Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-02-06
2004-06-08
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S565000
Reexamination Certificate
active
06747056
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel K99-5041 substance having inhibitory action for lipid metabolism and a process for production thereof.
BACKGROUND ART
Prior Art
Sterol such as cholesterol in human or ergosterol in fungi is biosynthesized. Enzymes involved in the sterol biosynthesis are recognized as the targets for development of preventive and therapeutic agents for human hyperlipidemia or arteriosclerosis and development of antifungal agents (Tomoda, H. and Omura, S.: Enzyme Technology for Pharmaceutical and Biological Applications, Ed. Kirst, A. et al., Chapter 15, pp. 343-378, Marcel Dekker, Inc. NY, 2001).
Statin series compounds represented by pravastatin specifically inhibit hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, a one of rate-limiting enzyme of cholesterol biosynthesis, and reduce cholesterol level in blood, and are used as preventive and therapeutic drugs for arteriosclerosis in clinical practice. However, in case of statin series compounds used at present, there is a possibility to inhibit biosynthesis of non-sterol compounds which are essential components in vivo. Consequently, enzymes involved in the downstream from squalene which is an intermediate in the biosynthesis are expected as superior target for drugs.
Azole series compounds used for treatment of mycosis such as 2,4-difluoro-&agr;,&agr;-bis-(1H,1,2,4-triazole-1-ylmethyl)benzyl alcohol (generic name: fluconazole, I.C.N. Pharmaceuticals Inc., U.S.A.) and 1-[2-(2,4-dichlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl]imidazole (generic name: miconazole, Sigma Inc., U.S.A.) are used in practice as antifungal agents which inhibit C-14 demethylation of ergosterol. However, appearance of drug resistant microorganisms caused by long-term or repetitive administration of azole series antifungal agents becomes problem. Consequently, development of drugs with high safety and low incidence of resistant strains is urgently necessary.
Lanosterol synthase is an enzyme generating lanosterol by cyclization of 2,3-oxidosqualene as a substrate and drugs which inhibit such enzyme has not been utilized. Consequently, discovery of pharmaceutical agents which inhibit such the enzyme is thought to solve above problems and are expected to be used in clinical practice as preventive and therapeutic agents for myocardial infarction and cerebral apoplexy caused by hyperlipidemia and arteriosclerosis, or new antifungal agents.
An object of the present invention is to provide novel K99-5041 substance, which is used for clinical practice as preventive or therapeutic agents for diseases caused by accumulation of cholesterol in humans by inhibitory action against lanosterol synthase, and process for production thereof.
DISCLOSURE OF THE INVENTION
We have studied on metabolites produced by microorganisms, and found that substances having inhibitory activity for lanosterol synthase were produced in a culture mass of a microbial strain K99-5041 which was newly isolated from soil. Subsequently, we have isolated and purified the active substance inhibiting lanosterol synthase from the cultured mass, and found substances having chemical structure represented by the formula [I] and [II] hereinbelow. Since these substances have not been known, the substances are designated as K99-5041-C1x substance and K99-5041-C2x substance, and totally designated as K99-5041 substance.
The present invention has been completed based on the above knowledge. An object of the present invention is to provide K99-5041-C1x substance represented by the following formula [I]:
Another object of the present invention is to provide K99-5041-C2x substance represented by the following formula [II]:
Further object of the present invention is to provide a composition of novel K99-5041 substance comprising especially K99-5041-C1x substance represented by the following formula [I]:
and especially K99-5041-C2x substance represented by the following formula [II]:
More further object of the present invention is to provide a process for production of K99-5041-C1x substance comprising culturing a microorganism belonging to genus Streptomyces and having ability to produce K99-5041-C1x substance in a medium, accumulating K99-5041-C1x substance in a culture fluid and isolating K99-5041-C1x substance from the cultured mass.
Still further object of the present invention is to provide a process for production of K99-5041-C2x substance comprising culturing a microorganism belonging to genus Streptomyces and having ability to produce K99-5041-C2x substance in a medium, accumulating K99-5041-C2x substance in a culture fluid and isolating K99-5041-C2x substance from the cultured mass.
Still more further object of the present invention is to provide a process for production of a composition of K99-5041 substance comprising culturing a microorganism belonging to genus Streptomyces having ability to produce K99-5041-C1x substance and/or K99-5041-C2x substance in a medium, accumulating K99-5041-C1x substance and/or K99-5041-C2x substance in a culture fluid and isolating K99-5041-C1x substance and/or K99-5041-C2x substance from the cultured mass.
Further object of the present invention is to provide a process for production of K99-5041-C1x substance and/or K99-5041-C2x substance wherein a microorganism belonging to genus Streptomyces and having ability to produce K99-5041-C1x substance and/or K99-5041-C2x substance is Streptomyces sp. K99-5041 FERM BP-8272.
Further object of the present invention is to provide a microorganism of Streptomyces sp. K99-5041 FERM BP-8272.
Further object of the present invention is to provide K99-5041-C1x substance, K99-5041-C2x substance or a composition of K99-5041-C1x substance and/or K99-5041-C2x substance for use as a medicament.
Further object of the present invention is to provide K99-5041-C1x substance, K99-5041-C2x substance or a composition of K99-5041-C1x substance and/or K99-5041-C2x substance used for inhibiting lanosterol synthase which synthesizes lanosterol generated by cyclization of 2,3-oxidosqualene as a substrate.
Further object of the present invention is to provide K99-5041-C1x substance, K99-5041-C2x substance or a composition of K99-5041-C1x substance and/or K99-5041-C2x substance used for preventing or treating diseases of myocardial infarction or cerebral apoplexy based on hyperlipidemia and arteriosclerosis caused by accumulation of cholesterol in humans.
Further object of the present invention is to provide K99-5041-C1x substance, K99-5041-C2x substance or a composition of K99-5041-C1x substance and/or K99-5041-C2x substance used for manufacture of drug preparations for inhibiting myocardial infarction, cerebral apoplexy or mycosis.
Further object of the present invention is to provide K99-5041-C1x substance, K99-5041-C2x substance or a composition of K99-5041-C1x substance and/or K99-5041-C2x substance used for prevention or treatment of diseases including myocardial infarction, cerebral apoplexy or mycosis.
The microorganism having ability to produce K99-5041-C1x substance represented by the above formula [I] and K99-5041-C2x substance represented by the above formula [II] or a composition thereof (hereinafter designates as “K99-5041 substance producing microorganism”) belongs to genus Streptomyces, and, for example, a strain Streptomyces sp K99-5041, which was isolated by us, is an example of the strain used most effectively in the present invention.
Taxonomical properties of the strain K99-5041 are as follows.
1. Morphological Properties
Vegetative mycelia grow well on various agar media and no fragmentation is observed. Aerial mycelia are abundantly grown on yeast-malt extract agar medium and show white to grayish white color. On microscopic observation, chains of more than 20 spores were observed on the aerial mycelia, and the morphological form is flexuous and size of spore is about 0.9-1.1×0.6-0.7 &mgr;m with cylindrical form. Surface of the spore is smooth. No sclerotia, sporangia and zoospore are observed
Ebizuka Yutaka
Omura Satoshi
Shibuya Masaaki
Takahashi Yoko
Tomoda Hiroshi
McKane Joseph K.
Small Andrea D.
The Kitasato Institute
Young & Thompson
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