Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1997-10-09
2001-03-27
Henderson, Christopher (Department: 1713)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S400000
Reexamination Certificate
active
06207842
ABSTRACT:
CROSS-REFERENCE TO RELATED APPLICATIONS
Reference is made to U.S. application Ser. No. 08/831,245, filed Apr. 2, 1997, Ser. No. 08/709,406, filed Sep. 6, 1996, U.S. Pat. No. 6,015,913, Ser. No. 08/631,661, filed Apr. 2, 1996, ABN and Ser. No. 08/317,226, filed Oct. 3, 1994 (now U.S. Pat. No. 5,554,645) and PCT/US96/04497, each of which is incorporated herein by reference.
FIELD OF THE INVENTION
This invention relates to synthetic polyphenol oligomers and methods for making and using the same.
Documents cited in this disclosure pertain to the field of this invention, and each document cited herein is hereby incorporated herein by reference.
BACKGROUND OF THE INVENTION
Polyphenols are a highly diverse group of compounds (Ferreira, D., Steynberg, J. P., Roux, D. G. and Brandt, E. V.,
Tetrahedron,
48, (10), 1743-1803 (1992)) which widely occur in a variety of plants, some of which enter into the food chain. In some cases they represent an important class of compounds for the human diet. Although some of the polyphenols are considered to be non-nutritive, interest in these compounds has arisen because of their possible beneficial effects on health.
For instance, quercetin (a flavonoid) has been shown to possess anticarcinogenic activity in experimental animal studies (Deschner, E. E., Ruperto, J., Wong, G. and Newmark, H. L.,
Carcinogenesis,
7, 1193-1196 (1991) and Kato, R., Nakadate, T., Yamamoto, S. and Sugimura, T.,
Carcinogenesis,
4, 1301-1305 (1983)). (+)-Catechin and (−)-epicatechin (flavan-3-ols) have been shown to inhibit Leukemia virus reverse transcriptase activity (Chu S.-C., Hsieh, Y.-S. and Lim, J.-Y.,
J. of Natural Products,
55, (2), 179-183 (1992)). Nobotanin (an oligomeric hydrolyzable tannin) has also been shown to possess anti-tumor activity (Okuda T., Yoshida, T., and Hatano, T., Molecular Structures and Pharmacological Activities of Polyphenols—Oligomeric Hydrolyzable Tannins and Others—Presented at the XVIth International Conference of the Groupe Polyphenols, Lisbon, Portugal, Jul. 13-16, 1992). Statistical reports have also shown that stomach cancer mortality is significantly lower in the tea producing districts of Japan. Epigallocatechin gallate has been reported to be the pharmacologically active material in green tea that inhibits mouse skin tumors (Okuda et al., Ibid.). Ellagic acid has also been shown to possess anticarcinogen activity in various animal tumor models (Boukharta M., Jalbert, G. and Castonguay, A., Efficacy of Ellagitannins and Ellagic Acid as Cancer Chemopreventive Agents—Presented at the XVIth International Conference of the Groupe Polyphenols, Lisbon, Portugal, Jul. 13-16, 1992). Proanthocyanidin oligomers have been patented by the Kikkoman Corporation for use as antimutagens. The use of phenolic compounds in foods and their modulation of tumor development in experimental animal models has been recently presented at the 202nd National Meeting of The American Chemical Society (Phenolic Compounds in Foods and Their Effects on Health I, Analysis, Occurrence & Chemistry, Ho, C.-T., Lee, C. Y., and Huang, M.-T editors, ACS Symposium Series 506, American Chemical Society, Washington, D.C. (1992); Phenolic Compounds in Foods and Their Effects on Health II. Antioxidants & Cancer Prevention, Huang, M.-T., Ho, C.-T., and Lee, C. Y. editors, ACS Symposium Series 507, American Chemical Society, Washington, D.C. (1992)).
However, none of these reports teaches or suggests cocoa extracts or compounds therefrom, any methods for preparing such extracts or compounds therefrom, or, any uses as described in U.S. application Ser. No. 08/831,245 filed Apr. 2, 1997.
Isolation, separation, purification, and identification methods have been established for the recovery of a range of procyanidin oligomers for comparative in vitro and in vivo assessment of biological activities. For instance, anti-cancer activity is elicited by pentameric through decameric procyanidins, but not by monomers through tetrameric compounds. Currently, gram quantities of pure (>95%) pentamer are obtained by time-consuming methods which are not satisfactory for obtaining a sufficient quantity of the pentamer for large scale pharmacological and bioavailability studies. Even greater effort is required to obtain gram quantities of higher oligomers, hexamers through dodecamers, for similar studies since they are present in the concentration in the natural product are much lower than the pentamer. Additionally, increasing oligomeric size increases structural complexity. Factors such as the chirality of the monomer units comprising the oligomer at different interflavan linkage sites, dynamic rotational isomerization of the interflavan bonds, and the multiple points of bonding at nucleophilic centers pose efficiency constraints on current analytical methods of separation and purification for subsequent identification.
These collective factors point to a need for synthesis methods to not only permit the unambiguous proof of both structure and absolute configuration of higher oligomers, but also to provide large quantities of structurally defined oligomers for in vitro and in vivo assessment. Such synthesis methods would lead to the creation of multiple configurational oligomers, some identical to those found in nature, as well as rare or “unnatural” types. Accordingly, it would be advantageous to develop a versatile synthetic process capable of providing large quantities of any desired polyphenol oligomer.
OBJECTS OF THE INVENTION
It is an object of the present invention to provide a method of synthesizing polyphenols and derivatives thereof.
It is another object of the present invention to provide a method of synthesizing an oligomeric compound of the formula A
n
, wherein A is a monomer having the formula:
wherein
n is an integer from 2 to 18, and higher;
a bond to carbon position 2 has alpha or beta stereochemistry;
a bond to carbon position 3 has alpha or beta stereochemistry;
a bond to carbon position 4 has alpha or beta stereochemistry;
R is hydrogen, hydroxyl, an O-glycoside, a substituted O-glycoside, OC(O)-aryl, substituted OC(O)-aryl, OC(O)-styryl, substituted OC(O)-styryl; wherein the substituted glycoside is substituted by C(O)-aryl, substituted C(O)-aryl, C(O)-styryl, substituted C(O)-styryl; wherein said substituted aryl or substituted styryl may contain the substituents selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, thiol, methylenedioxy, dihalomethylenedioxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
6
haloalkyl, C
1
-C
6
-haloalkoxy, C
3
-C
8
cycloalkyl, and C
3
-C
8
cycloalkoxy;
bonding between adjacent monomers takes place at positions 4, 6 or 8;
X, Y and Z are selected from the group consisting of A and hydrogen, with the provisos that as to at least one terminal monomer, bonding of the adjacent monomer thereto is at position 4 and optionally Y=Z=hydrogen; and
salts, derivatives and oxidation products thereof.
Preferably, the glycoside is selected from the group consisting of glucose, galactose, xylose, rhamnose and arabinose. Preferably, the —C(O)-aryl and —C(O)-styryl moieties are ester substituents derived from carboxylic acids selected from the group consisting of caffeic, cinnamic, coumaric, ferulic, gallic, hydroxybenzoic and sinapic acids. The glycoside or any or all of X, Y, and Z also can optionally be substituted at any position with substituted or unsubstituted —C(O)-aryl or —C(O)-styryl moieties via an ester bond.
These and other objects and embodiments are disclosed or will be obvious from the following Detailed Description.
REFERENCES:
patent: 0096007 (1983-12-01), None
J.J. Botha et al., “Synthesis of Condensed Tannins. Part 4. A Direct Biomimetic Approach to [4,6]-and [4,8]-Biflavanoids”,J. Chem. Soc., Perkin Trans. I, 1235-1245 (1981).
J.J. Botha et al., “Synthesis of Condensed Tannins. Part 5. The First Angular [4,6:4,8]-Triflavanoids and Their Natural Counterparts”,J. Chem. Soc., Perkin Trans I, 527-533 (1982).
H. Kolodziej, “Synthesis and Characterization of
Kozikowski Alan P.
Romanczyk Jr. Leo J.
Tueckmantel Werner
Clifford Chance Rogers & Wells LLP
Henderson Christopher
Kelley Margaret B.
Mars Incorporated
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