Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-03-03
1997-06-24
Krass, Frederick
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
549267, 435124, 504140, 504291, 504117, C07D32300, C12P 102
Patent
active
056418043
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of PCT/DK93/00293 filed Sep. 14, 1993, which is incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to biologically active compounds from microorganisms, including methods for the production and microorganisms capable of producing such compounds. The compounds of this invention are novel macrocyclic polylactones, composed of hydroxylated aromatic acids and aliphatic .beta.-hydroxy acids and showing interesting biological activities against various fungi.
BACKGROUND OF THE INVENTION
It is well known that some microorganisms are capable of producing metabolites showing interesting biological activities. Such compounds are of potential interest for use in various fields, such as medicine, agriculture, food industry etc.
In the agricultural field biocidal microbial metabolites are considered to be highly interesting alternatives to the synthetic and, from an environmental point of view, generally undesirable compounds normally used for controlling diseases and pests in valuable crops. Accordingly, a fair amount of research has been devoted to the identification and development of such metabolites, which research to date, however, has resulted in only few useful biological (i.e. metabolite based) biocides as compared to the vast number of synthetical biocides presently used. It is consequently desirable to find further microbial metabolites useful as biocidal agents.
Hydroxyalkanoic acids are commonly occurring metabolites in various organisms. Polymerics forms of these, and especially poly .beta.-hydroxybutyric acids, typically composed of several hundreds of units, occur in many bacteria as storage material, with the same function as starch and glycogen in higher organisms (Steinbuchel (1991)). Cyclic oligomers, being somewhat related to the compounds of the present invention, have also been described (Seebach et al. (1988)), but apparently no biological activity has been associated with these compounds.
The genus Penicillium is known to be an efficient producer of secondary metabolites having a diversity of structural features. One group of secondary metabolites encountered in said genus is macrocyclic lactones or the macrolides. An example from this group is the 16-membered dilactone vermiculin (P. vermiculatum) which exhibits antimicrobial effects (Fuska et al. (1972)), (Sedmera et al. (1973)), (Boeckman et al (1974)).
JP-A-3-262489 discloses a metabolite termed NG-012 produced by and isolated from a strain of Penicillium verruculosum F-4542. NG-012 was reported as a nerve growth factor potentiator, and no further activity of this compound was described or indicated. No mention or indication of the structure of NG-012 was given in the above cited Japanese application. The structure of this compound was reported only after the filing date of the present application, cf. the disclosure of Mayumi Ito et al., October 1992.
SUMMARY OF THE INVENTION
It has now surprisingly been found that novel macrocyclic polylactones structurally related to the above mentioned NG-012 and produced by the fungal genus Penicillium have interesting fungicidal activities. The present invention relates to such macrocyclic polylactones as well as their use as antifungal agents.
More specifically, in its first aspect the present invention relates to a group of novel macrocyclic polylactones composed of aliphatic .beta.-hydroxy acids and hydroxylated aromatic acids, having the general formula I, ##STR2## wherein R.sup.1 is hydrogen, hydroxy, --OR.sup.2, or --OCOR.sup.3, in which branched alkenyl with 2-10 carbon atoms, straight or branched alkynyl with 2-10 carbon atoms, benzyl or aryl, optionally mono- or plurisubstituted with straight or branched alkyl with 1-10 carbon atoms, hydroxy, alkoxy, halogen, an amino or a nitro group; and branched alkenyl with 2-10 carbon atoms, straight or branched alkynyl with 2-10 carbon atoms, or aryl, optionally mono- or plurisubstituted with straight or branched alkyl with 1-10 carbo
REFERENCES:
patent: 3836544 (1974-09-01), Urry et al.
Steinbuchler, Alexander, Nachr. Chem. Tech. Lab. 39 (1991), 1112 (SPEC).
JP Abstract 05,32658.
Ito et al., The Journal of Antibiotics, vol. 45, No. 10, pp. 1566-1572, (1992).
Ito et al., The Journal of Antibiotics, vol. 45, No. 10, pp. 1559-1565, (1992).
JP Abstract 03,262489.
Seuring et al., Chem, pp. 2044-2073, 1978.
P.A. Worthington, Natural Products Report, pp. 47-66, 1988.
Boeckman et al., Journal of American Chemical Society, pp. 5954-5957, 1974.
Fuska et al., The Journal of Antibiotics, vol. XXV, No. 4, pp. 208-211, 1972.
Seebach et al., Helvetica Chimica Acta, vol. 71, pp. 155-167, 1988.
Breinholt Jens
Nielsen Ruby Ione
Agris, Esq. Cheryl H.
Krass Frederick
Novo Nordisk A S
Zelson Esq. Steve T.
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