Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Patent
1996-01-31
1998-01-27
Bond, Robert T.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
4352535, 540456, 514291, C12P 1718, C12R 1465, A61K 31455, C07D49818
Patent
active
057121290
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB 94/01600, filed 25 Jul. 1994, which claims priority of British Application 9315914.3 filed 31, Jul. 1993.
The present invention relates to a novel compound and derivatives to processes for their production, to pharmaceutical formulations containing them, to their use in medical therapy, particularly in the treatment of microbial infections, and also to their use as immuno modulatory agents.
Rapamycin a known compound and was first isolated as an extract of the fungus Streptomyces hygroscopicus and reported to have antifungal activity (British Patent 1436447). Subsequently rapamycin has been implicated as an immunosuppressant (Martel R. R. et al Can. J. Physiol. Pharmacol, 55, 48-51, 1977).
A large number of microorganisms have been found to produce a variety of compounds which have subsequently been isolated and have been shown to possess useful therapeutic properties. Novel compounds have also been obtained by the incubation or cultivation of a microorganism in the presence of known compounds. One such new compound is 42-O-demethylrapamycin. This novel compound has been found to have useful antimicrobial and anticancer and immunomodulation activity.
Accordingly the present invention provides 42-O-demethylrapamycin and derivatives thereof.
The invention in a second aspect, further provides a process for the production of 42-O-demethylrapamycin which comprises contacting a micoorganism with rapamycin and subsequently isolating 42-O-demethylrapamycin or derivatives thereof from the incubation.
42-O-demethylrapamycin is believed to have the structure shown in formula (I): ##STR2##
This compound is referred to herein as 42-O-demethylrapamycin according to the numbering system of J. Findlay et al., Can. J. Chem. (1980) 58, 579. However according to the more recent numbering system of J. Mc Alpine et al., J. Antibiotics (1991) 44. 688 this would be known as 39-O-demethylrapamycin.
Following the numbering system according to Chemical Abstracts (11th Cumulative Index 1982-86 page 60719CS), the compound of the present invention would be called 41-O-demethylrapamycin.
The compound in formula (I) has the following characteristics:
i) it has an apparent molecular weight of 899 by fast atom bombardment (FAB) mass spectroscopy;
ii) it is obtainable by the cultivation of a microorganism from the genus Streptomyces, in the presence of rapamycin and the recovery of 42-O-demethylrapamycin or a derivative thereof from the culture medium;
iii) .sup.13 CNMR spectroscopy reveals 50 carbons in the molecule;
iv) it shows antifungal activity;
v) it shows immunomodulatory activity.
The term `cultivation` (and derivatives of that term) as used herein means the deliberate aerobic growth of an organism in the presence of assimilable sources of carbon, nitrogen, sulphur and mineral salts. Such aerobic growth may take place in a solid or semi-solid nutritive medium, or in a liquid medium in which the nutrients are dissolved or suspended. The cultivation may take place on an aerobic surface or by submerged culture. The nutritive medium may be composed of complex nutrients or may be chemically defined.
It has been found that suitable microorganisms for use in the process according to the invention include bacterial strains belonging to the genus Streptomyces which are capable of elaborating 42-O-demethylrapamycin. It has further been found that an example of such a strain is sp. NCIMB 40515, which has been isolated from nature and also mutants thereof.
The term `mutant` as used herein includes any mutant strain which arises spontaneously or through the effect of an external agent whether that agent is applied deliberately or otherwise. Suitable methods of producing mutant strains including those outlined by H. I. Adler in `Techniques for the Development of Microorganisms` in `Radiation and Radioisotopes for Industrial Microorganisms`, Proceedings of a Symposium, Vienna, 1973, page 241, International Atomic Energy Authority, and these include:
(i) Ionizing radiation (e.g. X-rays and .gamma.-rays), u.v. l
REFERENCES:
patent: 5256790 (1993-10-01), Nelson
patent: 5310901 (1994-05-01), Parsons et al.
patent: 5310903 (1994-05-01), Goulet et al.
Bond Robert T.
Lentz Edward T.
SmithKline Beecham p. l. c.
Stercho Yuriy P.
Venetianer Stephen A.
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