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Mycophenolic acid derivative, preparation method thereof and application thereof

Inactive Publication Date: 2013-03-06
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, due to the complexation of mycophenolic acid in the gastrointestinal cavity, narrow absorption window, high bioavailability caused by metabolism before absorption, and side effects such as intestinal irritation, we designed and prepared a series of mycophenolic acid derivatives , we found that this class of compounds has strong immunosuppressive activity, and there is no literature report

Method used

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  • Mycophenolic acid derivative, preparation method thereof and application thereof
  • Mycophenolic acid derivative, preparation method thereof and application thereof
  • Mycophenolic acid derivative, preparation method thereof and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0098] Example 1 (E)-6-(1,3-dihydro-4-hydroxyl-6-methoxy-7-methyl-3-oxobenzofuran-5-yl)-4-methyl- Preparation of 4-Hexenol

[0099] (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxobenzofuran-5-yl)-4-methyl-4- Hexenoic acid (3.2g, 10mmol, purchased from Changzhou Huaren Chemical Co., Ltd.) was dissolved in tetrahydrofuran (50mL), triethylamine (2.8mL) was added, the mixed solution was cooled to -10°C, and ethyl chloroformate was added dropwise Solution (prepared by dissolving 1.958mL of ethyl chloroformate in 5mL of tetrahydrofuran), stirred and reacted at -10°C for 1h, then filtered the reaction solution, and the filtrate was dropped into an aqueous sodium borohydride solution cooled by an ice-water bath (from 2.3g Sodium borohydride was dissolved in 20mL of water), slowly returned to room temperature after dropping, stirred and reacted for 5h, then stopped stirring, slowly poured the reaction solution into hydrochloric acid (1mol / L, 100mL), stirred evenly and used Extr...

Embodiment 2

[0101] Example 2 (E)-6-(1,3-dihydro-4-hydroxyl-6-methoxy-7-methyl-3-oxobenzofuran-5-yl)-4-methyl- Preparation of methyl 4-hexenoate

[0102] (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxobenzofuran-5-yl)-4-methyl-4- Hexenoic acid (3.2g, 10mmol) and p-toluenesulfonic acid (138mg, 0.801mmol) were dissolved in methanol (80mL), stirred and reacted at room temperature for 6h, during which a large amount of white solid precipitated, after the reaction, distilled methanol After drying, the obtained solid was washed several times with water, and dried to obtain 3.079 g (yield: 92%) of the title compound having the following structure.

[0103] 1 H-NMR (300MHz, CDCl 3 , δppm): 7.67(s, 1H), 5.24(t, J=6.6Hz, 1H), 5.20(s, 2H), 3.76(s, 3H), 3.62(s, 3H), 3.38(d, J= 6.9Hz, 2H), 2.40(td, J=2.1Hz, 8.1Hz, 2H), 2.30(t, J=8.1Hz, 2H), 2.15(s, 3H), 1.80(s, 3H)

[0104]

Embodiment 3

[0105] Example 3 (E)-6-(1,3-dihydro-4-hydroxyl-6-methoxy-7-methyl-3-oxobenzofuran-5-yl)-4-methyl- Preparation of ethyl 4-hexenoate

[0106] (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxobenzofuran-5-yl)-4-methyl-4- Hexenoic acid (1.0g, 3.122mmol) was dissolved in ethanol (50mL), 3 drops of concentrated sulfuric acid was added, and the reaction was stirred at room temperature for 6h. After the reaction, the ethanol was evaporated to dryness, and the obtained solid was washed several times with water, and dried to obtain 3.079g (Yield: 92%) The title compound having the following structure.

[0107] 1 H-NMR (300MHz, CDCl 3 , δppm): 7.07(s, 1H), 5.24(td, J=1.8Hz, 6.6Hz, 1H), 5.20(s, 2H), 4.07(q, J=6.9Hz, 2H), 3.76(s, 3H ), 3.38(d, J=6.6Hz, 2H), 2.39(td, J=2.4Hz, 7.8Hz, 2H), 2.30(t, J=7.8Hz, 2H), 2.15(s, 3H), 1.80( s, 3H)

[0108]

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Abstract

The invention relates to a mycophenolic acid derivative as shown in a formula V and a pharmaceutically acceptable salt thereof, wherein L is -O-R2, -QCOOR2 or -QCONR2R3, Q is alkylene of C1 to C10 or alkenylene of C1 to C6, and -O-R1, or -O-*M+. The invention further relates to a pharmaceutical composition containing the mycophenolic acid derivative, the pharmaceutically acceptable salt and pharmaceutical adjuvants, a preparation method of the mycophenolic acid derivative and the pharmaceutically acceptable salt, and an application of the mycophenolic acid derivative and the pharmaceutically acceptable salt in immunosuppressant drugs, especially in preparing drugs for treating organ transplants such as skin transplant, liver transplant and heart transplant, and autoimmune diseases such as psoriasis, rheumatoid arthritis, systemic lupus erythematosus, vasculitis, lupus nephritis, IgA nephritis, glomerulus nephritis, etc.

Description

technical field [0001] The invention relates to a class of mycophenolic acid derivatives with good biological activity, their preparation method and their use as immunosuppressants. Background technique [0002] Mycophenolic acid (MPA) is an antibiotic with immunosuppressive effect belonging to microbial sources. It is produced by the fermentation and metabolism of Penicillium brevistum. In 1896, Gosio isolated the enzyme phenolic acid for the first time from the corn broth containing Penicillium. And proved that it has antibacterial activity. Subsequent studies have shown that it has the advantages of anti-tumor, anti-virus, immunosuppressive, anti-psoriasis and anti-inflammatory activities, especially the immunosuppressive activity is more prominent, but the bioavailability is low. The low bioavailability of mycophenolic acid may be complexed in the gastrointestinal lumen, resulting in a narrow absorption window, causing metabolism before absorption, etc. Therefore, rese...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/88C07D407/12A61K31/5377A61K31/496A61K31/4525A61K31/4025A61K31/365A61P37/06A61P37/02A61P19/02A61P29/00A61P17/06A61P13/12
CPCC07D307/88C07D407/12A61P13/12A61P17/00A61P17/06A61P19/02A61P29/00A61P37/02A61P37/06
Inventor 段文虎左建平李川陈炜唐炜左理孔芳园牛巍
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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