Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-09-27
2004-08-24
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S824000
Reexamination Certificate
active
06780886
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a vitamin E metabolite which exhibits anti-oxidant action and belongs to the field of food and pharmaceuticals.
PRIOR ART
Tocopherol and tocotrienol are known to have anti-oxidant action.
On the other hand, carboxyethylhydroxychromanes are in vivo metabolites of tocopherol and tocotrienol. Among all, 2,7,8-triethyl-2-(&bgr;-carboxyethyl)-6-hydroxychromane is known to have natriuretic activity (Wechter et al., Proc. Natl. Acad. Sci. USA, 93, 6002-6007, 1996) but other activities thereof are still unknown.
It has been suggested that &agr;-tocopherol has anti-oxidant action to inhibit LDL (low density lipoprotein) oxidization which may possibly prevent crisis of arterial sclerosis. On the other hand, it has not been determined yet whether its analogues such as &ggr;-tocopherol and tocotrienol have in vivo anti-oxidant action or not, since little of them could be detected in unchanged forms in blood after oral administration.
DISCLOSURE OF THE INVENTION
After examining the activities of carboxyethylhydroxychromane, (in vivo metabolites of tocopherol and tocotrienol), the present inventors unexpectedly found that the compounds described below have anti-oxidant action and accomplished the present invention.
The invention provides a method of preventing or treating a disease caused by oxidation in vivo by administering a pharmacologically effective amount of at least one compound selected from the group consisting of:
(1) 2,5,7.8-tetramethyl-2-(&bgr;-carboxyethyl)-6-hydroxychromane, a pharmacologically acceptable salt thereof or a pharmacologically acceptable hydrate thereof and
(2) 2,7.8-trimethyl-2-(&bgr;-carboxyethyl)-6-hydroxychromane, a pharmacologically acceptable salt thereof or a pharmacologically acceptable hydrate thereof.
The invention then provides use of the compound as defined above (1) or (2) for manufacturing an anti-oxidant medicine.
The invention moreover provides use of a compound selected from the group consisting of (3) &agr;-tocopherol, (4) &agr;-tocotrienol, (5) &ggr;-tocopherol and (6) &ggr;-tocotrienol for generation in vivo of any of the compounds as above (1) and (2) to treat a disease caused by oxidated low density lipoprotein (LDL).
It is preferable that the disease is that caused by oxidated low density lipoprotein (LDL), especially being arteriosclerosis.
The present invention relates to antioxidants which are 2,5,7,8-tetramethyl-2-(&bgr;-carboxyethyl)-6-hydroxychromane or a salt thereof and/or 2,7,8-trimethyl-2-(&bgr;-carboxyethyl)-6-hydroxychromane, a salt thereof or a hydrate thereof. The present invention also relates to an antioxidant comprising 2,5,7,8-tetramethyl-2-(&bgr;-carboxyethyl)-6-hydroxychromane or a salt thereof and/or 2,7,8-trimethyl-2-(&bgr;-carboxyethyl)-6-hydroxychromane, a salt thereof or a hydrate thereof. The present invention also relates to an antioxidant comprising &agr;-tocopherol and/or &agr;-tocotrienol which exhibit anti-oxidant action when metabolized to 2,5,7,8-tetramethyl-2-(&bgr;-carboxyethyl) -6-hydroxychromane by metabolizing enzyme, or to an antioxidant comprising &ggr;-tocopherol and/or &ggr;-tocotrienol which exhibit anti-oxidant action when metabolized to 2,7,8-trimethyl-2-(&bgr;-carboxyethyl)-6-hydroxychromane by metabolizing enzyme. The present invention further relates to an agent for preventing or treating arterial sclerosis, which comprises 2,5,7,8-tetramethyl-2-(&bgr;-carboxyethyl)-6-hydroxychromane or a salt thereof and/or 2,7,8-trimethyl-2-(&bgr;-carboxyethyl)-6-hydroxychromane, a salt thereof or a hydrate thereof.
2,5,7,8-Tetramethyl-2-(&bgr;-carboxyethyl)-6-hydroxychromane according to the present invention is a metabolite of &agr;-tocopherol or &agr;-tocotrienol, which has the following formula (hereinafter referred to as “&agr;-CEHC”). &agr;-CEHC may also be referred to as 2,5,7,8-tetramethyl-2-(2′-carboxyethyl)-6-hydroxychromane.
Further, 2,7,8-trimethyl-2-(&bgr;-carboxyethyl)-6-hydroxychromane is a metabolite of &ggr;-tocopherol or &ggr;-tocotrienol, which has the following formula (hereinafter referred to as “&ggr;-CEHC”). &ggr;-CEHC may also be referred to as 2,7,8-trimethyl-2-(2′-carboxyethyl)-6-hydroxychromane.
When &agr;-CEHC and &ggr;-CEHC are produced by metabolizing enzyme, optically active substance (S-configuration) may be produced. Racemic modifications thereof may be used in antioxidants or agents for preventing or treating arterial sclerosis according to the present invention.
&agr;-CEHC and &ggr;-CEHC may be prepared according to any known method. These compounds may be present in a form of salt combined with organic or inorganic material. Further, hydrates of these compounds or salts thereof may be used.
The effective amount of &agr;-CEHC and/or &ggr;-CEHC as antioxidants in blood may be, but not limited to, about 200 pmol/ml, for example. &agr;-CEHC and/or &ggr;-CEHC show anti-oxidant action not only in vivo but also when contained in pharmaceuticals, foods, diet and the like. &agr;-CEHC or &ggr;-CEHC may be used alone or in combination.
Alternatively, &agr;-tocopherol, &agr;-tocotrienol, &ggr;-tocopherol or &ggr;-tocotrienol itself may also exhibit in vivo anti-oxidant action after administration, since &agr;-CEHC and &ggr;-CEHC are produced by metabolisms of &agr;-tocopherol, &agr;-tocotrienol, &ggr;-tocopherol or &ggr;-tocotrienol in vivo. Conventionally, in vivo anti-oxidant activity has been confirmed in &agr;-tocopherol but in &agr;-tocotrienol, &ggr;-tocopherol or &ggr;-tocotrienol. The dosage of &agr;-tocotrienol, &ggr;-tocopherol or &ggr;-tocotrienol required to obtain in vivo anti-oxidant action after oral administration is 10-2000 mg.
&agr;-CEHC and/or &ggr;-CEHC may be used as antioxidant directly or after formulated into any dosage form. Such formulation may be prepared by: mixing &agr;-CEHC and/or &ggr;-CEHC with an excipient such as lactose, mannitol and silicic acid anhydride, and then with a disintegrating agent (such as starch, low substitution hydroxypropylcellulose and crystalline cellulose) and a binder (such as hydroxypropyl cellulose, polyvinylpyrrolidone and hydroxypropylcellulose); granulating the mixture while adding solvent such as water and ethanol thereto; finely graining if necessary; and drying to form dry granules or fine granules. Further, such granules and the like may be formulated into capsules or tables, or dispersed into water to obtain liquid formulation. Optionally, organic solvent (e.g., ethanol), plant oil, synthetic oil, surfactant, flavors or the like may be added.
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Stahl et al., Anal. Bio
Igarashi Osamu
Kiyose Chikako
Kondo Kazuo
Yoshimura Hiroyuki
Yoshitake Shigehiro
Eisai Co. Ltd.
Webman Edward J.
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