Chemistry: molecular biology and microbiology – Micro-organism – per se ; compositions thereof; proces of... – Bacteria or actinomycetales; media therefor
Patent
1994-01-24
1996-02-27
Marx, Irene
Chemistry: molecular biology and microbiology
Micro-organism, per se ; compositions thereof; proces of...
Bacteria or actinomycetales; media therefor
435119, 435118, C12P 104, C12P 1718
Patent
active
054948207
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to a new macrocyclic lactone immunosuppressant agent, a process for its production and its use in a human host for treatment of autoimmune diseases and/or prevention of organ transplant rejections. This application is a continuation of U.S. application 683,639 first filed on Apr. 11, 1991. Priority is hereby claimed to that application. In 1983, the United States Food and Drug Administration licensed cyclosporin, an anti-rejection drug that revolutionized the field of organ transplant-surgery. The drug acts by inhibiting the body's immune system from mobilizing its vast arsenal of natural protecting agents to reject the transplant's foreign protein. Although cyclosporin is effective in fighting transplantation rejection, it suffers drawbacks in causing kidney failure, liver damage and ulcers which in many cases can be very severe. Newer, safer drugs exhibiting less side effects are constantly being searched for. European Patent Publication No. 0184162 of Fujisawa Pharmaceutical Co., Ltd., describes the macrolids immunosuppressants FK-506 and FK-520. The latter is produced by S. hygroscopicus subsp. yakushimaensis No. 7238. Other immunosuppressants are described in European Patent Application Publication Nos. 0323042, 0323865, 0356399 of Fisons plc, Merck & Co. Inc., and Sandoz, respectively.
SUMMARY OF THE INVENTION
The present invention relates to a new immunosuppressant of the formula ##STR2##
The compound of the formula I may be referred to as "C.sub.9 -desoxo-FK-520" because it differs from FK-520 in lacking an oxo group at the C.sub.9 position. In view of the compound's similarity to FK-520 its stereochemistry is expected to be as shown in the following formula ##STR3##
The present invention also relates to a process for preparing the compound of the formula I comprising fermenting a compound of the formula I producing strain of bacteria (e.g., a Streptomyces strain such as Streptomyces braegensis subsp. pulcherrimus Huang subsp. nov.) in an aqueous nutrient medium containing an assimilable carbon source and an assimilable nitrogen source, said fermentation being conducted preferably at a pH between about 4.0 and about 8.0, and extracting the compound of the formula I from the medium, preferably at a pH of about 4.0 to about 8.0.
The present invention also relates to a pharmaceutical composition containing an amount of the compound of the formula I effective in treating autoimmune disease (e.g. rheumatoid arthritis) or preventing organ transplant rejection in a mammal (e.g. a human) in combination with a pharmaceutically acceptable carrier.
The present invention also relates to a method of treating a mammal (e.g. a human) to prevent transplantation rejection or treating an autoimmune disease (e.g. rheumatoid arthritis) in a mammal (e.g. a human) comprising administering to said mammal a therapeutically effective amount of the compound of the formula I.
Finally, the present invention is directed to a biologically pure culture having the characteristics of Streptomyces braegensis subsp. pulcherrimus Huang subsp. nov., ATCC 55150, and ATCC 55150 per se, as well as mutants and transformants of any of the foregoing capable of producing the compounds of the formula I, including any such culture in freeze-dried form. Such a culture is capable of producing the compound of the formula I in a recoverable quantity upon fermentation in an aqueous nutrient medium comprising assimilable sources of carbon and nitrogen.
DESCRIPTION OF THE DRAWINGS
FIG. 1 is the proton NMR spectrum in CDCl.sub.3 of the compound of the formula I, C.sub.9 -desoxo-FK-520.
FIG. 2 is the carbon NMR spectrum in CDCl.sub.3 of C.sub.9 -desoxo-FK-520.
DETAILED DESCRIPTION OF THE INVENTION
In general, the compound of the formula I can be produced by culturing a compound of the formula I producing strain of bacteria in an aqueous nutrient medium containing sources of assimilable carbon and nitrogen, preferably under submerged aerobic conditions (e.g. shaking culture, submerged culture,
REFERENCES:
patent: 4404190 (1983-09-01), Dolak
Hatanaka et al, J. Antibiot., vol. 41, 1988 pp. 1592-1601.
Hatanaka et al, J. Antibiot, vol. 42, 1989 pp. 620-622.
Rance et al, J. Antibiot., vol. 42, 1989 pp. 206-217.
Cullen Walter P.
Guadliana Mark A.
Huang Liang H.
Kaneda Keiji
Kojima Nakao
Butterfield Garth
Ginsburg Paul H.
Marx Irene
Pfizer Inc.
Richardson Peter C.
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