Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1986-04-28
1989-06-06
Brust, Joseph Paul
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514457, 548525, 549289, A61K 3137, A61K 31395, C07D20709, C07D31178
Patent
active
048372226
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a new class of compounds, known as xenocoumacins, which comounds may be isolated from the culture of strains of bacteria of the genus Xenorhabdus.
BACKGROUND ART
Insect pathogenic nematodes of families Heterorhabitidae and Steinernematidae are known to be symbiotically associated with bacteria of the genus Xenorhabdus. It has been observed that these bacteria have the ability to inhibit the activity of other bacterial growth.
International Application No. PCT/AU83/00156 (WO84/01775) discloses certain lipid soluble antibiotics isolated and characterised from cultures of the genus Xenorhabdus. The disclosures of that application are incorporated herein by reference.
DISCLOSURE OF INVENTION
The compounds of the present invention include those isolated from the water soluble component of the culture supernatant of Xenorhabdus nematophilus and Xenorhabdus luminescens and their derivatives and have been found to have the structure of fomula I. ##STR2## wherein 1 R.sub.1 is hydrogen, straight or branched chain, alky or acyl unsubstituted or substituted by one or more substituents selected from hydroxy, acyl, acyloxy, halogen; or ##STR3## taken together represents a 5 to 7 membered heterocyclic ring which may contain a further nitrogen, oxygen or sulfur heteroatom,
Particularly preferred compounds of the present invention have the structure of formulae II and III below, and are designated xenocoumacin 1 and xenocoumacin 2 respectively. ##STR4##
The invention also provides a process for preparing xenocoumacin 1 and xenocoumacin 2 which comprises culturing an antibiotic producing strain of Xenorhabdus nematophilus, or Xenorhabdus luminescens, in a suitable culture medium and separating the compounds of the invention and their precursors from the culture broth.
Preferably, the process is a continuous process wherein culture medium is continuously added to the fermenter and culture medium is continually removed from the fermenter at a rate to maintain the volume of the culture within predetermined limits. The compounds of the invention and their precursors are separated from the collected culture.
The invention also provides for preparing compounds of formula 1 as defined above, which process comprises hydroxy, R.sub.5 is hydrogen, n is O and A is --(CH.sub.2).sub.m --B wherein m is 3 and B is guanidino; and are hydroxy, R.sub.5 is hydrogen, n is O and ##STR5## is a pyrrolidinyl ring, culturing a xenocoumacin producing strain of Xenorhabdus nematophilus or Xenorhabdus luminescens in a suitable culture medium and separating the desired compounds from the culture broth; R.sub.4, R.sub.5, R.sub.6, n, A, m and B are other than as defined under (a) R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, n, A, m and B are as defined under (a) to produce an aldehyde of the formula 2 ##STR6## (ii) reacting the compound of formula 2 with a phosphane of formula 3: ##STR7## wherein Ar is aryl and R.sub.4, R.sub.5, and A are as defined above to produce a compound of formula 4: ##STR8## (iii) oxidising the compound of formula 4 to produce a compound of formula 1 in which R.sub.3 is hydroxy; R.sub.4, R.sub.5, R.sub.6, n, A, m and B are as defined under (b), alkylating compound of formlua 1 as defined above wherein R.sub.1 is hydrogen, R.sub.3 and/or R.sub.4 are hydroxy, to produce compounds of formula 1 as defined above wherein one or more of R.sub.1, R.sub.3 and/or R.sub.4 are alkyl; or R.sub.4, R.sub.5, R.sub.6, n, A, m and B are as defined under (c), acylating a compound of formula 1 as defined above wherein R.sub.1 is hydrogen, R.sub.2 and/or R.sub.4 is hydroxy, or R.sub.5 is hydrogen to produce compounds of formula 1 as defined above wherein R.sub.1 is acyl, one or more of R.sub.3, R.sub.4 and R.sub.5 is acyloxy and/or B is substituted by acyloxy.
In a further aspect of the invention provides pharmaceutical formulations characterised in that the active ingredient comprises a compound of the invention.
Xenocoumacins have been found to possess antibacterial, antifungal, acaricidal, an
REFERENCES:
patent: 4393225 (1983-07-01), Hayashi et al.
Chemical Abstracts, vol. 98, No. 18 Issued 1983, Abstract No. 143174u, Itoh et al.
"Chemical Structures of Amicoumacins Produced by the Bacillus pumilis", by Itoh et al., Agric. & Bio. Chem., vol. 46 (1982), pp. 2659-2665.
Chemical Abstracts, vol. 99, No. 15, Issued 1983, Abstract No. 122155u, Shimojima et al.
"1H-2-Benzopyran-1-One Derivatives, Microbial Products with Pharmacological Activity", by Shimojima et al., & Journal of Med. Chem., 1983, vol. 26, pp. 1370-1374.
Gregson Richard P.
McInerney Bernard V.
Biotechnology Australia Pty. Ltd.
Brust Joseph Paul
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