Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Cyclic peptides
Patent
1995-08-16
1997-12-16
Tsang, Cecilia J.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Cyclic peptides
530323, 514 9, 514 11, C07K 1102, C07K 500, A61K 3812, A61K 3800
Patent
active
056986700
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to Aureobasidins which are of value as the therapy of fungal infections.
PRIOR ART
Fungi infect internal organs and brain to induce systemic mycosis or the skin, oral cavity and other tissues to induce superficial mycosis in man. They also cause similar infections in pet, domestic and other animals. It is also known that fungi cause a variety of diseases in plants such as orchard trees and vegetables.
The principal causative agents of systemic mycosis in man are fungi of the genus Candida, those of the genus Cryptococcus, and those of the genus Aspergillus. Superficial mycosis in man are caused by fungi of the genus Candida (infecting the skin, oral cavity, vagina, etc.) or those of the genus Trichophyton (infecting the skin of the hand and foot). In addition, a broad spectrum of other fungi are members of the earth's ecology and are regarded as etiologic factors in many infections and pollutions in animals and plants. Against such fungal infections, a variety of counter-measures have been undertaken.
A large number of antifungal agents are known that can be used for the treatment and prevention of fungal infections and pollutions but few are satisfactory enough in safety and efficacy. Among the therapeutic drugs heretofore available for systemic infections in man and animals are Amphotericin B, Flucytosine, Miconazole and Fluconazole but these drugs are not impeccable, either, in efficacy, toxicity and/or potential of expression of resistance. Particularly, only a very few drugs are available that can success fully control systemic infections which are steadily increasing in these years.
Aureobasidins have been disclosed in, inter alia, Japanese Kokai Publication Hei-2-138296, Japanese Kokai Publication Hei-3-22995, Japanese Kokai Publication Hei-3-44398, Japanese Kokai Publication Hei-3-220199, Japanese Kokai Publication Hei-5-279384 and Japanese Kokai Publication Hei-6-65291. Among the Aureobasidins described in the above literature are Aureobasidin A of the following structural formula (4) and its various analogs. ##STR1##
In the above formula, .sub.D -Hmp represents 2(R)-hydroxy-3(R)-methylpentanoic acid. All the amino acids are L-types.
Aureobasidin A is one of the most active and least toxic of all the known Aureobasidins and is active against many pathogenic fungi inclusive of Candida species. However, this substance is not sufficiently active against Aspergillus and not as active against Cryptococcus as against Candida, so that no sufficient therapeutic efficacy can be expected in infections associated with the former fungi.
Many other Aureobasidins are also highly active against Candida but only weakly active against Cryptococcus and little active against Aspergillus.
DESCRIPTION OF THE INVENTION
This invention has for its object to provide a novel class of Aureobasidins which are broader in antifungal spectrum than the hitherto-known Aureobasidins.
In summary, this invention relates to an Aureobasidin compound of general formula (1): ##STR2## wherein A.sup.1, B.sup.1, F.sup.1, G.sup.1 and H.sup.1 are the same or different and each represents a straight-chain or branched lower alkyl having 1 to 6 carbon atoms; C.sup.1 represents a straight-chain or branched lower alkyl having 1 to 6 carbon atoms, a cycloalkyl having 3 to 7 carbon atoms, benzyloxymethyl, benzyl, a substituted benzyl, phenyl or a substituted phenyl (said substituted benzyl or substituted phenyl means benzyl or phenyl substituted by at least one substituent selected from the class consisting of a straight-chain or branched lower alkoxy having 1 to 6 carbon atoms, cycloalkoxy having 3 to 7 carbon atoms, benzyloxy and halogen); D.sup.1 represents a straight-chain or branched lower alkyl having 1 to 6 carbon atoms, hydroxymethyl or benzyl (where C.sup.1 is benzyl, D.sup.1 is a group other than benzyl and hydroxymethyl); E.sup.1 represents a straight-chain alkylene having 1 to 5 carbon atoms; I.sup.1 represents a hydroxy-substituted lower alkyl having 1 to 6 carbon atoms.
For the purpose of
REFERENCES:
Ikai, et al., NMR Studies of Aureobasidins A and E, Journal of Antibiotics, vol. 44, No. 11, pp. 1199-1207, Nov. 1991.
Ikai, et al., Structures of Aureobasidins B to R, Journal of Antibiotics, vol. 44, No. 11, pp. 1187-1198, Nov. 1991.
Yoshikawa et al., Isolation, Structures, and Antifungal Activities of New Aureobasidins, The Journal of Antibiotics, vol. 46, No. 9, 1993, pp. 1347-1354.
Inami Kaoru
Inoue Tetsuya
Kato Ikunoshin
Kurome Toru
Takesako Kazutoh
Harle Jennifer
Takara Shuzo Co. Ltd.
Tsang Cecilia J.
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