in CH 2 Cl 2 (15mL) solution, used for 1 hour, continued to react for 3 hours after dripping. The reaction solution was sequentially washed with saturated NaHSO 3 , saturated Na 2 CO 3 Wash with saturated NaCl solution, Na 2 SO 4 Drying, evaporation of the solvent under reduced pressure, separation on a silica gel column (petroleum ether / ethyl acetate=5:1, v / v) gave 4-phenylsulfinyl-6-phenylpyrimido[4,5-b][1 , 4] benzothiazep...

Embodiment 2

[0357] Example 2: p38 Kinase Inhibition - In Vitro Assay

[0358] Experimental method: Kinase assay adopts the SelectScreen of Invitrogen Corporation (501 Charmany Drive, Madison, Wisconsin, 53719) TM Kinase Profiling Service conducted. The specific experimental steps are as follows: the compound is dissolved in DMSO to prepare a 100x mother solution. Then with kinase buffer (50mM HEPES, pH 7.5, 0.01% BRIJ-35, 10mM MgCl 2 , 1mM EGTA) to make a 4x working solution, take 2.5μL and add it to a 384-well plate, set up a 0 inhibition control and a 100% inhibition control, and then add 5μL to the well to prepare 2x MAPK14(p38α), inactivation MAPKAPK2 and Ser / Thr04 peptide mixture, and then add 2.5μL of 4x ATP solution diluted with kinase buffer to each well to form a 10μL reaction system, shake the plate for 30s, and incubate at room temperature for 1h; then add 5μL of developing solution (1:1024 dilution), shake the plate for 30s, incubate at room temperature for 1h, detect and ...

Embodiment 3

[0361] Example 3: Cell model inhibits p38α phosphorylation test

[0362] Cells used in the experiment: MM1S cell line, U266 cell line

[0363] Test method: MM1S cell line and U266 cell line are both at 37°C, 5% CO 2 1640 medium was used for cultivation under the conditions, and 1640 medium contained 10% calf serum, 1% double antibody, and 1% L-glutamine. Dissolve compound 2.3.2 in DMSO to make a solution with a concentration of 10 mM, and use 1640 medium to prepare a solution with a concentration of 10 μM, which acts on MM1S cells and U266 cells respectively. Separately set up a solvent group and a control group, at 37 ° C, 5% CO 2 Cultivate in the incubator for 3 hours, collect the cells, extract the protein, and detect the effect of the compound on p38α phosphorylation by Western blot kit (Cell Signaling Antibody, cat.#9211); at the same time, compound 2.3.2 was formulated into 10 μM, 1 μM, 0.1 μM , 0.01 μM and other different concentrations (the content of DMSO is 0.2%),...

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Abstract

The invention provides novel pyrimidine-fused cyclic compounds with low molecular weights and compositions thereof as cytokine inhibitors. In particular, the compounds summarized in the invention can be used as anti-inflammatory agents. The invention further provides a method for preparing this kind of medicaments and an application of the medicaments in preventing or treating diseases mediated by cytokines. The diseases comprise arthritis, aches, angiocardiopathy, and cancers.

Description

technical field [0001] The present invention relates to novel low molecular weight pyrimidocyclic compounds useful as cytokine inhibitors, compositions thereof, and their preparation. The present invention also relates to methods of treating, preventing, alleviating and controlling various diseases, including cytokine-mediated and disorder-related diseases, including administration of cytokine inhibitors, alone or in combination with known therapies. The present invention also relates to the medicament prepared by using these compounds, the dosage and its application in treating a series of diseases such as autoimmune disease, inflammation, cardiovascular disease and cancer. These preparations can also be used concurrently with other treatments to achieve a therapeutic effect. Background technique [0002] The delicate balance of immune system function is controlled by the activity of pro-inflammatory and anti-inflammatory mediators, or cytokines. Some cytokines promote in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/04A61K31/554A61P19/02A61P1/04A61P17/06A61P37/06A61P37/02A61P39/02A61P1/00A61P21/00A61P1/18A61P13/12A61P19/06A61P29/00A61P15/00A61P25/00A61P9/04A61P7/06A61P9/10A61P9/14A61P3/06A61P7/04A61P27/06A61P27/02A61P11/02A61P11/06A61P11/16A61P11/00A61P17/00A61P25/16A61P25/28A61P31/12A61P25/08A61P31/18A61P3/10A61P3/00A61P25/30A61P25/24A61P25/22A61P25/18A61P35/00A61P43/00A61P3/04A61P19/10A61P19/00A61P7/00A61P31/14A61P33/06A61P35/02
CPCY02A50/30
Inventor 柏旭项金宝裴亚中
Owner CHANGCHUN DISCOVERY SCI
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