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N-containing biheterocyclic acylamide compounds as well as application thereof as immunosuppressor

A technology of heterocyclic amides and compounds, applied in the field of medical immunology, can solve problems such as poor targeting, and achieve simple preparation methods, small molecular weight, and significant application effects

Active Publication Date: 2015-02-18
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 biheterocyclic acylamide compounds as well as application thereof as immunosuppressor
  • N-containing biheterocyclic acylamide compounds as well as application thereof as immunosuppressor
  • N-containing biheterocyclic acylamide compounds as well as application thereof as immunosuppressor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1: Preparation of 3-(2,6-dichlorophenyl)-5-methyl-N-2-(6-methylsulfonylbenzothiazolyl)isoxazole-4-carboxamide :

[0042] 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 4 mL of anhydrous dichloromethane and place it in a pre-dried constant pressure funnel. Add 0.212 g (1 mmol) of 2-amino-6-thiamphenicol benzothiazole to a dry 50 mL three-neck round bottom flask, and add 5 mL of anhydrous dichloromethane and 1 mL of anhydrous N,N-di Methylformamide (DMF) was dissolved as a reaction solubilizer, and 0.25 mL of anhydrous triethylamine was used as an acid-binding agent. Add dropwise 4 mL of dichloromethane solution in which 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbonyl chloride was dissolved in a round-bottomed flask placed in a low-temperature reactor . Keep the temperature at 40~45 o C. After the dropwise addition was completed...

Embodiment 2

[0043] Example 2: Preparation of 3-(2,6-dichlorophenyl)-5-methyl-N-[2-(6-ethylbenzothiazole)isoxazole]-4-formamide:

[0044] Under anhydrous and oxygen-free conditions (argon protection), take 0.178 g (1 mmol) of 2-amino-6-ethylbenzothiazole in a three-necked round-bottomed flask, add 5 mL of anhydrous dichloroethane and 1 mL of anhydrous DMF was used as the reaction solvent, 0.25 ml of anhydrous triethylamine was used as an acid-binding agent, mixed at low temperature and cooled to 0 o C, and keep for 15 minutes. A dichloromethane solution of 0.347 g (1.2 mmol) of 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbonyl chloride was added dropwise to the reaction system. After stirring at low temperature for 30 minutes, transfer to the oil bath 60 o C was reacted for 18 hours. The solution turned from yellow to tan. The progress of the reaction was monitored by thin-layer chromatography (petroleum ether: ethyl acetate = 1:5). After the reaction was completed, 30 mL of ice w...

Embodiment 3

[0047] Example 3: CCK-8 method compound 4a, namely 3-(2,6-dichlorophenyl)-5-methyl-N-2-(6-methylsulfonylbenzothiazolyl)isoxazole-4-carboxamide Inhibition assay of Jurkat cells.

[0048] For Jurkat cells in good logarithmic phase, discard the supernatant after centrifugation, add 1ml of fresh 10% FBS RPMI-1640 complete culture solution, and gently blow the cells to avoid the generation of air bubbles, and prepare a single-cell suspension. For cell counting, 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 the 36 wells around the experimental wells of the 96-well cell culture plate. Starting from well B2 of the culture plate, add 50 μL of cell suspension to the experimental wells in turn, and then add 200 mmol / L, 100 mmol / L, 50 mmol / L, 25 mmol / L, and 12.5 mmol to each experimental well in turn. / L, 2 mmol / L, 1 mmol / L, 500 mmol / L, 250 nmol / L, 125 nmol / L drug solutions containing N-contai...

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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. [0002] Background technique [0003] 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. The imbalance of immune regulation, excessive proliferation of immune cells such as T cells and B cells or excessive accumulation of immunoglobulins during the response process often lead to autoimmune diseases such as rheumatoid arthritis , lupus erythematosus, dermatophytosis, membranous glomerulus Nephritis , inflammatory bowel disease...

Claims

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Application Information

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Patent Type & Authority Applications(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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