Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Patent
1995-08-10
1996-12-10
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, A61K 31435, A61K 3171
Patent
active
055830188
DESCRIPTION:
BRIEF SUMMARY
This present invention relates to a novel compound and derivatives thereof, to process 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 is a known compound and was first isolated as an exact 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 13,14-Bis(dihydro)rapamycin. This novel compound has been found to have useful antimicrobial and anticancer and immunomodulation activity.
Accordingly the present invention provides 13,14-Bis(dihydro)rapamycin and derivatives thereof.
The invention in a second aspect, further provides a process for the production of 13,14-Bis(dihydro)rapamycin which comprises contacting a microorganism with rapamycin and subsequently isolating 13,14-Bis(dihydro)rapamycin or derivatives thereof from the incubation.
13,14-Bis(dihydro)rapamycin is believed to have the structure shown in formula (I): ##STR2## This compound is referred to herein as 13,14-Bis(dihydro)rapamycin 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 9-10-Bis(dihydro)rapamycin.
Following the numbering system according to Chemical Abstracts (11th Cumulative Index 1982-86 page 60719CS), the compound of the present invention would be called 13,15-Bis(dihydro)rapamycin.
The compound in formula (I) has the following characteristics: (FAB) mass spectroscopy; Streptomyces, in the presence of rapamycin and the recovery of 13,14-Bis(dihydro)rapamycin or a derivative thereof from the culture medium; 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 13,14-Bis(dihydro)rapamycin. It has further been found that an example of such a strain is sp. NCIMB 40535, 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: light plus a photosensitizing agents (e.g., 8-methoxypsoralen), nitrous acid, hydroxylamine, pyrimidine base analogues (e.g. 5-bromouracil), acridines, alkylating agents (e.g. mustard gas, ethyl-methane sulphonate), hydrogen peroxide, phenols, formaldehyde, heat, and transformation, transduction, lysogenisation, lysogenic conversion, protoplast fusion and selective techniques for spontaneous routants.
Using the methods of Becker B. Lechevalier M. P., Gordon R. E., Lechevalier H. A., 1964, Appl. Micr
REFERENCES:
P. Hughes et al., Tetrahedron Letters, vol. 33, No. 33, 1992, pp. 4739-4742.
Romo, J. Am. Chem. Soc., vol. 115, No. 17, 25 Aug. 1993, pp. 7906-7907.
Bond Robert T.
Dinner Dara L.
Lentz Edward T.
SmithKline Beecham p.l.c.
Venetianer Stephen
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