Fusidic acid derivatives

Details Fusidic acid derivatives Fusidic acid derivatives

2001-08-14

2003-07-15

Qazi, Sabiha (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C552S523000, C552S525000, C552S530000, C552S540000, C546S077000, C514S023000, C514S025000, C514S172000, C514S182000, C536S018600

Reexamination Certificate

active

06593319

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel series of 17,20-dihydrofusidic acid derivatives, to salts and to easily hydrolysable esters thereof, to the preparation of these compounds, to pharmaceutical compositions containing the compounds and to the use of such compounds in medicine. In particular, these compounds exhibit antimicrobial activity, thus they are useful for the treatment of infectious diseases. The compounds of the present invention can be used both in systemic treatment of infections and in topical treatment of infections related to skin and eyes.
BACKGROUND OF THE INVENTION
The antibacterial properties of fusidic acid are well known. It is also known that structural variations may cause significant or total loss of such activity (cf. Godtfredsen et al,
J. Med. Chem.,
Vol. 9, p. 15-22, 1966). It has until now been generally accepted that the double bond between the carbon atoms C-17 and C-20 which connect the side-chain to the tetracyclic ring system was essential for any antibacterial activity. Reduction of the double bond between C-24 and C-25 of fusidic acid to a single bond resulted in a marginal effect on the antibacterial activity of the molecule whereas additional reduction of the double bond between C-17 and C-20 yielding tetrahydrofusidic acid caused almost complete loss of activity. Two epimers in the series of tetrahydrofusidic acids have earlier been prepared by means of catalytic hydrogenation of fusidic acid or its isomer lumi-fusidic acid, having the configuration 17(R),20(S) and 17(R),20(R) respectively (cf. von Daehne et al.,
Adv. Appl. Microbiol.,
25, p. 95-146,1979, and references cited therein).
SUMMARY OF THE INVENTION
The purpose of the invention is to provide semisynthetic analogues of fusidic acid having antimicrobial activity. Said purpose is achieved with the compounds of the present invention belonging to the series of dihydro- and tetrahydrofusidic acids having the essential configuration 17(S),20(S) which in vitro show high antimicrobial activity and favourable stability and pharmacokinetic properties, whereby the compounds of the invention may be used in treatment of infections in humans and animals.
The present invention provides compounds of the general formula Ia:
wherein
Q
1
, Q
2
and Q
3
are the same or different and independently represent a —(CO)— group; a —(CHOH)— group; a —(CHOR)— group; a —(CHSH)— group; a —(NH)— group; a —(CHNH
2
)— group; or a —(CHNHR)— group, wherein R represents an alkyl radical having 1 to 4 carbon atoms or an acyl radical having 1 to 4 carbon atoms; and wherein Q
2
and Q
3
may also independently represent a —(CH
2
)— group;
Y represents hydrogen, hydroxy, an alkyl radical having 1 to 4 carbon atoms, or an acyl radical having 1 to 4 carbon atoms; A represents an oxygen or a sulphur atom;
R
1
represents an alkyl radical having 1 to 4 carbon atoms, an olefinic group having 2 to 4 carbon atoms, a (C
1
-C
6
) acyl group, (C
3
-C
7
)cycloalkylcarbonyl group or a benzoyl group, R
1
optionally being substituted with one or more halogen atoms and/or hydroxy, alkoxy or azido groups;
and pharmaceutically acceptable salts and easily hydrolysable esters thereof.
In formula Ia and subsequent formulas herein the dotted lines between C-1 and C-2 and/or C-24 and C-25 indicate that the atoms in question are connected with either a double bond or a single bond.
DETAILED DESCRIPTION OF THE INVENTION
Preferred compounds of the invention are compounds of formula I
wherein
Q
1
and Q
2
are the same or different and both represent a —(CHOH)— group; a —(CO)— group; or a —(CHSH)— group;
A represents an oxygen or a sulphur atom;
R
1
represents an alkyl radical having 1 to 4 carbon atoms, an olefinic group having 2 to 4 carbon atoms, a (C
1
-C
6
)acyl group, (C
1
-C
7
)cycloalkylcarbonyl group or a benzoyl group, R
1
optionally being substituted with one or more halogen atoms and/or hydroxy, alkoxy or azido groups; and
pharmaceutically acceptable salts and easily hydrolysable esters thereof.
Preferably Q
1
and Q
2
are selected from the group consisting of —(CO)— and —(CHOH)—. More preferred compounds of the invention are compounds of formula I wherein Q
1
and Q
2
both represent a
group or one of Q
1
or Q
2
represents —(CO)—; A represents oxygen; R
1
represents a (C
1
-C
4
)alkyl group, optionally substituted with one or more substituents selected from the group consisting of azido, hydroxy, and halogen selected from fluoro, chloro and bromo, or R
1
represents an acyl group with 1 to 4 carbon atoms or a benzoyl group, both optionally substituted with one or more halogen atoms, preferably selected from the group consisting of fluoro and chloro. R
1
is preferably selected from the group consisting of ethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-azidoethyl, 2-hydroxyethyl, propyl and isopropyl, 1,3-difluoro-isopropyl, acetyl, propionyl, chloroacetyl and trifluoroacetyl, or R
1
is selected from the preferred group consisting of ethyl, 2,2,2-trichloroethyl, 2-azidoethyl, isopropyl, tert-butyl and acetyl. Also preferred are compounds of formula I and Ia wherein the bond between C-24 and C-25 is a double bond.
Examples of compounds of the invention which can all be prepared by the methods described below are:
17(S),20(S)-Dihydrofusidic acid,
17(S),20(S),24,25-Tetrahydrofusidic acid,
11-Dehydro-17(S),20(S)-dihydrofusidic acid,
3-Dehydro-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-propionyloxy-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-(3′-chloropropionyloxy)-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-(2′-methylpropionyloxy)-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-cyclopropylcarbonyloxy-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-chloroacetoxy-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-bromoacetoxy-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-benzoyloxy-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-(4′-fluorobenzoyloxy)-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-cyclohexylcarbonyloxy-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-acryloyloxy-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-isopropylthio-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-ethylthio-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-(2′,2′,2′-trichloroethylthio)-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-tert-butylthio-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-methoxymethylthio-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-isopropylthio-17(S),20(S);24,25-tetrahydrofusidic acid,
16-Deacetoxy-16&bgr;-acetylthio-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-benzoylthio-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-ethoxy-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-(2′,2′,2′-trifluoroethoxy)-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-propoxy-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-isopropoxy-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-(1′,3′-difluoroisopropoxy)-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-methoxymethoxy-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-(2′,2′,2′-trichloroethoxy)-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-(2′-azidoethoxy)-17(S),20(S)-dihydrofusidic acid,
16-Deacetoxy-16&bgr;-(2′-hydroxyethoxy)-17(S),20(S)-dihydrofusidic acid,
and pharmaceutically acceptable salts and easily hydrolysable esters thereof.
In contrast to natural fusidic acid (1) wherein C-17 and C-20 are connected with a double bond, all compounds described herein and by formula I and Ia have a single bond between C-17 and C-20. The configuration of the two asymmetric carbon atoms in question is 17(S) and 20(S). This epimer is one of four possible epimers differing solely in the configuration of C-17 and C-20, and biological tests have shown this to be the only epimer exhibiting potent activity.
The compounds of the invention can be used as such or in the form of salts or easily hydrolysable e

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