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Novel fusidic acid derivatives

A fusidic acid and compound technology, applied in the field of new fusidic acid derivatives, can solve the problems of activity reduction and loss

Inactive Publication Date: 2002-11-06
LEO PHARMA PROD LTD AS LOVENS CHEM FAB PRODUKTIONS AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is also known that structural changes may cause a marked reduction or complete loss of such activity (see Godtfredsen et al., J. Med. Chem., Vol. 9, p. 15-22, 1966)

Method used

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  • Novel fusidic acid derivatives
  • Novel fusidic acid derivatives
  • Novel fusidic acid derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0197] Example 1: 17(S), 20(S)-dihydrofusidic acid (10) (Compound 101)

[0198] The compound of formula 9 (2 g, 3.3 mmol) was dissolved in anhydrous dichloromethane (50 mL) in an oven-dried two necked round bottom flask under argon and cooled at -20 °C. To this solution was added 4 Angstrom molecular sieves (6 g) and bromotrimethylsilane (2.7 mL, 20 mmol) was slowly injected with continuous stirring. The reaction mixture was stirred until complete (approximately 5 hours). The reaction mixture was then transferred to a separatory funnel with ethyl acetate and water and the two layers were shaken and separated. The aqueous layer was extracted three times with ethyl acetate (3 x 20 mL) and the combined organic layers were washed with brine (30 mL). The organic solution was dried over anhydrous sodium sulfate and concentrated in vacuo to afford 1.4 g of compound 101 as a colorless solid. Recrystallization from methanol-water gave 1.2 g of colorless crystals, melting at 195-195....

Embodiment 1a

[0200] Example 1a: Another preparation method of 17(S), 20(S)-dihydrofusidic acid (10) (compound 101)

[0201] The compound of formula 16 (3.6 g, 5.7 mmol) was dissolved in THF (15 mL) and 4% aqueous hydrogen fluoride (10 mL) in a round bottom Teflon flask. The reaction mixture was stirred at room temperature for 2 days. The reaction was then neutralized to pH 8 with 27% sodium hydroxide solution and finally adjusted to pH 4 with acetic acid. The reaction mixture was then transferred to a separatory funnel with ethyl acetate and water, the two layers were shaken and separated. The aqueous phase was extracted three times with ethyl acetate (3 x 50 mL), and the combined organic layers were washed with brine (50 mL). Drying over anhydrous sodium sulfate and concentration under vacuum gave 4 g of crude product 101 as a colorless solid. Using ethyl acetate, a mixture of low-boiling petroleum ether and a trace of formic acid as an eluent, purified by column chromatography to obta...

Embodiment 2

[0203] Example 2: 17(S), 20(S), 24,25-tetrahydrofusidic acid (compound 102)

[0204] A solution of compound 101 (280 mg, 0.54 mmol) in ethanol (3 mL) was hydrogenated under atmospheric pressure hydrogen in the presence of 5% palladium (30 mg) on ​​calcium carbonate. The reaction mixture was stirred vigorously until the theoretical amount of hydrogen was consumed, and the catalyst was filtered off. Water was added dropwise to the filtrate to obtain 255 mg of crystalline 17(S), 20(S), 24, 25-tetrahydrofusidic acid, melting point 138.5-140°C.

[0205]13 C NMR, (DMSO-d 6 ): 210.7, 176.6, 169.1, 131.2, 123.7, 75.3, 69.0, 57.7, 48.9, 43.8, 43.6, 43.3, 41.8, 41.7, 37.7, 37.2, 34.4, 32.6, 30.1, 27.9, 25.3, 24.8, 22.7, 20. 20.4, 20.1, 17.4, 16.3, 16.0.

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Abstract

The present invention relates to novel 17,20-dihydrofusilic acid derivatives (Ia) for use in pharmaceutical compositions for the treatment of infections, in particular topical compositions for the treatment of skin infections or eye infections.

Description

field of invention [0001] The present invention relates to a series of novel 17,20-dihydrofusidic acid derivatives, to its salts and to its easily hydrolyzed esters, to the preparation methods of these compounds, to pharmaceutical compositions containing said compounds, and to Use of such compounds in medicine. In particular, these compounds exhibit antimicrobial activity, so they are useful for the treatment of infectious diseases. The compounds of the present invention can be used in the systemic treatment of infections and in the topical treatment of infections associated with the skin and eyes. Background of the invention [0002] The antibacterial properties of fusidic acid are well known. It is also known that structural changes may cause a marked reduction or complete loss of such activity (see Godtfredsen et al., J. Med. Chem., Vol. 9, p. 15-22, 1966). It was generally accepted until now that a double bond between the C-17 and C-20 carbon atoms linking the side ch...

Claims

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Application Information

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IPC IPC(8): A61K9/06A61K31/575A61K45/00A61P17/00A61P27/02A61P31/00C07J9/00C07J13/00
CPCC07J9/00C07J13/00A61P17/00A61P27/02A61P31/00A61P31/04
Inventor T·杜沃尔德W·冯迪尼
Owner LEO PHARMA PROD LTD AS LOVENS CHEM FAB PRODUKTIONS AS
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