Rapamycin derivative

Details Rapamycin derivative Rapamycin derivative

1994-06-01

1996-02-13

Bond, Robert T.

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

435119, 43525235, A61K 31305, C07D49100

Patent

active

054912296

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/GB92/02235, filed Dec. 1, 1992.
The present invention relates to a novel compound and derivatives thereof, to processes for their production, to pharmaceutical formulations containing them, to their use in medical therapy, particularly in the treatment of bacterial and fungal infections, and also to their use as immunosuppressants and in treating carcinogenic tumours. Rapamycin is a known compound and is a member of the triene class of antibiotics. It was first isolated as an extract of the bacterium 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). At least one rapamycin-producing strain of Streptomyces hygroscopicus was deposited with the Northern Utilization and Research Division, Agricultural Research Service, U.S. Department of Agriculture, Peoria, Ill., U.S.A under accession number NRRL 5491. Rapamycin, and methods for its preparation by culturing NRRL 5491 are disclosed by U.S. Pat. No. 3,929,992 issued Dec. 30, 1975, the entire disclosure of which is hereby incorporated by reference.
A large number of microorganisms have been found to produce a variety of metabolites which have subsequently been isolated and have been shown to possess useful therapeutic properties. One such compound is 14-methylene rapamycin. This is believed to be a novel compound and has been found to have useful antifungal activity, anticancer activity and also immunomodulatory properties.
Accordingly the present invention provides a compound of the formula (I) which is believed to have the following structure: ##STR2##
This novel compound has been found to have useful antimicrobial anticancer and immunomodulatory activity.
This compound is referred to as 14-methylene 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. McAlpine et al., J. Antibiotics (1991) 44, 688 this would be known as 9-methylene rapamycin.
The effect of the differing nomenclatures on the numbering of formula I is shown in formulas II and III below. Formula II represents 14-methylene rapamycin in one of its isomeric forms and formula III 9-methylene rapamycin. ##STR3##
The compound could alternatively be referred to as 14-desoxorapamycin.
For simplicity, 14-methylene rapamycin is referred to in the following text, however where relevant both systems are also referred to.
The invention in a second aspect, further provides a process for the production of 14-methylene rapamycin which comprises cultivating a producing microorganism and subsequently isolating 14-methylene rapamycin or derivatives thereof.
The compound of the present invention has the following characteristics: (FAB) Mass spectroscopy, Streptomyces,
The compound of the present invention may be obtained by the cultivation of a producing organism and the recovery of it or a derivative thereof from the culture.
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 cultivation process according to the invention include bacterial strains belonging to the genus Streptomyces which are capable of elaborating 14-methylene rapamycin. It has further been found that an example of such a strain is sp. NCIB 40319 and also mutants thereof, which has been isolated from nature.
The term `mutant` as used herein includes any mutant strain which arises spontaneously or through the effect

REFERENCES:
patent: 5102876 (1992-04-01), Caufield

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