Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-02
2003-07-29
Owens, Amelia (Department: 1628)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S407000, C549S408000
Reexamination Certificate
active
06599933
ABSTRACT:
RELATED APPLICATION
The present application claims the priority of Japanese Patent Application No.2000-268885 filed on Sep. 5, 2000, which is incorporated herein.
1. Field of the Invention
The present invention relates to a tocotrienol derivative, a process for producing the same and a &ggr;-CEHC delivering agent, in particular, an improvement in its bioavailability.
2. Background of the Invention
It was revealed that LLU-&agr; (Loma Linda University-&agr;) is one of natriuretic factors isolated and purified from urine of a uremic patient (Murry E. D. Jr. D., DeWind S. A., Bigornia A. E., D'Amico D. C., King J. G., Pham T., Levine B. H., Jung M. E., Wechter W J., Life Sci. 57, 2145-2161(1995)) and is the same compound as 2,7,8-trimethyl-(&bgr;-carboxyethyl)-6-hydroxychromane (&ggr;-CEHE: the following formula) which is a &ggr;-tocopherol metabolite (Wechter W. J., Kantoci D., Murray E. D. Jr. D'Amico D. C., Jung M. E. Wang W -H., Ptoc. Natl. Acad. Sci USA 93, 6002-6007(1996)).
This LLU-&agr; is considered to be a natriuretic factor because it does not affect on a sodium pump of nephron, average arterial pressure and filtration rate of glomerulus, does not inhibit an isozyme of Na+/K+-ATPase and shows the reversible inhibition only on a 70 pS potassium channel of ascending leg of Henle ansa. Therefore, LLU-&agr; is expected as a diuretic having little side effects on cardiac muscle accompanied by potassium transfer. LLU-&agr; has an asymmetric carbon at 2-position and there are S-LLU-&agr; and R-LLU-&agr;. S-LLU-&agr; has the strongest potassium channel inhibiting activity and S-LLU-&agr; has a R part at a 2-position and is a main metabolite of d-&ggr;-tocopherol.
&ggr;-CEHC was revealed to have effects of inhibiting cyclooxygenase-2 (COX-2)(Jiang Q., Elson-Schwab I., Courtemanche C., Ames B. N., Proc. Natl. Acad. Sci. USA97, 11494-11499(2000)) and is expected as an anti-inflammatory agent or an anti-cancer agent having little side effect. In addition, since &ggr;-CEHC has the chromanol structure, it can function also as an excellent antioxidant.
On the other hand, it has been revealed that natural type d-&ggr;-tocotrienol in which an asymmetric carbon at a 2-position of chroman is R is metabolized effectively into S-&ggr;-CEHC in the living body of a rat (Hattori A., Fukushima T., Yoshimura H., Abe K., Imai K., Biol. Pharm Bull.,23, 1395-1397(2000)).
As described above, in order that &ggr;-CEHC exerts the functions as a diuretic, an anti-inflammatory agent, an anti-cancer agent or an antioxidant effectively, it is essential to maintain dynamic bioavailability and quantitative bioavailability of &ggr;-CEHC. For attaining the maintenance, a method of using &ggr;-CEHC itself is contemplated. However, it was revealed that when racemic &ggr;-CEHC is administered to a SD rat intravenously, a biological half-life of S-&ggr;-CEHC in plasma is 2 minutes or shorter, that of R-&ggr;-CEHC is about 1 hour and, in particular, S-&ggr;-CEHC having the high activity has a very short half-life (Hattori A., Fukushima T., Hamamura K., Kato M., Imai K., Biomed. Chromatogr., in press). Therefore, it is very difficult to maintain bioavailability of &ggr;-CEHC using &ggr;-CEHC itself.
On the other hand, since &ggr;-tocotrienol and &ggr;-tocopherol are metabolized effectively into &ggr;-CEHC in the living body, there can be contemplated a method of maintaining bioavailability of &ggr;-CEHC by maintaining a level of &ggr;-tocotrienol or &ggr;-tocopherol in the living body. A method of performing drug delivery of LLU-&agr; (&ggr;-CEHC) using &ggr;-tocopherol is described in U.S. Pat. No. 6,048,891. However, both &ggr;-tocotrienol and &ggr;-tocopherol are unsteable to oxidation and are a compound which is an oily substance having the high viscosity and is not dissolved to water at all, these physicochemical properties make them impossible to be administered by injection. In addition, it is difficult to handle them from a viewpoint of manufacturing pharmacy and there is a problem on storage stability. For these reasons, a method of solubilizing them by adding a large amount of a nonionic surfactant has been studied in order to prepare an aqueous preparation or aqueous cosmetic of tocotrienol. However, a large amount of an surfactant may cause a severe problem such as anaphylaxis shock and the like. In addition, as a tocotrienol derivative having water dispersion or water solubility, tocotrienolsuccinic acid ester and polyethylene glycol derivative of tocotrienolsuccinic acid ester are known (U.S. Pat. No. 5,869,704). However, there is still left a problem that these compounds are oily or waxy at room temperature and reconversion into tocotrienol in the living body is very slow. Therefore, it is difficult to maintain bioavailability of &ggr;-tocotrienol and &ggr;-tocopherol and, consequently, it is also difficult to maintain bioavailability of &ggr;-CEHC.
Like this, the natures normally harbored by tocopherol and tocotrienol have many disadvantageous points in order to enhance their bioavailability.
SUMMARY OF THE INVENTION
The first object of the present invention is to provide a tocotrienol derivative which is highly water-soluble and can produce free tocotrienol in the living body.
The second object of the present invention is to provide a &ggr;-CEHC delivering agent containing a 6-chromanolcarboxylic acid ester derivative which can produce &ggr;-CEHC in the living body.
That is, present tocotrienolcarboxylic acid ester derivative is characterized in that it is represented by the general formula (I):
(wherein R
2
means a carboxylic acid residue having a nitrogen substituent, and R
1
and R
3
mean a hydrogen atom or a methyl group.)
In addition, in the present invention, it is suitable that the carboxylic acid residue having a nitrogen substituent is at least one selected from the group consisting of residues of amino acid, N-acylamino acid, N-alkylamino acid, N,N-dialkylamino acid, pyridinecarboxylic acid and hydrogen halide salt or alkylsulfonic acid salt thereof.
In addition, a process for producing the tocotrienolcarboxylic acid ester derivative of the present invention comprises protecting a primary or secondary amino group or an amino group of an amino acid having a hydroxy group or a thiol group on a side chain with a protecting group, and subjecting the protecting group-coupled amino acid and tocotrienol to an esterifying reaction.
In addition, the other process for production of the present invention comprises performing an esterifying reaction of a hydrogen halide salt of N,N-dialkylamino acid and tocotrienol in the presence of an active esterifying reagent.
Since a tocotrienol derivative represented by the general formula (I) has an asymmetric carbon at a 2-position of a chromanol skeleton, steric isomers such as d isomer and dl isomer exist The present invention includes these isomers.
In addition, a &ggr;-CEHC delivering agent of the present invention includes a water-soluble 6-chromanol derivative represented by the general formula (II) and releases 2,7,8-trimethyl-(&bgr;-carboxyethyl)-6-hydroxychromane (&ggr;-CEHC) in the living body. (II):
(wherein R
2
means a carboxylic acid residue having a nitrogen substituent.)
In addition, an agent for oral administration of the present invention contains a water—soluble 6—chromanolcarboxylic acid ester derivative represented by general formula (III):
(wherein R
2
means a carboxylic acid residue having a nitrogen substituent, and R
1
and R
3
mean a hydrogen atom or a methyl group.) In the above general formulas II and III, R
4
is a residue represented by the following formula:
In addition, a method of improving bioavailability of &ggr;-CEHC of the present invention comprises administering the compound of the general formula (II) to the living body.
REFERENCES:
patent: 5604450 (1997-02-01), Borkar et al.
patent: 5869704 (1999-02-01), Hyatt
patent: 6048891 (2000-04-01), Wechter
patent: WO 00/18009 (2000-03-01), None
Takata, Jiro; Ito, Sanae; Karube, Yoshiharu; Nagata, Yoshiko; Matsushima, Yoshikazu; Water-soluble prod
Fujiwara Michihiro
Fukushima Takeshi
Hattori Akihiro
Hidaka Ryoji
Imai Kazuhiro
Owens Amelia
Snider Ronald R.
Snider & Associates
Takata Jiro
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