Antifungal sordaridin derivatives

Details Antifungal sordaridin derivatives Antifungal sordaridin derivatives

1997-07-16

2000-04-25

Owens, Amelia

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

549416, 549417, 549418, A61K 3135, C07D31500

Patent

active

060544783

DESCRIPTION:

BRIEF SUMMARY
This invention relates to novel sordarin derivatives having antifungal activity, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine, more particularly in the prevention or treatment of diseases in animals, including humans, caused by fungal infection.
British Patent Specification No. 1,162,027 describes the preparation of an antibiotic, SL2266, by the cultivation of the strain NRRL 3196 of the fungus species Sordaria araneosa. SL 2266, later named sordarin, is reported to have fungistatic activity. The same research group also described in Helvetica Chimica Acta (1971), 51, 119-120 the degradation of sordarin to sordaricin. Published Japanese Patent Application No. J6 2040292A describes the preparation of an antibiotic, zofimarin, which is reported to have antifungal activity.
Sordarin, sordaricin and zofimarin may be represented by formula (A) below ##STR2## where OR as ##STR3## describes sordarin; OR as OH describes sordaricin; and ##STR4## describes zofimarin.
Although sordarin and zofimarin exhibit antifungal activity, both compounds are only moderately active and have limited spectra of action when tested against a battery of fungal organisms. We now describe hereinafter a novel group of fungicidal sordarin derivatives which exhibit excellent antifungal activity and a broad spectrum of action. Thus, according to a first aspect of the present invention, we provide compounds of formula (I) ##STR5## and pharmaceutically acceptable salts and solvates (e.g. hydrates) or metabolically labile derivatives thereof, C.sub.1-10 alkylthio, C.sub.1-6 alkoxyC.sub.1-4 alkoxy, arylC.sub.1-6 alkyloxy, arylC.sub.3-6 alkenyloxy, azido, NR.sup.5 COR.sup.5 (where each R.sup.5 is independently hydrogen or C.sub.1-6 alkyl), OR.sup.6 (where R.sup.6 is a cyclic ether containing 4 to 8 atoms linked to the oxygen atom via a ring carbon atom adjacent to the ring oxygen atom) or a group ##STR6## where Y is oxygen, sulphur or NH, X is either a bond, an oxygen atom or a moiety NR.sup.8 in which R.sup.8 is hydrogen or C.sub.1-6 alkyl, and R.sup.7 is C.sub.1-10 alkyl optionally containing one or two double bonds, aryl, arylC.sub.1-4 alkyl, arylC.sub.2-4 alkenyl, haloC.sub.1-6 alkyl or C.sub.1-6 alkoxyC.sub.1-4 alkyl), and R.sup.3 represents hydrogen, or R.sup.2 and R.sup.3 may together with the carbon atom to which they are attached represent C.dbd.O or C.dbd.NOR.sup.9 (where R.sup.9 is C.sub.1-6 alkyl); and ##STR7## (where R.sup.7 is as defined above); with the proviso that when R.sup.1 represents a hydroxyl group in the axial configuration and R.sup.4 is methoxy then R.sup.2 cannot represent a group in the axial configuration selected from hydroxyl and OCOCH.dbd..sup.Z CH--CH.dbd..sup.E CHCH.sub.3.
Suitable pharmaceutically acceptable salts of the compounds of formula (I) include inorganic base salts such as alkali metal salts (for example sodium and potassium salts) and ammonium salts and organic base salts. Suitable organic base salts include amine salts such as trialkylamine (e.g. triethylamine), dialkylamine (e.g. dicyclohexylamine), optionally substituted benzylamine (e.g. phenylbenzylamine or p-bromobenzylamine), procaine, ethanolamine, diethanolamine, N-methylglucosamine and tri(hydroxymethyl)methylamine salts and amino acid salts (e.g. lysine and arginine salts).
References hereinafter to a compound of formula (I) includes that compound and its pharmaceutically acceptable salts.
Other salts which are not pharmaceutically acceptable may be useful in the preparation of compounds of formula (I) and these form a further aspect of the invention.
Metabolically labile derivatives of compounds of formula (I) are compounds which are converted in the body into compounds of formula (1). Examples of such derivatives include conventional metabolically labile esters formed from the free carboxylic acid in the molecule.
It is to be understood that the present invention encompasses any individual isomers, including optical isomers, of compounds represented by formula (I) above as

REFERENCES:
Alarcon, B. et al `Screening for New Compounds with Antiherpes Activity`. CA 102:39536, 1984.
Hauser, D et al `Sordarin 1. Isolation and Degradation of Sordarin` CA 75:49503, 1971.

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