Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-02-17
2001-03-20
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06204266
ABSTRACT:
SUBJECT OF THE INVENTION
The present invention relates to a pharmaceutical, cosmetic and/or food composition intended especially for the prevention and/or treatment of pathologies associated with prooxidant agents.
The present invention also relates to the use of the pharmaceutical, cosmetic and/or food composition according to the invention.
TECHNOLOGICAL BACKGROUND AND PRIOR ART UNDERLYING THE INVENTION
Coelenterazine, imidazolopyrazine, constitutes the substrate of bioluminescent reactions in many marine organisms.
In these organisms, the oxidation of coelenterazine by molecular oxygen, a reaction catalyzed by an enzyme (luciferase), is responsible for the light-emitting reaction. Studies have demonstrated the presence of coelenterazine in many non-bioluminescent organisms (Schimomura, Comp. Biochem. Physiol. 86B, pp. 361-363 (1987)).
The synthesis of imidazolopyrazine is known to a person skilled in the art from the following documents: Inoue et al., Chemistry Letters, pp. 299-300 (1980); Tiranishi and Goto, Bulletin of Chemical Society Japanese 63, pp. 3132-3140 (1990); Qi et al., Journal of Chemical Society Perkin Trans 1, pp. 1607-1611 (1982); Mc Capra and Roth, Journal of Chemical Society Chemistry Community, pp. 894-895 (1972); Inoue et al., Chemistry Letters, pp. 141-144 (1975); Inoue et al., Tetrahedron Letters No. 31, pp. 2685-2688 (1977); Qi et al. Journal of Chemical Society Chemistry Community, pp. 1307-1309 (1991); Hori et al., Biochemistry, Vol. 12 No. 22, pp. 4463-4468 (1973); Hart et al., Biochemical and Biophysical Research Communication, pp. 980-986, (1978).
However, none of these documents describes a pharmaceutical, cosmetic or food composition comprising one of these imidazolopyrazine derivatives, or the antioxidant properties of these products, or any other therapeutic application of these products.
Antioxidant molecules such as vitamins, for instance vitamin E (fat-soluble) or cysteine derivatives (water-soluble), are also used already in cosmetic, pharmaceutical and/or food applications. However, these antioxidant molecules have the drawback either of not being water-soluble, or of having an excessively high toxicity as well as an excessively low efficacy.
OBJECTIVES OF THE INVENTION
The present invention is directed towards obtaining a new pharmaceutical, cosmetic and/or food composition advantageously permitting the prevention and/or treatment of pathologies associated with prooxidant agents, and especially a pharmaceutical, cosmetic and/or food composition having anti-inflammatory and/or anticarcinogenic properties.
An additional objective of the present invention is to obtain said pharmaceutical, cosmetic and/or food compositions which shall be characterized by a low toxicity or an absence of toxicity, by a high solubility in a large number of solvents (H
2
O, alcohols, etc.) and/or lipids and/or by a high stability, especially at acid pH.
CHARACTERISTIC FEATURES OF THE PRESENT INVENTION
The present invention relates to a pharmaceutical, cosmetic and/or food composition comprising a pyrazine derivative of formula
and/or its precursor of formula
in which formulae
B is a radical chosen from the group consisting of X, X-SO
3
H, X-PO
4
, X-alkyl═O, the said alkyl consisting of 1 to 20 carbon atoms optionally comprising 1 to 10 hetero atoms and in which the carbon atoms can be optionally substituted with any element of the Mendeleev table, preferably an element chosen from the group consisting of H. B, N, O, F, P, S, Cl, As, Se, Br, Te and I,
X being an element chosen from the group consisting of O, S, Se and Te;
R
1
, R
2
, R
3
and R
4
are H, radicals chosen from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroalkyl and hetero(alkylaryl and arylalkyl), preferably consisting of 1 to 20 carbon atoms optionally comprising 1 to 10 hetero atoms and in which the carbon atoms can be optionally substituted with any element of the Mendeleev table, preferably an element chosen from the group consisting of H, B, N, O, F, P, S, Cl, As, Se, Br, Te and I, or chains of formula (R
5
×R
6
)
n
, where n≧1, x represents one or more hetero atoms and R
5
and R
6
are radicals chosen from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroalkyl and hetero(alkylaryl and arylalkyl), consisting of 1 to 20 carbon atoms optionally comprising 1 to 10 hetero atoms and in which the carbon atoms can be optionally substituted with any element of the Mendeleev table, preferably an element chosen from the group consisting of H, B, N, O, F, P, S, Cl, As, Se, Br, Te and I; and optionally an appropriate pharmaceutical, cosmetic and/or food vehicle.
Preferably, in the pyrazine derivatives according to the invention,
R
1
is H,
R
2
and R
4
are aryl or alkylaryl groups, preferably consisting of 1 to 20 carbon atoms optionally comprising 1 to 10 hetero atoms and in which the carbon atoms can be optionally substituted with any element of the Mendeleev table, preferably an element chosen from the group consisting of H, B, N, O, F, P, S, Cl, As, Se, Br, Te and I,
R
3
represents a phenol group or a chain of formula (R
5
×R
6
)
n
in which
n=1,
x represents O,
R
5
is a phenyl, and
R
6
is a methyl.
Preferably, the pyrazine derivative of the pharmaceutical, cosmetic and/or food composition according to the invention is chosen from the group consisting of:
3,7-dihydro-2-(p-hydroxybenzyl)-6-(p-hydroxyphenyl)-8-benzylimidazo[1,2-a]pyrazyn-3-one [sic] (CLZN)
3,7-dihydro-2-methyl-6-(p-metoxyphenyl)-8-benzylimidazo[1,2-a]pyrazyn-3-one [sic] (CLZN-7)
3,7-dihydro-2-phenyl-6-(p-metoxyphenyl)-8-benzylimidazo[1,2-a]pyrazyn-3-one [sic] (CLZN-8)
3,7-dihydro-2-methyl-6-(p-hydroxyphenyl)-8-benzylimidazo[1,2-a]pyrazyn-3-one [sic] (CLZN-9)
3,7-dihydro-2-phenyl-6-(p-hydroxyphenyl)-8-benzylimidazo[1,2-a]pyrazyn-3-one [sic] (CLZN-10)
3,7-dihydro-2-benzyl-6-(p-hydroxyphenyl)-8-benzylimidazo[1,2-a]pyrazyn-3-one [sic] (CLZN-1l)
and optionally an appropriate pharmaceutical, cosmetic and/or food vehicle.
Another aspect of the present invention relates to the use of the composition according to the invention for the binding of prooxidant agents (free radicals) such as peroxides, superoxides, etc.
The present invention also relates to a method of treatment and/or prevention of pathologies associated with the action of prooxidant agents, especially inflammatory or carcinogenic pathologies, in which the pharmaceutical, cosmetic and/or food composition according to the present invention is administered to a patient.
The pharmaceutical, cosmetic and/or food vehicles according to the invention are vehicles which are appropriate, in particular, for oral administration, for example in the form of lozenges, coated or uncoated, pills, capsules, solutions, essential oils and/or syrups.
Other appropriate pharmaceutical, cosmetic and/or food vehicles can be used, depending on the chosen mode of administration.
In particular, these pharmaceutical, cosmetic and/or food vehicles can be creams or sun oils which are well known to a person skilled in the art, which can coat various parts of the human or animal body in combination with other skin-protecting agents.
In addition, the products of the invention can be readily incorporated in solvents (aqueous media, alcohols, etc.) or lipids (for example in combination with food oils or suntan oils).
The pharmaceutical, cosmetic and/or food compositions according to the invention are prepared according to processes generally used by a person skilled in the art, especially by pharmacists, and can comprise any vehicle or any adjuvant which is pharmaceutically appropriate, solid or liquid, and non-toxic.
The incorporation of the derivatives according to the invention in a pharmaceutical formulation medium can also be envisaged.
The percentage of active product (pyrazine derivatives) in the pharmaceutical vehicle can vary over very wide ranges, limited onl
Goldberg Jerome D.
Knobbe Martens Olson & Bear LLP
Universite Catholique De Louvain Halles Universitaires
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