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N-containing bis-heterocyclic amide compounds and their application as immunosuppressants

A technology of heterocyclic amides and compounds, which is applied in the field of medical immunology, can solve problems such as poor targeting, and achieve the effect of simple preparation method, simple structure and small molecular weight

Active Publication Date: 2017-06-16
CHONGQING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The advantage of mTOR inhibitors is very strong activity; the disadvantage is poor targeting

Method used

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  • N-containing bis-heterocyclic amide compounds and their application as immunosuppressants
  • N-containing bis-heterocyclic amide compounds and their application as immunosuppressants
  • N-containing bis-heterocyclic amide compounds and their application as immunosuppressants

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Example 1: Preparation of 3-(2,6-dichlorophenyl)-5-methyl-N-2-(6-methanesulfonylbenzothiazolyl)isoxazole-4-carboxamide:

[0036] Under anhydrous and oxygen-free conditions (argon protection), 0.347 g (1.2 mmol) of 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbonyl chloride (product 2) was dissolved in in 4 mL of dry dichloromethane and placed in a pre-dried constant pressure funnel. A dry 50mL three-neck round bottom flask was added with 0.212g (1mmol) of 2-amino-6-methylsulfonylbenzothiazole, followed by 5mL of anhydrous dichloromethane and 1mL of anhydrous N,N-dimethylmethane Amide (DMF) was dissolved as a reaction solubilizer, and 0.25 mL of anhydrous triethylamine was used as an acid binding agent. A solution of 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbonyl chloride in 4 mL of dichloromethane was added dropwise to a round bottom flask placed in a cryogenic reactor. The temperature was kept at 40-45°C, and after the dropwise addition was completed, the react...

Embodiment 2

[0037] Example 2: Preparation of 3-(2,6-dichlorophenyl)-5-methyl-N-[2-(6-ethylbenzothiazole)isoxazole]-4-carboxamide:

[0038] Under anhydrous and oxygen-free conditions (argon protection), 0.178g (1mmol) of 2-amino-6-ethylbenzothiazole was placed in a three-neck round bottom flask, and 5mL of anhydrous dichloroethane and 1mL of Anhydrous DMF was used as the reaction solvent, and 0.25 ml of anhydrous triethylamine was used as the acid binding agent. The mixture was mixed at a low temperature and cooled to 0° C. and kept for 15 minutes. A solution of 0.347 g (1.2 mmol) of 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbonyl chloride in dichloromethane was added dropwise to the reaction system. After stirring at low temperature for 30 minutes, it was transferred to an oil bath at 60° C. to react for 18 hours. The solution changed from yellow to tan. The progress of the reaction was monitored by thin layer chromatography (developing solvent petroleum ether:ethyl acetate=1:5). A...

Embodiment 3

[0041] Example 3: CCK-8 method compound 4a, i.e. 3-(2,6-dichlorophenyl)-5-methyl-N-2-(6-methanesulfonylbenzothiazolyl)isoxazole-4 - Inhibition experiment of formamide on Jurkat cells.

[0042] For Jurkat cells in log phase condition, the supernatant was discarded after centrifugation, and 1 ml of fresh 10% FBS RPMI-1640 complete culture medium was added to gently pipet the cells to avoid air bubbles to prepare a single cell suspension. Count the cells, dilute the cell suspension in proportion to make the cell density reach 6×105 cells / ml, and mix well. Plating: First, add 100 μL of PBS to 36 wells around the experimental wells of a 96-well cell culture plate. Starting from the B2 hole of the culture plate, 50 μL of cell suspension was added to the experimental wells in turn, and then 200 mmol / L, 100 mmol / L, 50 mmol / L, 25 mmol / L, 12.5 mmol / L and 2 mmol were added to each experimental well. / L, 1mmol / L, 500mmol / L, 250nmol / L, 125nmol / L of the drug solution containing N-heterocy...

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Abstract

The invention discloses novel N-containing biheterocyclic acylamide compounds and a preparation method as well as application of the compounds in immunology and particularly relates to the N-containing biheterocyclic acylamide compounds shown in a general formula (I). The compounds have an obvious inhibiting effect on a cell strain Jurkat cell of acute T lymphocytic leukemia and can be applied to treatment of autoimmune diseases and graft rejection. The formula is shown in the specification.

Description

technical field [0001] The present invention relates to a class of N-containing biheterocyclic amide compounds, corresponding preparation methods, inhibitory activity on PI3K receptors and mTOR receptors in the immune system, and application of such N-containing biheterocyclic amide compounds in immunosuppressants , belonging to the field of medical immunology. Background technique [0002] Immunity refers to the property of protecting the body from external aggressions. Substances from inside and outside the body that cannot be recognized by the immune system can easily cause the body's own defense response - immune response. Immune regulation is out of balance, and immune cells such as T cells and B cells are excessively proliferated or immunoglobulins are excessively accumulated during the response process, often causing autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, skin fungal disease, membranous glomerulonephritis , inflammatory bowel disease ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/12A61P37/02A61P37/06A61P3/10A61P29/00A61P19/02A61P37/08A61P13/12A61P7/06
CPCC07D413/12C07D417/12
Inventor 林治华常自超王锐安春红杨文娟舒茂王远强
Owner CHONGQING UNIV OF TECH
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