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7-carboxy-flavone derivatives, preparation method and therapeutic use

A kind of derivative, the technology of dihydroxyflavonoids, applied in the field of novel flavonoids and isoflavone derivatives, can solve problems such as serious side effects

Inactive Publication Date: 2007-02-28
NEGMA LERADS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, one of the drawbacks associated with the use of these compounds is the serious dose-related side effects in some patients, especially with laxative effects

Method used

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  • 7-carboxy-flavone derivatives, preparation method and therapeutic use
  • 7-carboxy-flavone derivatives, preparation method and therapeutic use
  • 7-carboxy-flavone derivatives, preparation method and therapeutic use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] 5-Hydroxy-2-phenyl-4-oxo-4H-chromene-7-carboxylic acid

[0055] 12.7 ml of pyridine and 6.6 ml of trifluoromethanesulfonic anhydride were successively added to 200 ml of a dichloromethane solution containing 10 g of 5,7-dihydroxyflavone while maintaining the temperature at 0°C. After reacting at 0°C for about 3 hours, the reaction mixture was neutralized with 1N hydrochloric acid solution, followed by extraction with dichloromethane.

[0056] After evaporation of the solvent, 13.9 g (92% yield) of 7-trifluoromethanesulfonyloxy-5-hydroxy-2-phenyl-4-oxo-4H-chromene was obtained as a white powder, the chemical structure of which was given by Confirmed by chromatography and infrared spectroscopy and calibrated by NMR and mass spectroscopy.

[0057] Rf=0.58 (AcOEt / PE=30 / 70)

[0058] IR (cm -1 ): 1655 (C=O), 1620 (C=C), 1436 (S=O)

[0059] To a solution of the above-obtained product (330 mg) in 4 ml of pyridine was added 0.16 ml of pivaloyl chloride at 0°C, an...

Embodiment 2

[0073] 7-Dimethoxyphosphoryl-5-hydroxy-2-phenyl-4-oxo-4H-chromene

[0074] The intermediate product 7-trifluoromethanesulfonyloxy-2-phenyl-5-pivaloyloxy-4-oxo-4H-chromene (500 mg) obtained in Example 1 was treated with 0.12 ml of phosphorous acid Dimethyl ester treatment in which 0.24 ml of diisopropylethylamine and 61 mg of tetrakis(triphenylphosphine)palladium in 2.5 ml of acetonitrile were present.

[0075] After heating at 70°C for 7 hours, the reaction mixture was neutralized with 1N hydrochloric acid solution, followed by extraction with dichloromethane.

[0076] After separation by flash chromatography (eluent: AcOEt / PE=5 / 95-50 / 50), 383 mg of 7-dimethoxyphosphoryl-2-phenyl-5-pivaloyloxy was obtained as a white powder - 4-Oxo-4H-chromene (84% yield), melting point Mp = 165-167°C.

[0077] The above derivative was added to sodium hydroxide solution (5ml), water (10ml) and methanol (10ml). After reacting at room temperature for 23 hours, the reaction mixture wa...

Embodiment 3

[0081] 7-Dihydroxyphosphoryl-5-hydroxy-2-phenyl-4-oxo-4H-chromene

[0082] 0.55 ml of bromotrimethylsilane were added to a solution of the product obtained in Example 2 in 13 ml of dichloromethane. After reacting at room temperature for 21 hours, the solvent was evaporated.

[0083]After recrystallization from a methanol / chloroform mixture, 7-dihydroxyphosphoryl-5-hydroxy-2-phenyl-4-oxo-4H-chromene was obtained as a yellow powder in a yield of 68%.

[0084] Melting point Mp=293-296°C (decomposition)

[0085] IR (cm -1 ): 1655 (C=O), 1616 (C=C), 1261 (P=O)

[0086] 1 H NMR (DMSO) δppm: 6.98 & 7.44 (2s, 2H, J=13.5Hz, H-6 & H-8), 7.16 (s, 1H, H-3), 7.59-7.65 (m, 3H, H- 3'&H-4'), 8.15(d, 2H, J=6.9Hz, H-2'), 12.63(s, OH)

[0087] 13 C NMR (DMSO) δppm: 107.7 (C-3), 110.8 (C-4a), 111.3 & 113.9 (J=9Hz, C-6 & C-8), 128.4 (C-2′), 130.9 (C- 3'), 132.1(C-1'), 134.2(C-4'), 156.9 & 161.1(J=20Hz, C-5, C-2, C-8a), 166.3(C-2), 183.2( C-4)

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Abstract

The invention concerns novel flavone and isoflavone derivatives of formulae (Ia) and (Ib) wherein: X represents a group of formula -COOR, or -PO(OR)2; R represents a hydrogen atom or an alkaline or alkaline-earth metal, or a lower alkyl group; R1 represents a hydroxy group, a lower alkoxy group or an acyloxy group; R2 and R3, identical or different, represent a hydrogen or halogen atom, or a trifluoromethyl group, a trichloromethyl group, a hydroxy group, an alkoxy group or an acyloxy group comprising 1 to 5 carbon atoms, or R2 and R3 can combine to form an alkylene dioxy group. The invention is useful for rheumatic diseases.

Description

technical field [0001] The present invention relates to novel flavone and isoflavone derivatives having therapeutic applications. More specifically, the present invention relates to novel flavone derivatives carrying acid groups, the application of the flavone derivatives in treating rheumatic diseases and the preparation method thereof. Background technique [0002] A large number of various substituted flavone derivatives have been disclosed in the literature because of their pharmacological properties useful in various therapeutic applications, such as the treatment of asthma, inflammatory diseases, gastrointestinal diseases, allergies or certain cancer tumors. [0003] For example, US Patent No. 5 399 584 discloses flavonoid derivatives that can be used to protect the walls of the gastrointestinal tract to complement the treatment of non-steroidal anti-inflammatory drugs. European Patent 290 915 discloses that flavone-3-carboxylic acids have pharmacological activities, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D311/30C07D311/36C07F9/655A61K31/352A61P29/00A61P19/02A61P43/00B01J31/24
CPCC07D311/36C07D311/30C07F9/65522A61P19/02A61P29/00A61P43/00
Inventor 让-皮埃尔·热松纳迪亚·丰特诺马丁内·蒙东苏济·沙尔比埃尔韦·菲舍弗朗索瓦·舒策
Owner NEGMA LERADS
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