Macrolide compound JK

Details Macrolide compound JK Macrolide compound JK

2001-10-26

2004-02-17

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S033000, C536S004100, C536S016800, C536S016900, C536S017200, C536S018100, C536S018200, C536S018400, C536S018500, C536S029100

Reexamination Certificate

active

06693085

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel compound JK. More particularly, it relates to novel compounds JK-
1
and JK-
2
, and a process for producing them, and use of them. The novel compounds JK-
1
and
2
, which are so far unknown novel macrolide compounds isolated from microorganisms, particularly from a culture of actinomycetes, have excellent physiological activities, particularly potent antimicrobial effect, especially activity against MRSA (methicillin-resistant
Staphylococcus aureus
). Known MM46115, which is analogous to the compounds of the invention (R. J. Ashton et al., J. Antibiot., Vol. 43, 1387-1393 (1990); K. Luk et al., J. Chem. Soc. Perkin Trans. 1, Vol. 7, pp. 1641-1644 (1991)), exhibits strong cytotoxicity, whereas the novel compounds JK-
1
and JK-
2
are characterized in that they do not have cytotoxicity at all. Further study has to be continued to elucidate the detailed mechanisms, though it is presumed as a mechanism that the CH
3
group at 3′ position is important for generation of the cytotoxicity due to structural difference.
Therefore, the novel macrolide compounds JK-
1
and JK-
2
of the invention are very useful as antimicrobials in preventive and/or therapeutic agents, which can be effectively utilized. The compounds of the invention have potent antimicrobial activities and are not only effective against MRSA (methicillin-resistant
Staphylococcus aureus
) which has become a problem in recent years, but also much more active against MRSA than currently employed vancomycin. In addition to these characteristics, they have no problem on safety and show a distinctive feature in practical use.
PRIOR ART
A large number of novel compounds have been discovered and synthesized as antimicrobial agents, some of which have been put to practical use. On the other hand, since multiple-drug resistant strains have occurred as represented by hospital-acquired infection, a new type of antimicrobial agents which have a different active site from that of the existing antimicrobial agents and are effective against the resistant strains have been required.
Though a variety of superior antimicrobial agents have long been known, it has been required to develop antimicrobial agents which are effective against MRSA and other resistant strains and highly appreciated in safety and productivity.
PROBLEMS THAT THE INVENTION IS TO SOLVE
The present invention was made in response to such demands in this field. In this situation, extensive screenings were conducted along the technological trend of development of antimicrobial agents and consequently it was found that so far unknown novel compounds had anti-microbial activities. The present invention was completed based on these findings. The purpose of the present invention is to provide novel antimicrobial compounds that are much better than the known compounds in antimicrobial activities against various microorganisms including resistant strains, safety such as no toxicity and no side effects, and productivity such as easy mass production.
MEANS FOR SOLVING THE PROBLEMS
In order to obtain novel antimicrobial compounds, the present inventors searched widely natural products, particularly metabolites of microorganisms, to reach more effective antimicrobials. As a result, they found materials that have the aimed action in the cell extract of an actinomycete,
Actinomadura pelletieri
IFM0903 (FERM BP-7030). They investigated physicochemical properties of the materials to reveal the chemical structures, and confirmed that the materials are so far unknown and novel. As described in Claims 1 to 3, the materials are novel macrolide compounds as shown by the general formula (1). The inventors have designated these compounds generally JK, and specifically one JK-
1
in which R in the formula (1) is a methyl group and the other JK-
2
in which R is a hydrogen atom.
That is, the present invention relates to novel compound JK of the formula (1) as shown in
FIG. 1
(which involve JK-
1
wherein R═CH
3
and JK-
2
wherein R═H) or a pharmaceutically acceptable salt thereof.
In the present invention, the salt includes all of pharmaceutically acceptable salts, for example, alkali metal salts such as sodium salts, potassium salts, etc., alkaline earth metal salts such as calcium salts, magnesium salts, etc., inorganic acid salts such as hydrochloride, sulfate, nitrate, etc., and organic salts such as organic acid salts, amine salts, pyridinium salts, etc.
In addition, the present invention relates to an antimicrobial agent comprising as the effective component a novel macrolide compound JK-
1
, JK-
2
or a pharmaceutically acceptable salt thereof. The present invention will be explained in detail hereinafter.


REFERENCES:
patent: 5096817 (1992-03-01), Nishio et al.
patent: 0 345 078 (1989-12-01), None
patent: 0 398 588 (1990-11-01), None
Ashton et al., “MM 46115, a New Antiviral Antibiotic fromActinomadura pelletieri”, The Journal of Antibiotics, vol. 43, No. 11, pp. 1387-1393, 1990.*
R. J. Aston, et al., The Journal of Antibiotics, vol. 43, No. 11, pps. 1387-1393, “MM46115, A New Antiviral Antibiotic fromActinomadura pelletieriCharacteristics of the Producing Cultures, Fermentation, Isolation, Physico-Chemical and Biological Properties”, 1990.
K. Luk, et al., J. Chem. Soc. Perkin Trans. 1, vol. 7, pps. 1641-1644, “Structural Studies of MM46115, A Novel Tetronic Acid Containing Macrolide with Antiviral and Antibacterial Activity Isolated FormActinomadura pelletieri”, 1991.
I. Momose, et al., The Journal of Antibiotics, vol. 52, No. 9, pps. 781-786, “Decatromicins A and B, New Antibiotics Produced by Actinomadura Sp. MK73-NF4 I. Taxonomy, Isolation, Physico-Chemical Properties and Biological Activities”, Sep. 1999.
I. Momose, et al., The Journal of Antibiotics, vol. 52, No. 9, pps. 787-796, “Decatromicins A and B, New Antibiotics Produced by Actinomadura Sp. MK73-NF4 II. Structure Determination”, Sep. 1999.

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