Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-08-21
1998-08-11
Dees, Rose G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5483381, 5483385, A61K 31415, C07D23364
Patent
active
057927847
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/FR94/00189 filed Feb. 21, 1994.
BACKGROUND OF THE INVENTION
The present invention relates to histamine-derived products and more particularly to a coupling product between histamine or methyl substituted histamine and an amino-acid, its way of preparation and its applications as an active principle on the therapeutic and cosmetologic field or as an agent improving the stability of formulations in the therapeutic, cosmetologic or agro-alimentary field.
The biological characteristics of dipeptides such as .beta.-alanyl-histidine are particularly interesting as far as they contribute to increase the natural ways of defense and repair of the organism. Nevertheless compounds including an amino-acid or more in their structure such as .beta.-alanyl-histidine, form a range of active principles generally well tolerated by the organism but which efficiency is considerably reduced because these products are quickly degraded by the organism. Moreover, though the sensitivity to enzymatic desactivation is considerably reduced for the very small peptides (J.Dressman "Opportunities for peptide absorbtion in the GI tract", Communication GTRV 1992, Paris), the enzymatic desactivation of dipeptides could lead in some instances, to the liberation of histamine. This activity "pro-histamine" associated with the loss of activity of the original dipeptide, is not desired in the scope of this invention.
Therefore, the main object of this invention is to finalize peptide products close to the dipeptides mentioned above, but which efficiency is not reduced, owing to the fact they are not degraded by the organism.
Another object of the invention is to carry out a pseudo-peptide product derived from histamine having the characteristics of increasing the natural ways of defense and repair of the organism.
Still another object of the invention is to carry out a pseudo-peptide product as defined above, and which bioavailability is improved in acetylating the amino extremity.
Still another object of the invention is to carry out a peptide product having an acetylated group as defined above, so that hydrolysis by enzymes of the acetylpeptide hydrolase type permits sustaining the release in situ of an active product.
Other features and advantages of the present invention will become apparent from the following description of the invention which refers to the accompanying drawings.
The invention relates therefore to a pseudo-dipeptide product obtained by coupling between histamine or methyl-sustituted histamine and an amino-acid having as a formula: ##STR2## in which A represents a radical selected from the group consisting of amine, amide, lactam, and urethane radicals, R.sub.1, R'.sub.1, R.sub.2, R'.sub.2. . . R.sub.n, R'.sub.n each represent an hydrogen atom or an hydrocarbon radical which can be substituted by one or several functional groups, Y and Z represent each an hydrogen or fluorine atom, or an hydrocarbonated radical that may be substituted by one or several functional groups, and n is an integer number superior or equal to 1, the covalent bond with histamine or methyl-substituted histamine being a peptide bond between the carboxylic radical of the amino-acid and the amine radical of the histamine.
Another object of the invention is a pseudo-dipeptide as defined in the previous object in which the oxygen atom of the carbonyl group obtained by coupling of the amino-acid and histamine is replaced by a sulphur atom.
Among the amino-acids corresponding to the formula of the invention, the following amino-acids give the best results: ##STR3## 5-aminovaleric acid whose formula is ##STR4## 6-aminocaproic acid ##STR5## L-glutamic acid ##STR6##
The amino-acids in which we have acted to pyroglutamination of the radical NH.sub.2 ##STR7## or the following amino-acids in which the amine extremity has been acetylated. As a matter of fact, the hydrolysis of this group with some enzymes (acetylpeptide hydrolase type) allows one to sustain the release in situ of an active product. ##STR8## N-acetyl-3-phenyl-3-a
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Gajda et al., J. Chem. Soc. Dalton Trans., 15, 2313-19, 1992.
Flancbaum et al., Life Sciences, 47, 1587-93, 1990.
Fesus et al., J. Biol. Chem., 260(25), 13771-8, Nov. 1985.
Babizhayev Marc
Seguin Marie-Christine
Babizhayev Marc
Cross Lutz Laura R.
Dees Rose G.
Exsymol Societe Anonyme Monegasque
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