Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-10-18
1998-12-29
Owens, Amelia Averill
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514457, 514460, 549362, 549416, A61K 3135
Patent
active
058542809
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 ##STR3## where OR as ##STR4## describes sordarin; OR as OH describes sordaricin; and ##STR5## 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) ##STR6## wherein Z is a tetrahydro-pyrano group selected from ##STR7## and pharmaceutically acceptable salts and solvates (e.g. hydrates) or metabolically labile derivatives thereof, acyloxy; alkyl or C.sub.1-4 alkoxy C.sub.1-4 alkyl or R.sup.2 and R.sup.3 may together with the carbon atom to which they are attached represent C.dbd.O, C.dbd.S or C.sub.3-8 cycloalkyl; hydroxyl, C.sub.1-4 alkoxy or a group OCOR.sup.8 in which R.sup.8 is C.sub.1-4 alkyl or aryl); alkyl or C.sub.1-4 alkoxy C.sub.1-4 alkyl or R.sup.5 and R.sup.6 may together with the carbon atom to which they are attached represent C.dbd.O, C.dbd.S or C.sub.3-8 cycloalkyl; R.sup.10 (where R.sup.9 and R.sup.10 may each independently represent hydrogen, C.sub.1-6 alkyl, C.sub.1-4 alkoxy or C.sub.1-4 alkoxyC.sub.1-4 alkyl or R.sup.9 and R.sup.10 may together with the carbon atom to which they are attached represent C.dbd.O, C.dbd.S, C.sub.3-8 cycloalkyl or C.dbd.CHR.sup.11 where R.sup.11 represents hydrogen or C.sub.1-4 alkyl); or when X or Y is oxygen and n is zero then --Y--CR.sup.2 R.sup.3 or --X--CR.sup.2 R.sup.3 -- respectively may also represent --N.dbd.CR.sup.3 -- or --NR.sup.12 --CR.sup.2 R.sup.3 -- (where CR.sup.2 and R.sup.3 are C.dbd.O and R.sup.12 is C.sub.1-4 alkyl an acyl group COR.sup.13 where R.sup.13 is C.sub.1-6 alkyl) or when Y is oxygen and n is zero X may be represent the group CR.sup.11 (wherein R.sup.11 has the meanings defined above) which is attached to the pyran ring by a double bond; C.sub.1-6 alkoxy (optionally substituted by 1 or 2 hydroxy or a ketal thereof or 1 or 2 C.sub.1-3 alkoxy groups), arylC.sub.1-4 alkoxy, C.sub.3-6 alkenyloxy, a group OCOR.sup.18 (where R.sup.18 is arylC.sub.1-4 alkoxy or a C.sub.1-10 alkyl group optionally containing one or two double bonds) or C.sub.1-6 alkoxycarbonyl C.sub.1-4 alkoxy, and R.sup.16 represents hydrogen or R.sup.15 and R.sup.16 may together with the carbon atom to which they are attached represent C.dbd.O or C.dbd.CH.sub.2 ; C.sub.1-4 alkoxy or a group OCOR.sup.20 in which R.sup.20 is C.sub.1-4 alkyl); and additional bond;
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)met
REFERENCES:
Patent Abstracts of Japan vol. 18, No. 485 (C-1248), 1994 JP,A,06 157582 Banyu Pharmadeut Co. Ltd. Jun. 1994.
Patent Abstracts of Japan vol. 11, No. 119 (C-436), 1987 JP,A,62 040292 Sankyo Co Ltd. Feb. 1987.
Helvetica Chimica Acta, vol. 54, No. 119, Basel, CH pp. 1178-1190, XP002000182 Hauser D. and Sigg H.P.: "Isolierung und Abbau von Sordarin" (1971).
Bueno Calderon Jose Maria
Cuevas Zurita Juan C.
Fraile Gabaldon Maria T.
Garcia-Ochoa Dorado Silvestre
Gargallo Viola Domingo
Glaxo Wellcome S.A.
Owens Amelia Averill
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