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Method for preparing AS-605240 and application thereof on preparing medicines for treating inflammatory diseases

A technology of AS-605240 and reaction, applied in the direction of drug combination, medical preparations containing active ingredients, antipyretics, etc., can solve problems such as difficult to achieve, unfriendly environment, and difficult to obtain 6-quinoxaline carboxylic acid , to achieve the effect of mild reaction conditions and good curative effect

Inactive Publication Date: 2009-10-07
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The shortcoming of this method is that raw material 6-quinoxaline carboxylic acid is not easy to get, and the first step reaction needs to use unfriendly thionyl chloride (SOCl 2 ); the second step reaction requires the use of expensive tri-tert-butyl lithium aluminum hydride3 .>, and the reaction is carried out at a low temperature that is difficult to achieve, and it is not easy to achieve large-scale preparation

Method used

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  • Method for preparing AS-605240 and application thereof on preparing medicines for treating inflammatory diseases
  • Method for preparing AS-605240 and application thereof on preparing medicines for treating inflammatory diseases
  • Method for preparing AS-605240 and application thereof on preparing medicines for treating inflammatory diseases

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054]

[0055] This method consists of the following four steps:

[0056] A) 6.1 grams of 3,4-diaminotoluene (1), 14.5 grams of 40% aqueous solution of glyoxal (2) and 5.3 grams of sodium carbonate (Na 2 CO 3 ) was reacted at 100°C for 2 hours; after being cooled to room temperature, extracted three times with n-heptane (30mL×3); the organic layer was dried with anhydrous sodium sulfate, and after filtering anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain light yellow Oily product Compound (3).

[0057] B) 0.72 g of the product compound (3) obtained from A), 1.78 g of N-bromosuccinimide (NBS) and 0.1 g of benzoyl peroxide, under 15 mL of carbon tetrachloride, reflux for 2 hours ; Filtration while hot, after the filtrate was evaporated to dryness, separated by flash column chromatography to obtain fluffy white solid compound (4).

[0058] C) 1.34 grams of white solid compound (4) prepared by B), 2.5 grams of sodium bicarbonate and 25 ...

Embodiment 2

[0062]

[0063] 1) Experimental materials and animals: ① Balb / mouse (32 males aged 6-8 weeks). ② Pertussis toxin (Chengdu Institute of Biological Products). ③Complete Freund's adjuvant (1mg / L sigma). ④ Peptide (The myhca peptide 614-629Ac-SLKLMATLFSTYASAD-OH Shanghai Jier Biological Company 10 mg). ⑤ AS605240. ⑥ Gastrointestinal injection.

[0064] 2) Experimental process:

[0065] : A. Dissolve the polypeptide in sterilized phosphate buffer solution (PBS) to prepare a 1 mg / mL solution, emulsify and mix with an equal volume of complete Freund's adjuvant (operate on ice, use 2 sterilized glass syringes Repeated suction for 1 hour).

[0066] B. The mice are divided into 4 groups (10 in the model group, 10 in the treatment group, 6 in the control group, and 6 in the normal group),

[0067] The model group and the model treatment group were subcutaneously injected with the above-mentioned emulsion at multiple points in the bilateral armpit and groin, and the control group ...

Embodiment 3

[0076]

[0077] 1) Experimental materials and animals: ①Healthy female Balb / C mice aged 6-8 weeks, clean grade, provided by Animal Experiment Center of Sichuan University. ② The dose of ConA is 15mg / Kg, mixed with sterile normal saline. ③The dosage of AS605240 is 50mg / Kg. Prepare sterile saline. ④ The dose of dexamethasone is 500ug / Kg.

[0078] 2) Experimental method: The experiment is divided into 5 groups: normal group, control group, model group, treatment group, and no-load group. Normal group: no treatment. Control group: One hour after intraperitoneal injection of dexamethasone, ConA was administered via tail vein. Model group: ConA administered via tail vein. Treatment group: Half an hour after the administration of ConA through the tail vein, 5 mg / kg AS605240 was given by intragastric administration. Empty group: half an hour after the administration of ConA through the tail vein, the vehicle was administered by intragastric administration.

[0079] 3) Evaluat...

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Abstract

The invention relates to a method for preparing AS-605240 and an application thereof on medicines for treating inflammatory diseases. An improvement of the preparation method disclosed to the international patent is supplied to 5-quinoxaline methylene-2, 4-thiazolidinedione (AS-605240 with a structural formula I). 3, 4-diaminotoluene and glyoxal water solution as raw materials are relatively easy to obtain, reactive reagent, such as sodium bicarbonate, N-bromosuccinimide, carbon tetrachloride, and the like in each step is cheap and easy, and the reaction condition is mild. A great deal of mouse experimental curative effect observation of myocarditis, acute and chronic hepatitis, acute colitis and pancreatitis, which is induced by concanavalin A, is performed by the AS-605240, and the favorable curative effects of the AS-605240 are all confirmed. The prior TZDs, such as troglitazone, and the like are mainly used for aspects on treating diabetes mellitus, angiocardiopathy, and the like. In recent years, a study confirms that the AS-605240 protects the mouse joint and treats rheumatoid arthritis through restraining an osphatidylinositol 3 (PI3K) kinase gamma subtype signal way, therefore, the AS-605240 application on medicines for treating the inflammatory diseases opens up a new medical treatment field on the discovery of thiazolidinedione compound.

Description

(1) Technical field: [0001] The invention relates to a preparation method of thiazolidinedione compound AS-605240 and the application of AS-605240 in the preparation of medicines for treating inflammatory diseases. It belongs to the category of medical preparations (A61K) and heterocyclic compounds (C07D). (two) background technology: [0002] A thiazolidinedione compound involved in the present invention is AS-605240, the chemical name is (Z)-5-quinoxaline-6-methylene-2,4-thiazolidinedione. [0003] The marketed drugs with thiazolidinedione structure or thiazolidinedione analogues that are chemically synthesized and have definite physiological effects are collectively referred to as thiazolidinedione drugs (TZDs). TZDs (TZDs) such as troglitazone, rosiglitazone, pioglitazone, and ciglitazone are mainly used for the treatment of diabetes. In recent years, studies have found that TZDs also have good medical value in the treatment of cardiovascular diseases, inhibition of ps...

Claims

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Application Information

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IPC IPC(8): C07D417/06A61K31/498A61P29/00
Inventor 陈俐娟魏于全罗有福吴晓华
Owner SICHUAN UNIV
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