Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heavy metal containing doai
Reexamination Certificate
2001-08-22
2003-01-28
Lilling, Herbert J. (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heavy metal containing doai
C435S118000, C435S128000, C435S253500
Reexamination Certificate
active
06512008
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to WK-5344A substance and WK-5344B substance and production thereof. More particularly, the present invention pertains novel substances, WK-5344A substance and WK-5344B substance having inhibitory action for cholesteryl ester transfer protein and production thereof.
2. Description of Related Art
Various preventive medicaments for myocardial infarction and cerebral accident due to accumulation of cholesterol in vascular wall such as arteriosclerosis caused by adult hypertension have been known. These include, for example, pravastatin, mevinolin and fluvastatin (Endo, A. Journal of Medicinal Chemistry 28, 401-405, 1985 and Endo, A. Journal of Lipid Research 33, 1569-1582, 1992).
Onset of myocardial infarction and cerebral accident and the process of these diseases are very complicate and complex. Consequently, substances having different mechanism of action for treatment of these diseases have been strongly required.
Recently, as a result of westernization of the daily life for foodstuffs, cause of death due to myocardial infarction and cerebral accident as a result of accumulation of cholesterol in the vascular wall is increased and is problem of the life-style related diseases. Most cholesterol is mainly esterified in liver and intestine by long chain fatty acids to form cholesteryl esters, which are secreted into blood as components of chylomicron and very low density lipoprotein, and are circulated in blood mainly as components of low density lipoprotein and high density lipoprotein.
Low density lipoprotein, which transfers cholesterol supplied from the liver into the peripheral tissues, is a risk factor for stimulating arteriosclerosis. On the contrary, the high density lipoprotein collects the cholesterol from the peripheral tissues and is thought to be a factor for suppressing progress of arteriosclerosis. It is cholesteryl ester transfer protein to be involved in the exchange reaction of cholesteryl ester between both lipoproteins, and that is involved in maturation of low density lipoprotein.
Consequently, a substance, which inhibits function of the cholesteryl ester transfer protein, develops decrease of low density lipoprotein, the risk factor for arteriosclerosis, in the blood, and, contrary to that, develops anti-arteriosclerotic action as a result of increase in the high density lipoprotein, which suppresses arteriosclerosis, and is effective for these diseases.
SUMMARY AND OBJECT OF THE INVENTION
We have studied metabolic product of microorganisms isolated from soils in order to find out novel bioactive substances, and found that cultured mass of newly isolated microbial strain WK-5344 from soil produced substances having inhibitory action on cholesteryl ester transfer protein. As a result of isolation and purification of said cholesteryl ester transfer protein inhibitor from said cultured mass, since such substances having such the chemical structures have not been known, we have designated these substances as WK-5344A substance and WK-5344B substance.
The present invention has been completed accordingly to such knowledge.
Further object of the present invention is to provide a process for production of WK-5344A substance and WK-5344B substance or salt thereof comprising culturing a microorganism belonging to genus Streptomyces and having ability to produce WK-5344A substance and WK-5344B substance, accumulating WK-5344A substance and WK-5344B substance in a cultured mass and isolating WK-5344A substance and WK-5344B substance from said cultured mass.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
According to the preferred embodiment of the present invention, the present invention pertains the process for production of novel substance, WK-5344A substance and WK-5344B substance, or salt thereof wherein the microorganism belonging to genus Streptomyces having ability to produce WK-5344A substance and WK-5344B substance is Streptomyces sp. WK-5344. The present invention further relates to a microorganism belonging to genus Streptomyces having ability to produce WK-5344A substance and WK-5344B substance and said microorganism is Streptomyces sp. WK-5344 (FERM BP-6668).
The microorganism having ability to produce WK-5344A substance and WK-5344B substance of the present invention (hereinafter designates as WK-5344 substance producing microorganism) belongs to genus Streptomyces, and is sufficient to have ability to produce WK-5344A substance and WK-5344B substance without no limitation. Example of the preferable microbial strain used to produce WK-5344A substance and WK-5344B substance of the present invention is Streptomyces sp. WK-5344, which is isolated from newly collected soil by the present inventors.
The taxonomical properties of the present strain are as follows.
(I) Morphological Properties
Vegetative mycelia grow well in various agar media and no fragmentation was observed. Aerial mycelia grow abundantly on inorganic salts-starch agar and glycerol-asparagine agar to show white to gray color. In microscopic observation, aerial mycelia showing spiral and chains of more than 20 spores are observed. Form of spores is oval with size of 1.0×0.5 &mgr;m. Surface of spore is spiny. No sclerotium, sporangium and zoospore are observed.
(II) Cultural Properties on Various Agar Media
The cultural properties of the present producing strain observed according to the method of E. B. Shirling and D. Gottlieb (International Journal of Systematic Bacteriology, 16, 313, 1966) are shown in Table 1.
Color tones are determined referring to Color Harmony Manual, 4th ED. (Container Corporation of America, Chicago, 1958) as standard color, and are indicated as name of color tone with its cord in parenthesis. The following table indicates, if not specifically defined, results of visual observation of the state of culture of this strain in various culture media at 27° C. for 2 weeks.
TABLE 1
Sucrose-nitrate agar
growth
good, light mustard tan (2ie)
reverse
light mustard tan-moss green (2ie-241g)
aerial mycelium
abundant, ashes (5fe)
soluble pigment
no production
Glucose-asparagine agar (ISP)
growth
good, bamboo (2gc)
reverse
bamboo (2gc)
aerial mycelium
abundant, alabaster tint-ashes (13ba-5fe)
soluble pigment
pastel yellow (1db)
Glycerol-asparagine agar (ISP)
growth
good, biscuit (2ec)
reverse
bamboo (2gc)
aerial mycelium
abundant, alabaster tint-ashes (13ba-5fe)
soluble pigment
pastel yellow (1db)
Inorganic salts-starch agar (ISP)
growth
good, bamboo (2gc)
reverse
camel (3ie)
aerial mycelium
abundant, ashes (5fe)
soluble pigment
no production
Tyrosine agar (ISP)
growth
good, bamboo (2gc)
reverse
light mustard tan-moss green (2ie-241g)
aerial mycelium
abundant, alabaster tint (13ba)
soluble pigment
no production
Oatmeal agar (ISP)
growth
moderate, bamboo-golden yellow
(2fb-2kb)
reverse
bamboo-covert brown (2fb-2li)
aerial mycelium
moderate, ashes (5fe)
soluble pigment
citron (1gc)
Yeast extract-malt extract agar
(ISP)
growth
good, bamboo (2gc)
reverse
mustard (2le)
aerial mycelium
abundant, pearl gray (13cb)
soluble pigment
olive yellow (1le)
Nutrient agar
growth
moderate, bamboo (2gc)
reverse
nugget gold (2nc)
aerial mycelium
moderate, ashes (5fe)
soluble pigment
no production
Peptone-yeast extract-iron agar
(ISP)
growth
moderate, dull gold (2ng)
reverse
light mustard tan (2ie)
aerial mycelium
poor, white (a)
soluble pigment
no production
Glucose-nitrate agar (ISP)
growth
moderate, light mustard tan (2ie)
reverse
mustard (2le)
aerial mycelium
moderate, white (a)
soluble pigment
gold (1½lc)
Glycerol calcium-malate agar
growth
moderate, bamboo (2gc)
reverse
light wheat-bamboo (2ea-2gc)
aerial mycelium
abundant, pearl (3ba)
soluble pigment
citron (1gc)
Glucose-peptone agar
growth
moderate, bamboo (2gc)
reverse
light wheat-golden yellow (2ea-2kb)
aerial mycelium
poor, white (a)
soluble pigment
no production
(III) Physiological properties
(1)
Melanin pigment
(a) Tyrosine agar
negative
(b) Peptone-yeast extract-iron agar
negative
(c) Glucose-peptone-gelatin medium
negative
(d) Tryptone-yeast extrac
Omura Satoshi
Takahashi Yoko
Tomoda Hiroshi
Kitasato Institute
Lilling Herbert J.
Young & Thompson
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