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Application of sodium teriflunomide to preparation of medicine for treating autoimmune diseases

A technology for sodium tirimide and autoimmune diseases, which is applied in the field of sodium salt of the active metabolite of leflunomide, which can solve the problems of autoimmune diseases such as lupus erythematosus without tirimide sodium, and avoid the first-pass effect , Large exposure in vivo, high bioavailability

Inactive Publication Date: 2016-03-16
CINKATE PHARMA INTERMEDIATES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, Terimide was approved by the FDA for marketing in 2012. The clinical indication is multiple sclerosis. There is no report on the use of Terimide sodium in the treatment of autoimmune diseases such as systemic lupus erythematosus.

Method used

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  • Application of sodium teriflunomide to preparation of medicine for treating autoimmune diseases
  • Application of sodium teriflunomide to preparation of medicine for treating autoimmune diseases
  • Application of sodium teriflunomide to preparation of medicine for treating autoimmune diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Preparation of Terimide Sodium

[0073] 1.1 Preparation of Terimide

[0074] Leflunomide is dissolved in alkali solution for hydrolysis reaction, acidified to obtain Terimide, and filtered to obtain Terimide wet product. This wet product directly enters the next step of reaction.

[0075] 1.2 Preparation of Terimide Sodium

[0076] The wet product of Terimide was put into aqueous sodium hydroxide solution, and the temperature was raised to react for 2 hours, the insoluble matter was filtered off, the filtrate was lowered to room temperature to grow crystals, and the crude product of Terimide Sodium was filtered and dried. After recrystallization from ethanol, pure product Terimide Sodium (purity ≥ 99.5) was obtained.

Embodiment 2

[0078] Safety evaluation of tirimide sodium in primary human hepatocytes

[0079] The purpose of this experiment is to detect the toxicity of tirimide sodium to human liver cells, and compare its toxicity with leflunomide and tirimide, including cell viability test (MTT), lactate dehydrogenase ( LDH) release experiment and mitochondrial membrane potential experiment.

[0080] Experimental steps:

[0081] Rat primary hepatocytes and human primary hepatocytes were used in this experiment. Among them, the primary rat hepatocytes are derived from SD rats, and the isolation of primary hepatocytes has been approved by IACUC2013-06-PGY-03 of the Institute of Medicine. Primary human hepatocytes were purchased from Yingwei Jieji (Shanghai) Trading Co., Ltd., batch number HU4239. The test products are: Terimide, Terimide Sodium and Leflunomide.

[0082] Rat primary hepatocytes were cultured for 3 hours in WilliamsEMedium medium containing 1% penicillin, streptomycin, 1% glutamine, 0.1...

Embodiment 3

[0103] Observation of curative effect of tirimide sodium in spontaneous lupus erythematosus model in female MRL / lpr mice

[0104] The purpose of this study is to observe the therapeutic effect of different doses of the test compound tirimide sodium on lupus model animals, and compare it with glucocorticoids and leflunomide. The animal model used in this study is the MRL / lpr mouse, which has autoreactive CD4 due to the deletion of the Fas gene. + T cells cannot be cleared through the apoptotic pathway, and then produce autoimmune disease symptoms similar to human SLE. In the field of international pharmacology research, it is widely used in the study of the pathogenesis of SLE and the study of drug pharmacodynamics. Considering that female MRL / lpr mice usually start to show symptoms of SLE between the age of 8 weeks and 12 weeks, drug intervention was given to the model mice at the age of 10-11 weeks for 8 consecutive weeks.

[0105] Test design:

[0106] grouping:

[0107] ...

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PUM

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Abstract

The invention discloses an application of sodium teriflunomide, which is a sodium salt with low hepatotoxicity of a leflunomide active metabolite, to preparation of a medicine for treating autoimmune diseases. Compared with leflunomide or teriflunomide, sodium teriflunomide has lower hepatotoxicity and a larger therapeutic window. Sodium teriflunomide or a medical combination taking sodium teriflunomide as an active component is used as an immunosuppressor, and is used for treating autoimmune diseases.

Description

technical field [0001] The invention relates to the application of triamide sodium, an active metabolite sodium salt of leflunomide with low hepatotoxicity, in the preparation of medicines for treating autoimmune diseases. Background technique [0002] Leflunomide (LEF) is a small molecule immunosuppressant. The product was approved by the State Food and Drug Administration in 1999, and its indication is adult rheumatoid arthritis. The curative effect of leflunomide is stable, but the drug’s onset time is relatively slow and individual differences are large; during clinical application, especially when used in combination with methotrexate, gastrointestinal reactions and abnormal liver function Adverse drug reactions such as hair loss and hair loss are more common. Among them, liver toxicity is the most important reason restricting the clinical application of leflunomide. [0003] Teriflunomide (TER) is a product developed by Sanofi-Aventis. The product was approved by th...

Claims

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Application Information

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IPC IPC(8): A61K31/277A61P37/02A61P19/02A61P29/00A61P17/06A61P25/00
Inventor 刘荣军贺利军李秋实肖飞
Owner CINKATE PHARMA INTERMEDIATES
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