Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-11-25
2004-12-07
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C424S059000, C424S062000, C424S078030, C549S317000
Reexamination Certificate
active
06828348
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel and useful L-ascorbic acid-2-O-maleic acid-&agr;-tocopherol diester.1-propanol adduct or pharmacologically acceptable salts of the same, to processes for producing the same and to uses of the same as a cosmetic component or ingredient, antioxidant, radical scavenger, anti-inflammatory agent or elastase inhibitor.
BACKGROUND OF THE INVENTION
There have heretofore been known L-ascorbic acid-2-O-maleic acid-&agr;-tocopherol diesters represented by the following formula (I) (International Publication No. WO 01/04114):
The international publication discloses that the diester compounds are usable as a cosmetic ingredient, antioxidant, radical scavenger or anti-inflammatory agent.
However, the process as described in the said international publication suffers from the defects that the resultant L-ascorbic acid-2-O-maleic acid-&agr;-tocopherol diesters are difficult to crystallize, that the said diesters, even after being made crystalline, are difficult to be filtered, and that even the crystals obtained in any way are inferior in stability, and can be considered incomplete and defective in terms of a commercial-scale process. Therefore, there is strongly demanded a crystallization process for the L-ascorbic acid-2-O-maleic acid-&agr;-tocopherol diesters which process can eliminate such defects.
Under these circumstances, the present inventors conducted repeatedly extensive investigation, and as a result, found that the post-reaction treatment with use of 1-propanol and a solution mixture of 1-propanol with an organic solvent can yield L-ascorbic acid-2-O-maleic acid-&agr;-tocopherol diesters with enhanced crystallinity and improved filtrability and that the 1-propanol adduct obtained in this manner is excellent in stability. These findings, followed by further research work, have culminated into completion of the present invention.
DISCLOSURE OF THE INVENTION
The present invention relates to:
(1) L-Ascorbic acid-2-O-maleic acid-&agr;-tocopherol diester.1-propanol adduct or pharmacologically acceptable salts of the same (hereinafter referred to in some instances as “Compounds”),
(2) L-Ascorbic acid-2-O-maleic acid-&agr;-tocopherol diester.1-propanol adduct or their pharmacologically acceptable salts of the same in the crystalline form,
(3) A process for producing L-ascorbic acid-2-O-maleic acid-&agr;-tocopherol diester.1-propanol adduct, characterized in that said process comprises subjecting a solution containing a L-ascorbic acid-2-O-maleic acid-&agr;-tocopherol diester to extraction with an extraction solvent, distilling off the extraction solvent, and admixing the resultant residue with 1-propanol or a solution mixture of 1-propanol with an organic solvent to thereby allow crystallization,
(4) A process as described above under the item (3), wherein the said organic solvent is n-hexane, cyclohexane and/or petroleum ether,
(5) A process as described above under the item (3) or (4), wherein the said extraction solvent is chloroform, ethyl acetate or a solvent mixture thereof,
(6) Compositions, characterized in that said compositions comprise L-ascorbic acid-2-O-maleic acid-&agr;-tocopherol diester.1-propanol adduct or pharmacologically acceptable salts of the same,
(7) Cosmetic compositions, characterized in that said compositions comprise L-ascorbic acid-2-O-maleic acid-&agr;-tocopherol diester.1-propanol adduct or pharmacologically acceptable salts of the same,
(8) Antioxidant compositions, characterized in that said compositions comprise L-ascorbic acid-2-O-maleic acid-&agr;-tocopherol diester.1-propanol adduct or pharmacologically acceptable salts of the same,
(9) Radical scavenging compositions, characterized in that said compositions comprise L-ascorbic acid-2-O-maleic acid-&agr;-tocopherol diester.1-propanol adduct or pharmacologically acceptable salts of the same,
(10) Anti-inflammatory compositions, characterized in that said compositions comprise L-ascorbic acid-2-O-maleic acid-&agr;-tocopherol diester.1-propanol adduct or pharmacologically acceptable salts of the same, and
(11) Elastase inhibitory compositions, characterized in that said compositions comprise L-&agr;-ascorbic acid-2-O-maleic acid-&agr;-tocopherol diester.1 -propanol adduct or pharmacologically acceptable salts of the same.
Also, the present invention provides a method of enhancing the elastase inhibition, a method of suppressing erythema caused by ultraviolet radiation, a method of preventing suntan caused by ultraviolet radiation, a method of skin beauty care, skin whitening care or skin-crease prevention, a method of preventing oxidation, a method of radical scavenging and a method of treating inflammatory diseases.
Furthermore, the present invention provides uses of L-ascorbic acid-2-O-maleic acid-&agr;-tocopherol diester.1-propanol adduct or pharmacologically acceptable salts of the same in the manufacture of cosmetics, antioxidants, radical scavengers or elastase inhibitors.
The process for producing L-ascorbic acid-2-O-maleic acid-&agr;-tocopherol diesters as claimed in the above-mentioned international publication, comprising use of ethanol in the purification step, yields the crystallized ethanol adducts of said diesters, which are considered to be freed of the alcohol (dealcoholization) by subsequent drying under reduced pressure.
Intensive investigation into these phenomena led to the finding that use of an alcohol can allow L-ascorbic acid-2-O-maleic acid-&agr;-tocopherol diesters to crystallize through addition of the alcohol. In the crystallization and production processes for these compounds, an alcohol may be used solely, but is preferably used in combination with one or two or more of n-hexane, cyclohexane and petroleum ether. It was found out that these crystalline alcohol adducts are freed of the alcohol (dealcoholization), when dried at about 60° C. under reduced pressure, but are held intact in the form of an alcohol adduct consisting of 1 mole of L-ascorbic acid-2-O-maleic acid-&agr;-tocopherol diester and 1 mole of an alcohol, when dried at a temperature in the neighborhood of 30° C. Among these alcohols, 1-propanol or 1-butanol can afford the best crystallinity to the adduct products, whereas 2-propanol has the defect of inferior production yields since L-ascorbic acid-2-O-maleic acid-&agr;-tocopherol diesters are more soluble in it. It is added that methanol and butanol are not desirable in terms of toxicity and disagreeable odor, respectively. Comparison between ethanol and 1-propanol adducts led to the finding that 1-propanol adduct is by far superior to the ethanol one in thermal stability.
The pharmacologically acceptable salts of the present invention are exemplified by their alkali metal salts, such as their sodium and potassium salts, and their alkaline earth metal salts, such as their calcium and magnesium salts, and may include any miscellaneous salts, only if they are pharmacologically acceptable.
The L-ascorbic acid-2-O-maleic acid-&agr;-tocopherol diester.1-propanol adduct of the present invention can property be synthesized, for example, by the following synthetic procedure or any other procedures similar to the same:
Maleic acid monotocopherol and ascorbic acid having the hydroxy groups protected at the 5 and 6 positions can be reacted in a highly polar solvent in the presence of a base, such as alkali carbonate compounds or triethylamine to effect esterification by the mixed acid anhydride method, followed by removal of the protective groups with an acid to give a L-ascorbic acid-2-O-maleic acid-&agr;-tocopherol diester mainly having an ester linkage at the 2 position of ascorbic acid. In this case, examples of the highly polar solvent include dimethylsulfoxide (DMSO), dimethylformamide (DMF), acetonitrile, etc., while the alkali carbonate compounds include, for example, sodium carbonate and potassium carbonate. A solution containing a diester compound as obtained by this manner is subjected to extraction with an extraction solvent, such as chloroform and ethyl acetate, and after distilling off the extraction s
Maruyama Genta
Ogata Kazumi
Saito Noriko
Yamada Kazuhiko
Dentz Bernard
Senju Pharmaceutical Co. Ltd.
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