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Novel fusidic acid derivatives

A technology of fusidic acid, compounds, applied in the field of new fusidic acid derivatives

Inactive Publication Date: 2006-08-09
LEO PHARMA AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, as mentioned above, the substance itself has a rather limited antimicrobial spectrum, therefore, it may be desirable to develop new analogues based on fusidic acid with antibacterial activity against a wider range of pathogenic microorganisms, especially streptococci

Method used

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Examples

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preparation example

[0281] THF = Tetrahydrofuran

[0282] TLC = Thin Layer Chromatography

[0283] rt = room temperature

[0284] Saturated NaCl = saturated aqueous sodium chloride solution

[0285] TMS = Trimethylsilyl

[0286] v = volume

[0287] Preparation of compounds of the present invention

[0288] Compounds of formula I can be synthesized from known starting materials by different synthetic routes, depending on the requirements presented by each individual compound I, such as the availability of starting materials, temporary protection of sensitive substituents, the purity and yield of the synthetic steps and the number of steps. Choice of preferred order.

[0289] Illustrative, non-limiting synthesis methods and examples of the different compounds of formula I or Ia are given below. Various synthetic methods can be combined with each other, as is conveniently judged by those skilled in the art, to provide the desired compound of formula I or Ia and the free acid, salt or easily hy...

Embodiment 36-43

[0309] 24-Bromo-fusidic acid - or 24-bromo-fusidic acid analog -acetoxymethyl ester or -pivaloyloxymethyl ester can be hydrolyzed to the corresponding free acid, e.g. by using methanol and base Aqueous treatment. Heating the bromo-acid with copper(I) iodide and potassium iodide in HMPA at 120°C yields the corresponding 24-iodic acid of formula I. The acid was esterified to the corresponding phenacyl ester by treatment with phenacyl bromide and potassium fluoride in DMF. The phenacyl ester yields the corresponding 24-trifluoromethyl ester, for example by reaction with trifluoromethylcopper in HMPA. The ester is finally converted to free 24-trifluoromethylfusidic acid (or a fusidic acid analogue) of formula I by hydrolysis, such as base hydrolysis.

[0310] Alternatively, 24-iodic acids can be esterified to their acetate or pivaloyloxymethyl esters as described above, and they can be converted to the corresponding 24-aryl or alkene by a suitable coupling reaction yl esters et...

preparation example 1

[0338] Preparation Example 1: Acetoxymethyl Fusidate (2a)

[0339] Will Et 3 N (45ml; 33g; 320mmol) was added to a solution of fusidic acid (201) (128.6g; 250mmol) in DMF (375ml), and the mixture was stirred at room temperature for 30 minutes. Chloromethyl acetate (49ml; 55g; 500mmol) was then added and the reaction mixture was stirred at room temperature overnight before being worked up (EtOAc, water) to yield a crude product. The crude ester (2a) was crystallized from isopropyl ether to give pure compound (2a) as a colorless powder, m.p.103-105°C

[0340] 13 C NMR, (CDCl 3 ): 170.4, 169.6, 168.4, 150.6, 132.7, 129.3, 122.9, 79.4, 74.4, 71.4, 68.2, 49.2, 48.7, 44.3, 39.5, 39.0, 37.1, 36.2, 36.2, 35.5, 32.4, 30.3, 30.0, 28 28.3, 25.7, 24.2, 22.8, 20.9, 20.8, 20.7, 17.9, 17.7, 15.9

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Abstract

The present Invention relates to novel fusidic acid derivatives of general formula [I] wherein X represents halogen, trifluoromethyl, cyano, azido, alkyl, alkenyl or aryl, wherein. said alkyl, alkenyl or aryl are optionally substituted by one or more, same or. different substituents selected from the group consisting of alkyl, alkenyl, aryl, alkoxy, nitro, alkylthio, halogen, azido, trifluoromethyl and cyano; Y and Z both' represent hydrogen, or together with the C-17 / C-20 bond form a double bond between C-17 and C-20, or together are methylene and form a cyclopropane ring in combination with C-17 and C-20; A represents a bond,. O, S or S(O); B represents C1-6 alkyl, C2-6 alkenyl, CI-6 acyl, C3-7 cycloalkylcarbonyl or benzoyl, all of which are optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, aryl, heteroaryl and azido, or, if A represents a bond, B may also represent hydrogen; Q1 and 'Q2 independently represent. -CH2-, -C(O)-, -(CHOR)-, -(CHOR)-, -(CHSH)-, - (NH)<->, -(CHNH2)- or -(CHW)-., wherein R represents CI-6alkyl and W represents halogen, cyano, azido or trifluoromethyi; Q3 represents -CH2-, -C(O)- or -CHOH-; G represents hydrogen, OH or O-CO-CH3; two bonds in the pentacyclic ring being depicted with full and dotted lines to indicate that either of the two bonds may be a double bond, in which case Y is absent and Z represents hydrogen; the bond between C-1 and C-2 being either a single or a double bond; and pharmaceutically acceptable salts and easily hydrolysable esters thereof, to pharmaceutical compositions comprising said derivatives, as well as to their use in therapy.

Description

field of invention [0001] The present invention relates to novel fusidic acid derivatives, pharmaceutical compositions comprising the derivatives and their use in therapy. Background of the invention [0002] Fusidic acid belongs to the fusidanes, a small family of naturally occurring antibiotics. [0003] [0004] fusidic acid [0005] The fudeic acid family usually has a unique chair-boat-chair configuration of the tetracyclic ring system, which distinguishes the fudeic acid family from steroids. Thus, despite some structural resemblance to steroids (ie the tetracyclic ring system), the fudeic acid family does not exert any hormonal activity. The fudeic acid family also typically has a side chain with a carboxylic acid attached by a double bond to C-17 in the ring system, and an acetate group attached to C-16. Fusidic acid, a fermentation product of Fusidium coccineum, is the most antibacterial compound of the fusidic acid family and the only...

Claims

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Application Information

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IPC IPC(8): C07J9/00C07J13/00C07J51/00A61K31/575A61P31/04
Inventor T·迪沃德C·A·S·布雷丁P·R·拉斯穆森L·M·E·布埃拉特迪沃德J·托尔豪格
Owner LEO PHARMA AS
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