Macrocyclic lactone compounds and their production process

Details Macrocyclic lactone compounds and their production process Macrocyclic lactone compounds and their production process

1997-10-27

1999-12-14

Shah, Mukund J.

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

Organic compounds

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

C07D49818

Patent

active

060019980

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to a novel macrocyclic lactone compound, and particularly to a novel macrocyclic lactone compound produced by fermentation of a microorganism designated as Actinoplanes sp., which has been deposited as FERM BP-3832. This invention also relates to a process for producing the macrocyclic lactone compounds, and a pharmaceutical composition comprising the same, which is useful as immunosuppressive, antimycotic, antitumor agent or the like.


BACKGROUND ART

In 1983, the United States Food and Drug Administration approved cyclosporin for use in human subjects as an anti-rejection drug. Use of cyclosporin has revolutionized the filed of organ transplant surgery. The drug acts by the inhibition of 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. Accordingly, safer drugs exhibiting less side effects have been investigated.
It was reported that some macrolide compounds, rapamycin and its analogs have immunosuppressive activity or the like (European Patent Publication No. 0184162; U.S. Pat. Nos. 3,929,992 and 3,993,749). European Patent Publication No. 0589703A discloses 21-norrapamycin useful in the treatment or prevention of transplantation rejection, autoimmune diseases and the like. Also, some rapamycin analogs having immunosuppressive activity are disclosed in Japanese Patent Application Laid-Open No. 292948/1993.
The object of the present invention is to provide a novel macrocyclic lactone compound having an excellent immunosuppressive, antimycotic or antitumor activity, and a pharmaceutical composition comprising the same.
Other objects of the present invention are to provide a process for producing the novel macrocyclic lactones, pharmaceutical compositions containing them and methods for using them.


BRIEF DISCLOSURE OF THE INVENTION

Accordingly, the present invention provides the macrocyclic lactone compound identified as CJ-12,798, which has the following chemical formula: ##STR1##
Additionally, this invention provides the macrocyclic lactone compounds designated as CJ-13,502; CJ-13,503 and CJ-13,504 having characteristics described below.
Further, the present invention provides a process for producing the macrocyclic lactone compounds, CJ-12,798, CJ-13,502, CJ-13,503 and CJ-13,504, which comprises cultivating a microorganism having the identifying characteristics of Actinoplanes sp. FERM BP-3832, or a mutant or recombinant form thereof, in the presence of L-proline, L-hydroxyproline or L-nipecotic acid.
Also, the present invention provides a pharmaceutical composition for use in the treatment or prevention of transplantation rejection, autoimmune diseases, mycotic diseases or tumors, which comprises a compound selected from CJ-12,798, CJ-13,502, CJ-13,503 and CJ-13,504, and a pharmaceutically acceptable carrier.


BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is the .sup.1 H NMR spectrum of the compound of CJ-12,798.
FIG. 2 is the LSI mass spectrum of the compound CJ-12,798.
FIG. 3 is the ESI mass spectrum of the compound CJ-13,502.
FIG. 4 is the ESI mass spectrum of the compound CJ-13,503.
FIG. 5 is the ESI mass spectrum of the compound CJ-13,504.
FIG. 6 is the UV spectrum of the compound CJ-12,798.
FIG. 7 is the UV spectrum of the compound CJ-13,502.
FIG. 8 is the UV spectrum of the compound CJ-13,503.
FIG. 9 is the UV spectrum of the compound CJ-13,504.


DETAILED DESCRIPTION OF THE INVENTION

The microorganism which is used in this invention is a strain of Actinoplanes sp. which was deposited as Actinoplanes sp. FERM BP-3832 at National Institute of Bioscience and Human-Technology, Agency of Industrial Science and Technology (located at 1-3, Higashi 1-chome, Tsukuba, Ibaraki, 305, Japan) under the Budapest Treaty on Apr. 13, 1992. The details of this strain, including its taxonomical properties, are d

REFERENCES:
patent: 5091389 (1992-02-01), Ondeyka et al.
Nishida, et al., Journal Of Antibiotics, 48, pp. 657-666 (1995).

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