FR2698095A1 - N-aryl-methylene-imino-di:acetate(s) - Google Patents
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
- C07C229/16—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
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Abstract
Description
Utilisation de composés dibenzyléthylène diamino diacétate contre le stress oxydant, compositions pharmaceutiques ou cosmétiques les contenant, composés nouveaux et leur procédé de préparation.Use of dibenzylethylene diamino diacetate compounds against oxidative stress, pharmaceutical or cosmetic compositions containing them, new compounds and their preparation process.
La présente invention concerne des dérivés de dibenzyléthylène diamino diacétate utiles notamment pour protéger organisme contre le stress oxydant, leur procédé de préparation ainsi que les compositions pharmaceutiques ou cosmétiques comportant de tels composés. The present invention relates to dibenzylethylene diamino diacetate derivatives which are useful in particular for protecting the organism against oxidative stress, their process of preparation as well as pharmaceutical or cosmetic compositions comprising such compounds.
Dans le domaine de la santé et de la cosmétique, le concept du stress oxydant est connu, stress oxydant qui apparaît lors d'un certain nombre de situations physiopathologiques et pathologiques notamment, dès lors qu'il existe un déséquilibre de la balance antioxydant-prooxydant. Ce déséquilibre se traduit notamment par des processus oxydatifs au sein des tissus vivants, non contrôlés, qui mettent en jeu des radicaux libres oxygénés et conduisent notamment à des dégâts oxydatifs sur les molécules et les macromolécules biologiques (Sies, H., In Oxidative Stress, Academic Press Inc. In the field of health and cosmetics, the concept of oxidative stress is known, oxidative stress which appears during a certain number of physiopathological and pathological situations in particular, as soon as there is an imbalance in the antioxidant-prooxidant balance . This imbalance is expressed in particular by oxidative processes within living, uncontrolled tissues, which involve oxygenated free radicals and lead in particular to oxidative damage to biological molecules and macromolecules (Sies, H., In Oxidative Stress, Academic Press Inc.
(London) Ltd, 1985).(London) Ltd, 1985).
n est connu que des situations diverses provoquent, favorisent ou accompagnent le stress oxydant ou en sont la conséquence; il s'agit notamment de l'inflammation, du vieillissement, de la carcinogénèse, des situations d'ischémie reperfusion. L'exposition aux rayonnements ultraviolets ou ionisants, la toxicité et/ou le mode d'action de certains médicaments, peuvent également provoquer un tel stress. It is known that various situations cause, promote, accompany or are the result of oxidative stress; these include inflammation, aging, carcinogenesis, ischemia reperfusion situations. Exposure to ultraviolet or ionizing radiation, the toxicity and / or the mode of action of certain drugs, can also cause such stress.
Lors de ce phénomène du stress oxydant, il est connu que du fer est libéré de ses sites de stockage usuels comme la ferritine et, libéré, peut participer à certaines réactions, et notamment aux réactions de
Fenton (1) et Haber-Weiss (2) dont résulte la formation des radicaux hydroxyle, radicaux connus pour être responsables de nombreux dommages oxydatifs (Reif, D.W., Free Rad. Biol. Med. 12 417-427, 1992).
During this phenomenon of oxidative stress, it is known that iron is released from its usual storage sites such as ferritin and, released, can participate in certain reactions, and in particular in reactions of
Fenton (1) and Haber-Weiss (2) from which results the formation of hydroxyl radicals, radicals known to be responsible for numerous oxidative damage (Reif, DW, Free Rad. Biol. Med. 12 417-427, 1992).
n est connu que la protection des tissus vivants contre les attaques du radical hydroxyle est difficile. It is known that the protection of living tissues against attacks by the hydroxyl radical is difficult.
L'une des approches connue pour se protéger est d'utiliser des molécules, notamment le D-mannitot ou le DMSO (diméthylsulfoxyde), capables de piéger les radicaux hydroxyle. One of the known approaches for protecting oneself is by using molecules, in particular D-mannitot or DMSO (dimethylsulfoxide), capable of trapping hydroxyl radicals.
Néanmoins, le radical hydroxyle est une espèce si réactive qu'il faut utiliser des quantités très importantes de ces piégeurs, de manière à entrer en compétition avec toutes les molécules biologiques, cibles potentielles du radical hydroxyle (Halliwel, B., Free Rad. Ress.However, the hydroxyl radical is such a reactive species that it is necessary to use very large quantities of these scavengers, so as to compete with all the biological molecules, potential targets of the hydroxyl radical (Halliwel, B., Free Rad. Ress .
Comms., 9(1), 1-32, 1990). L'utilisation de fortes quantités de ces piégeurs pose des problèmes de toxicité.Comms., 9 (1), 1-32, 1990). The use of large quantities of these trappers poses toxicity problems.
L'autre approche connue pour se protéger contre les radicaux hydroxyle est d'utiliser des chelateurs du fer, notamment la deferoxamine, l'acide diéthylène triamine pentaacétique (DTPA) pour l'empêcher de participer aux réactions de Fenton et Haber-Weiss.. The other known approach to protect against hydroxyl radicals is to use iron chelators, in particular deferoxamine, diethylene triamine pentaacetic acid (DTPA) to prevent it from participating in the Fenton and Haber-Weiss reactions.
Cependant, si leurs constantes de complexation sont élevées, ces chelateurs peuvent être toxiques. C'est ainsi que le DTPA présente des effets secondaires importants, liés probablement pour une partie à la chelation de métaux, tels que le calcium. However, if their complexing constants are high, these chelators can be toxic. This is how DTPA presents significant side effects, probably linked in part to the chelation of metals, such as calcium.
La deferoxamine présente une toxicité chronique supposée Iiée à sa capacité à chelater les métaux des sites actifs des metalloenzymes ou hémoprotéines comme l'hémoglobine. Deferoxamine has a chronic toxicity supposedly linked to its ability to chelate metals from the active sites of metalloenzymes or hemoproteins such as hemoglobin.
Par ailleurs, des chelateurs puissants, qui peuvent complexer le fer, tels que l'EHPG (éthylène bis-O-hydroxy phényl glycine), sont également connus pour avoir des toxicités aiguës importantes. In addition, powerful chelators, which can complex iron, such as EHPG (ethylene bis-O-hydroxy phenyl glycine), are also known to have significant acute toxicities.
Enfin, le HBED [acide N,N'-bis(2-hydroxybenzyl)-éthylène diamine diacétique] qui est un chelateur du fer exceptionnellement efficace (cf. US-4.528.196), présente également des risques de toxicité car il forme un complexe occupant tous les sites de coordination du fer du fait des positions des groupes OH en position 2. Finally, HBED [acid N, N'-bis (2-hydroxybenzyl) -ethylene diamine diacetic] which is an exceptionally effective iron chelator (cf. US-4,528,196), also presents risks of toxicity because it forms a complex occupying all the iron coordination sites due to the positions of the OH groups in position 2.
La demanderesse a découvert que des dérivés du dibenzyl éthylène diarnine diacétate étaient particulièrement efficaces pour protéger l'organisme contre le stress oxydant. The Applicant has discovered that derivatives of dibenzyl ethylene diarnine diacetate are particularly effective in protecting the body against oxidative stress.
Sans que cette explication soit limitative, il semble que cet effet soit dû à la faculté de ces dérivés non seulement de former avec le fer des complexes, mais encore de piéger les radicaux hydroxyle, de façon quasi stoechiométrique, avant qu'ils ne puissent attaquer d'autres molécules. Without this explanation being limiting, it seems that this effect is due to the ability of these derivatives not only to form complexes with iron, but also to trap hydroxyl radicals, in an almost stoichiometric manner, before they can attack other molecules.
En effet, les composés selon l'invention forment des complexes avec Fe2+ et ces complexes sont capables de décomposer le peroxyde d'hydrogène sans libérer de radicaux hydroxyle. Ces radicaux sont en effet formés mais aussitôt piégés par un processus d'hydroxylation intramoléculaire, ce qui permet de n'utiliser que de très faibles concentrations des molécules selon l'invention. Ce dernier point constitue un avantage par rapport aux autres piégeurs de radicaux hydroxyle déjà cités qui nécessitent d'être utilisés en très large excès. Indeed, the compounds according to the invention form complexes with Fe2 + and these complexes are capable of decomposing hydrogen peroxide without releasing hydroxyl radicals. These radicals are in fact formed but immediately trapped by an intramolecular hydroxylation process, which makes it possible to use only very low concentrations of the molecules according to the invention. This last point constitutes an advantage compared to the other scavengers of hydroxyl radicals already mentioned which require to be used in very large excess.
Un autre avantage des composés selon l'invention, est que ceux-ci forment avec le fer des complexes dont les constantes d'association sont beaucoup plus faibles que celles des composés cités plus haut comme la deferoxamine ou 1'HBED. Les risques toxicologiques sont donc diminués. Another advantage of the compounds according to the invention is that they form with iron complexes whose association constants are much weaker than those of the compounds mentioned above such as deferoxamine or HBED. The toxicological risks are therefore reduced.
Enfin, les produits d'hydroxylation intramoléculaire des complexes ferreux des molécules selon l'invention ont une grande affinité pour le fer et forment avec celui-ci des complexes capables de l'empêcher de catalyser la formation d'autres radicaux hydroxyle. Finally, the intramolecular hydroxylation products of the ferrous complexes of the molecules according to the invention have a great affinity for iron and form with it complexes capable of preventing it from catalyzing the formation of other hydroxyl radicals.
L'invention a pour objet l'utilisation pour la protection contre le stress oxydant de dérivés de dibenzyléthylène diamino diacétate. The subject of the invention is the use for the protection against oxidative stress of dibenzylethylene diamino diacetate derivatives.
Un autre objet est constitué pour les compositions cosmétiques ou pharmaceutiques les mettant en oeuvre. Another object is made up for the cosmetic or pharmaceutical compositions using them.
L'invention a également pour objet les composés nouveaux de la famille des dibenzyl éthylène diamino di acétate et leur préparation. A subject of the invention is also the new compounds of the family of dibenzyl ethylene diamino di acetate and their preparation.
D'autres objets de l'invention apparaîtront à la lecture de la description et des exemples qui suivent. Other objects of the invention will appear on reading the description and the examples which follow.
Les composés utilisés conformément à l'invention pour la protection contre le stress oxydant, répondent à la formule (I)
The compounds used in accordance with the invention for protection against oxidative stress, correspond to formula (I)
Z1, Z2 et Z3, indépendamment l'un de l'autre, représentent H,
NO2, un atome halogène ou un groupement R1, OR1, SR1 ou NR1R2,
où R, R1 et R2, indépendamment l'un de l'autre, représentent H ou un groupement aliphatique, linéaire, ramifié ou cyclique, saturé ou non, substitué ou non, aromatique ou non,
ainsi que leurs sels, leurs complexes métalliques et dérivés acylés.Z1, Z2 and Z3, independently of one another, represent H,
NO2, a halogen atom or a group R1, OR1, SR1 or NR1R2,
where R, R1 and R2, independently of one another, represent H or an aliphatic group, linear, branched or cyclic, saturated or not, substituted or not, aromatic or not,
as well as their salts, their metal complexes and acylated derivatives.
Les groupements aliphatique, linéaire, ramifié ou cyclique, saturés ou non, substitués ou non, aromatiques ou non, sont de préférence des groupements alkyle en C1-C4, tels que méthyle, éthyle, cyclohexyle, allyle substitué par -OH, -NH2, -COOH ..., oléyle, phényle, benzyle. The aliphatic groups, linear, branched or cyclic, saturated or unsaturated, substituted or unsubstituted, aromatic or not, are preferably C1-C4 alkyl groups, such as methyl, ethyl, cyclohexyl, allyl substituted by -OH, -NH2, -COOH ..., oleyl, phenyl, benzyl.
Comme sel, on peut citer les sels d'addition avec un acide minéral comme les acides H2SO4, HC1, HN03 ou H3PO4, par exemple, et les produits de salification obtenus par une base minérale comme NaOH ou KOH par exemple. Comme complexes métalliques, on peut citer les complexes fournis par addition de ZnC12 par exemple. Les restes R préférés sont choisis de sorte que les composés de formule (I) se présentent sous forme d'ester ou d'amide. As salt, mention may be made of addition salts with a mineral acid such as H2SO4, HC1, HNO3 or H3PO4, for example, and the salification products obtained with a mineral base such as NaOH or KOH for example. As metal complexes, mention may be made of the complexes provided by the addition of ZnC12 for example. The preferred residues R are chosen so that the compounds of formula (I) are in the form of an ester or an amide.
Les composés nouveaux répondent à la formule (I), dans laquelle Z1, Z2, Z3, R, R1, R2 ont les significations indiquées ci-dessus, sous réserve que lorsque Z2 désigne H, Cl, NO2 ou CH3, l'un au moins de
Z1 et Z3 est différent de H, et lorsque Z1 désigne OH et Z2 désigne
OCH3, Z3 n'est pas H, ainsi que leurs sels et complexes métalliques. The new compounds correspond to formula (I), in which Z1, Z2, Z3, R, R1, R2 have the meanings indicated above, provided that when Z2 denotes H, Cl, NO2 or CH3, one at less of
Z1 and Z3 is different from H, and when Z1 denotes OH and Z2 denotes
OCH3, Z3 is not H, as well as their salts and metal complexes.
Les composés définis dans la formule (I) sont utilisés comme médicament, notamment pour se protéger des effets néfastes des radicaux libres dus en particulier au stress oxydant. Ils sont particulièrement utilisables pour traiter les situations de stress oxydant liées à des états pathologiques chez l'homme ou l'animal, comme les cancers, les états inflammatoires, l'ischémie reperfusion, les surcharges en fer, les maladies dégénératives du système nerveux, ou encore pour traiter les effets liés à l'exposition aux rayonnements ionisants ou à l'utilisation de certains médicaments connus pour générer des radicaux libres, notamment des médicaments anticancéreux comme l'adriamycine, etc. The compounds defined in formula (I) are used as a medicament, in particular to protect themselves from the harmful effects of free radicals due in particular to oxidative stress. They are particularly useful for treating situations of oxidative stress linked to pathological conditions in humans or animals, such as cancers, inflammatory conditions, ischemia reperfusion, iron overloads, degenerative diseases of the nervous system, or to treat the effects linked to exposure to ionizing radiation or to the use of certain drugs known to generate free radicals, in particular anticancer drugs such as adriamycin, etc.
Les composés conformes à l'invention peuvent également être utilisés pour traiter les situations de stress oxydant liées à des états non pathologiques, comme ceux résultant de l'exposition au soleil ou dus au vieillissement. Ils sont utilisés dans ce cas là pour leur effet cosmétique sur la peau ou les cheveux. The compounds according to the invention can also be used to treat situations of oxidative stress linked to non-pathological conditions, such as those resulting from exposure to the sun or due to aging. They are used in this case there for their cosmetic effect on the skin or the hair.
Les compositions cosmétiques ou pharmaceutiques mettant en oeuvre les composés de formule (I) comportent un composé de formule (I) ou ses sels, et complexes métalliques, dans un milieu cosmétiquement ou pharmaceutiquement acceptable. The cosmetic or pharmaceutical compositions using the compounds of formula (I) comprise a compound of formula (I) or its salts, and metal complexes, in a cosmetically or pharmaceutically acceptable medium.
Ces compositions contiennent les composés de formule (I) dans des proportions de 0,001 à 10% en poids. These compositions contain the compounds of formula (I) in proportions of 0.001 to 10% by weight.
Les compositions cosmétiques ou pharmaceutiques peuvent se présenter sous des formes diverses habituellement utilisées dans ce domaine, et en particulier sous forme d'onguent, de crème, de pommade, de gel, de spray, de lotion, d'émulsion ou de dispersion vésiculaire. The cosmetic or pharmaceutical compositions can be in various forms usually used in this field, and in particular in the form of an ointment, cream, ointment, gel, spray, lotion, emulsion or vesicular dispersion.
Lorsque les composés de formule (I) sont utilisés dans le cadre d'un traitement pharmaceutique, les formes d'administration peuvent adopter la voie orale, topique ou parentérale, le support pharmaceutiquement acceptable dépendant de la forme d'administration choisie. Les doses d' administrations sont généralement comprises entre 1 à 100 mg/kg/jour. When the compounds of formula (I) are used within the framework of a pharmaceutical treatment, the administration forms can adopt the oral, topical or parenteral route, the pharmaceutically acceptable carrier depending on the administration form chosen. The administration doses are generally between 1 to 100 mg / kg / day.
Le milieu cosmétiquement ou pharmaceutiquement acceptable est un milieu usuel dans le domaine cosmétique ou pharmaceutique. The cosmetically or pharmaceutically acceptable medium is a usual medium in the cosmetic or pharmaceutical field.
Les composés de formule (I) peuvent, selon une forme de réalisation préférée, être utilisés avec au moins un autre agent actif (ou un autre agent anti-radicaux libres). Ces agents peuvent être choisis plus particulièrement parmi
- les antilipopéroxydants comme la vitamine E, le trolox, le BHT (butylhydroxytoluène),
- un réducteur biologique comme le glutathion réduit et ses dérivés, la vitamine C et ses dérivés,
- un capteur d'oxygène singulet comme le ss-carotène,
- un système capable de décomposer le péroxyde d'hydrogène tel que des enzymes comme la catalase ou les péroxydases en présence de leur co-substrat,
- un système de protection contre l'anion supéroxyde comme la
SOD ou des analogues tels que le complexe Mn-desferal ou le diisopropyl salicylate de cuivre,
- un système capable de décomposer les hydropéroxydes organique s comme la glutathion péroxydase ou des systèmes à base de sélénium,
- les agents anti-inflammatoires, les filtres UV, les promoteurs de pénétration ou leurs associations.The compounds of formula (I) can, according to a preferred embodiment, be used with at least one other active agent (or another anti-free radical agent). These agents can be chosen more particularly from
- antilipoperoxidants such as vitamin E, trolox, BHT (butylhydroxytoluene),
- a biological reducing agent such as reduced glutathione and its derivatives, vitamin C and its derivatives,
- a singlet oxygen sensor like ss-carotene,
- a system capable of breaking down hydrogen peroxide such as enzymes such as catalase or peroxidases in the presence of their co-substrate,
- a protection system against the superoxide anion such as
SOD or analogs such as the Mn-desferal complex or copper diisopropyl salicylate,
- a system capable of breaking down organic hydroperoxides such as glutathione peroxidase or systems based on selenium,
- anti-inflammatory agents, UV filters, penetration promoters or their associations.
Ces agents peuvent être présents dans la même composition ou destinés à être utilisés, de façon séparée, décalée ou non dans le temps. These agents can be present in the same composition or intended to be used, separately, delayed or not in time.
Les composés de formule (I) (composant (A)) et les agents actifs ou agents anti-radicaux libres (composant (B)) définis ci-dessus, peuvent être mis en oeuvre dans la même composition ou être appliqués séparément, de façon décalée ou non, dans le temps, à l'aide d'une composition cosmétique ou pharmaceutique les contenant. The compounds of formula (I) (component (A)) and the active agents or anti-free radical agents (component (B)) defined above, can be used in the same composition or can be applied separately, so offset or not, over time, using a cosmetic or pharmaceutical composition containing them.
La présente invention concerne également le procédé de préparation des composés de foule (I) de l'invention. Selon ce procédé, l'aldéhyde de formule (11)
est mis en présence d'éthylènediamine pour obtenir l'imine correspondante. Cette imine, isolée ou non, est mise en présence de borohydrure de sodium ou d'hydrogène en présence de palladium sur charbon, pour obtenir l'amine correspondante. Dans une étape ultérieure, l'amine est traitée, en milieu basique, par exemple en présence d'hydroxyde de sodium, avec l'acide bromoacétique ou l'un de ses esters, en présence de monohydrogénocarbonate de sodium. On récupère alors le produit de formule (I) correspondant.Ce procédé est schématisé comme suit:
SCHEMA DE SYNTHESE GENERAL
The present invention also relates to the process for preparing the shed compounds (I) of the invention. According to this process, the aldehyde of formula (11)
is placed in the presence of ethylenediamine to obtain the corresponding imine. This imine, isolated or not, is placed in the presence of sodium borohydride or hydrogen in the presence of palladium on carbon, to obtain the corresponding amine. In a subsequent step, the amine is treated, in basic medium, for example in the presence of sodium hydroxide, with bromoacetic acid or one of its esters, in the presence of sodium monohydrogencarbonate. The corresponding product of formula (I) is then recovered. This process is shown diagrammatically as follows:
GENERAL SYNTHESIS DIAGRAM
Selon la nature de Z1, Z2 et Z3, une étape de protection/déprotection peut être nécessaire, notamment dans le cas où l'un de ces substituants est NH2. Cette étape supplémentaire est faite selon les techniques usuelles, de même que l'estérification finale des composés selon la formule (I) pour lesquels R est H, si on utilise l'acide bromo-acétique libre. Depending on the nature of Z1, Z2 and Z3, a protection / deprotection step may be necessary, in particular in the case where one of these substituents is NH2. This additional step is carried out according to the usual techniques, as is the final esterification of the compounds according to formula (I) for which R is H, if free bromo-acetic acid is used.
Par ailleurs, la demanderesse a constaté que les composés selon la présente invention peuvent être utilisables comme antioxydant pour conserver les compositions les contenant. Furthermore, the Applicant has found that the compounds according to the present invention can be used as an antioxidant for preserving the compositions containing them.
D'autres caractéristiques et avantages de l'invention apparaîtront à la lecture des exemples ci-après. Other characteristics and advantages of the invention will appear on reading the examples below.
EXEMPLES DE PREPARATION
Les composés de formule (I) définis par le tableau ci-après, sont préparés à partir des benzaldéhydes de formule (II) correspondants, de la façon suivante.PREPARATION EXAMPLES
The compounds of formula (I) defined by the table below, are prepared from the corresponding benzaldehydes of formula (II), as follows.
TABLEAU I
Z1 Z2 Z3
composé IA OH H H
composé IB OH OMe H
composé IC OMe OMe OMe
composé ID H OH H
R désignant hydrogène. TABLE I
Z1 Z2 Z3
compound IA OH HH
compound IB OH OMe H
compound IC OMe OMe OMe
compound ID H OH H
R denoting hydrogen.
Première étape
40 mmoles du benzaldéhyde de formule (II) de départ sont solubilisées dans 30 ml de méthanol. On additionne 20 mmoles d'éthylènediamine, puis le mélange est chauffé 30 minutes à 500C.First stage
40 mmol of the starting benzaldehyde of formula (II) are dissolved in 30 ml of methanol. 20 mmol of ethylenediamine are added, then the mixture is heated for 30 minutes to 500C.
Le précipité obtenu est filtré et lavé à l'éther. On obtient un produit blanc. The precipitate obtained is filtered and washed with ether. We get a white product.
benzaldéhyde rendement point de RMN 13C ou
de départ (II) fusion 1H et SM composé IIIA 3-hydroxy 83% 1980C conformes composé mi 3-hydroxy 81% 2100C conformes
4-méthoxy composé IIIC 3,4,5-triméthoxy nd (1) nd nd composé ED 4-hydroxy 85% 2100C conformes
nd : non détermine.benzaldehyde yield 13N NMR point or
starting (II) fusion 1H and SM compound IIIA 3-hydroxy 83% 1980C compliant mi 3-hydroxy compound 81% 2100C compliant
4-methoxy compound IIIC 3,4,5-trimethoxy nd (1) nd nd compound ED 4-hydroxy 85% 2100C conform
na: not determined.
(1) l'imine IIIC n'a pas été isolée mais a été réduite in situ en amine
par le borohydrure de sodium. (1) imine IIIC was not isolated but was reduced in situ to amine
by sodium borohydride.
Deuxième étane
17 mmoles de composé intermédiaire m sont mises en suspension dans 100 ml d'éthanol absolu. On additionne peu à peu 17 mmoles de borohydrure de sodium et on agite le mélange 1 heure à température ambiante.Second etane
17 mmol of intermediate compound m are suspended in 100 ml of absolute ethanol. 17 mmol of sodium borohydride are added little by little and the mixture is stirred for 1 hour at room temperature.
Après évaporation, on ajoute 50 ml d'eau au résidu et on ramène le pH à 8 par addition d'acide chlorhydrique. After evaporation, 50 ml of water are added to the residue and the pH is brought back to 8 by addition of hydrochloric acid.
Le précipité est filtré, lavé à l'eau puis séché. The precipitate is filtered, washed with water and then dried.
Deux procédés de traitement peuvent être alors utilisés. Two treatment methods can then be used.
Dans le cas de la synthèse des produits IA, IB et IC, le produit peut être recristallisé dans un mélange eau/éthanol. On obtient un produit blanc. In the case of the synthesis of products IA, IB and IC, the product can be recrystallized from a water / ethanol mixture. We get a white product.
Dans le cas de la synthèse du produit ID, le produit est solubilisé dans 30 ml d'éthanol, puis 4 ml d'une solution d'éthanol chlorhydrique à 8 moles/l sont ajoutés. Le précipité obtenu est filtré puis lavé à l'éther. On obtient le dichlorhydrate du composé IV sous forme d'un produit blanc. In the case of the synthesis of the product ID, the product is dissolved in 30 ml of ethanol, then 4 ml of a hydrochloric ethanol solution at 8 moles / l are added. The precipitate obtained is filtered and then washed with ether. The dihydrochloride of compound IV is obtained in the form of a white product.
rendement point de fusion RMN 13C ou
1H et SM
composé IVA 39% I620C conformes
composé IVB 39% 185"C conformes
composé IVC 34% 220"C conformes
composé IVD 35% 2500C conformes
Troisième étane
10 mmoles de composé IV aminé sont solubilisées dans 15 ml d'eau contenant 10 mmoles d'hydroxyde de sodium (30 mmoles si on part du dichlorhydrate).13C NMR melting point yield or
1H and SM
compound IVA 39% I620C compliant
compound IVB 39% 185 "C compliant
34% 220 "C IVC compliant
compound IVD 35% 2500C compliant
Third etane
10 mmol of amino compound IV are dissolved in 15 ml of water containing 10 mmol of sodium hydroxide (30 mmol if one starts from the dihydrochloride).
20 mmoles d'acide bromoacétique sont solubilisées dans 25 ml d'eau à 0 C contenant 20 mmoles de monohydrogénocarbonate de sodium. 20 mmol of bromoacetic acid are dissolved in 25 ml of water at 0 ° C. containing 20 mmol of sodium monohydrogencarbonate.
Les deux solutions sont mélangées et chauffées à 400C pendant 6 heures en maintenant le pH vers 12 par addition de soude à 30%. The two solutions are mixed and heated at 400C for 6 hours while maintaining the pH around 12 by adding 30% sodium hydroxide.
Après une nuit au repos à température ambiante, le mélange est acidifié par de l'acide chlorhydrique concentré jusqu'à pH 4-5. After standing overnight at room temperature, the mixture is acidified with concentrated hydrochloric acid to pH 4-5.
La solution est concentrée sous vide et le précipité obtenu est filtré puis recristallisé dans un mélange eau/éthanol. On récupère une poudre blanche. The solution is concentrated under vacuum and the precipitate obtained is filtered then recrystallized from a water / ethanol mixture. We recover a white powder.
rendement point de fusion RMN 13C ou
1H et SM
composé IA 39% 1750C conformes
composé IB 45% > 2600C conformes
composé IC 30% 1800C conformes
composé ID 30% 2550C conformes
EXEMPLES DE FORMULATION
EXEMPLE 1
COMPOSITION POUR L'APPLICATION TOPIQUE.13C NMR melting point yield or
1H and SM
compound IA 39% 1750C compliant
compound IB 45%> 2600C compliant
compound IC 30% 1800C compliant
compound ID 30% 2550C compliant
FORMULATION EXAMPLES
EXAMPLE 1
COMPOSITION FOR TOPICAL APPLICATION.
Selon les techniques usuelles de préparation, on mélange les constituants ci-dessous pour préparer une émulsion. According to the usual preparation techniques, the constituents below are mixed to prepare an emulsion.
composé lA 0,1 g
polyéthylèneglycol oxyéthyléné
par 50 motifs d'oxyde d'éthylène 3 g
monodiglycérylstéarate 3 g
huile de vaseline 24 g
alcool cétylique 5 g
eau qsp 100 g
EXEMPLE 2
De la même manière, on prépare une émulsion selon une technique classique, à partir des composés suivants.compound lA 0.1 g
oxyethylenated polyethylene glycol
per 50 units of ethylene oxide 3 g
monodiglyceryl stearate 3 g
vaseline oil 24 g
cetyl alcohol 5 g
water qs 100 g
EXAMPLE 2
In the same way, an emulsion is prepared according to a conventional technique, from the following compounds.
composé 113 0,02 g
octylpalmitate 10 g
glycérylisostéarate 4 g
huile de vaseline 24 g
vitamine E 1 g
glycérol 3 g
eau qsp 100 g
EXEMPLE 3
A partir des constituants ci-dessous, on formule la composition suivante.compound 113 0.02 g
octylpalmitate 10 g
glyceryl isostearate 4 g
vaseline oil 24 g
vitamin E 1 g
glycerol 3 g
water qs 100 g
EXAMPLE 3
From the constituents below, the following composition is formulated.
composé lA 0,02 g
huile de jojoba 13 g
parabenzoxy benzoate de méthyle
et d'isopropyle 0,05 g
sorbate de potassium 0,3 g
cyclopentadiméthylsiloxane 10 g
alcool stéarylique 1 g
acide stéarique 4 g
stéarate de polyéthylèneglycol 3 g
vitamine E 1 g
glycérol 3 g
eau qsp 100 g
EXEMPLE 4
COMPRIMES
composé lA 0,001 g
amidon 0,114 g
phosphate bicalcique 0,020 g
lactose 0,060 g
stéarate de magnésium 0,005 g
Après compactage, on obtient un comprimé de 0,2 g.compound lA 0.02 g
jojoba oil 13 g
methyl parabenzoxy benzoate
and isopropyl 0.05 g
potassium sorbate 0.3 g
cyclopentadimethylsiloxane 10 g
stearyl alcohol 1 g
stearic acid 4 g
polyethylene glycol stearate 3 g
vitamin E 1 g
glycerol 3 g
water qs 100 g
EXAMPLE 4
TABLETS
compound lA 0.001 g
starch 0.114 g
bicalcium phosphate 0.020 g
lactose 0.060 g
magnesium stearate 0.005 g
After compacting, a 0.2 g tablet is obtained.
EXEMPLE 5
SUSPENSION BUVABLE
composé IC 0,001 g
glycérol 0,500 g
sorbitol à 70% 0,500 g
saccharinate de sodium 0,010 g
parahydroxybenzoate de méthyle 0,040 g
arôme qs
eau purifiée qsp 5 g
EXEMPLE 6
AMPOULE INJECTABLE
composé ID 0,002 g
eau pour préparation injectable qsp 3 g EXAMPLE 5
ORAL SUSPENSION
compound IC 0.001 g
glycerol 0.500 g
sorbitol 70% 0.500 g
sodium saccharin 0.010 g
methyl parahydroxybenzoate 0.040 g
aroma qs
purified water qs 5 g
EXAMPLE 6
INJECTION BULB
compound ID 0.002 g
water for injection qsp 3 g
Claims (14)
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9213707A FR2698095B1 (en) | 1992-11-13 | 1992-11-13 | Use of dibenzylethylene diamino diacetate compounds against oxidative stress, pharmaceutical or cosmetic compositions containing them, new compounds and their preparation process. |
DE69326776T DE69326776T2 (en) | 1992-11-13 | 1993-11-10 | USE OF N-ARYLMETHYLEN ETHYLENDIAMINTRIACETATE, N-ARYLMETHYLEN IMINODIACETAT OR N, N'-DIARYLMETHYLEN ETHYLENDIAMINDIACETAT AGAINST OXIDATIVE STRESS |
PCT/FR1993/001109 WO1994011338A1 (en) | 1992-11-13 | 1993-11-10 | Use of n-arylmethylene, ethylenediaminetriacetates n-arylmethylene iminodiacentates or n, n'-diarylmethylene ethylenediaminacetates for use in combatting oxidative stress |
EP94900187A EP0668854B1 (en) | 1992-11-13 | 1993-11-10 | Use of n-arylmethylene, ethylenediaminetriacetates n-arylmethylene iminodiacetates or n,n'-diarylmethylene ethylenediaminacetates for use in combatting oxidative stress |
AT94900187T ATE185548T1 (en) | 1992-11-13 | 1993-11-10 | USE OF N-ARYLMETHYLENE ETHYLENEDIAMINE DIACETATE, N-ARYLMETHYLENE IMINODIACETATE OR N,N'-DIARYLMETHYLENE ETHYLENEDIAMINE DIACETATE AGAINST OXIDATIVE STRESS |
US08/436,203 US5703095A (en) | 1992-11-13 | 1993-11-10 | Use of N-arylmethylene, ethylenediaminetriacetates, N-arymethylene iminodiacetates or N,N'-diarylmethylene ethylenediamineacetates against oxidative stress |
JP51179294A JP3510627B2 (en) | 1992-11-13 | 1993-11-10 | Use of N-arylmethyleneethylenediaminetriacetate, N-arylmethyleneiminodiacetate or N, N'-diarylmethyleneethylenediamine acetate for oxidative stress |
ES94900187T ES2136723T3 (en) | 1992-11-13 | 1993-11-10 | USE OF N-ARYL-METHYLENE-ETHYL-DIAMINE-TRIACETATES, N-ARYL-METHYLENE-IMINO-DIACETATES OR N, N'-DIARYL-METHYLENE-DIAMINE-ACETATES AGAINST OXIDIZING STRESS. |
CA002149431A CA2149431A1 (en) | 1992-11-13 | 1993-11-10 | Use of n-arylmethylene ethylenediamine-triacetates, n-arylmethylene iminodiacetates or n,n'-diarylmethylene ethylenediaminacetates against oxidizing stress |
US08/469,751 US5629436A (en) | 1992-11-13 | 1995-06-06 | Use of N-arylmethylene ethylenediaminetriacetates N-arylmethylene iminodiacetates or N,N'-diarylmethylene ethylenediamineacetates against oxidative stress |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9213707A FR2698095B1 (en) | 1992-11-13 | 1992-11-13 | Use of dibenzylethylene diamino diacetate compounds against oxidative stress, pharmaceutical or cosmetic compositions containing them, new compounds and their preparation process. |
Publications (2)
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FR2698095A1 true FR2698095A1 (en) | 1994-05-20 |
FR2698095B1 FR2698095B1 (en) | 1994-12-30 |
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FR9213707A Expired - Lifetime FR2698095B1 (en) | 1992-11-13 | 1992-11-13 | Use of dibenzylethylene diamino diacetate compounds against oxidative stress, pharmaceutical or cosmetic compositions containing them, new compounds and their preparation process. |
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0700896A1 (en) * | 1994-09-08 | 1996-03-13 | L'oreal | Photochemically cleavable metal chelating agents and compositions containing them |
EP2204164A1 (en) | 2008-12-30 | 2010-07-07 | L'oreal | Combination of monosaccharides with antioxidizing agents and cosmetic use thereof |
WO2018159139A1 (en) | 2017-02-28 | 2018-09-07 | L'oreal | Composition comprising resorcinol or derivative thereof |
WO2020218022A1 (en) | 2019-04-26 | 2020-10-29 | L'oreal | Combination of specific particle and lipophilic antioxidant agent |
WO2021125070A1 (en) | 2019-12-16 | 2021-06-24 | L'oreal | Stable composition comprising combination of cinnamic acid derivatives with specific ingredients |
WO2023120259A1 (en) | 2021-12-20 | 2023-06-29 | Oreal | Stable composition comprising retinoid |
WO2023120390A1 (en) | 2021-12-20 | 2023-06-29 | L'oreal | Stable composition comprising retinoid and ascorbic acid compound |
FR3131837A1 (en) | 2022-01-19 | 2023-07-21 | L'oreal | STABLE COMPOSITION COMPRISING A RETINOID AND AN ASCORBIC ACID COMPOUND |
FR3131845A1 (en) | 2022-01-19 | 2023-07-21 | L'oreal | STABLE COMPOSITION COMPRISING RETINOID |
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US4528196A (en) * | 1981-02-23 | 1985-07-09 | The United States Of America As Represented By The Department Of Health And Human Services | Chelating agents for the treatment of iron overload |
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US4528196A (en) * | 1981-02-23 | 1985-07-09 | The United States Of America As Represented By The Department Of Health And Human Services | Chelating agents for the treatment of iron overload |
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AMERICAN JOURNAL OF HEMATOLOGY vol. 24, no. 3, Mars 1987, pages 277 - 284 BYOUNG-KOOK K. 'EFFECTIVENESS OF ORAL IRON CHELATORS ASSAYED IN THE RAT' * |
CHEMICAL ABSTRACTS, vol. 110, no. 13, 27 Mars 1989, Columbus, Ohio, US; abstract no. 110927, LI J ET AL. 'Specific sequestering agents for the actinides VI' page 344 ; * |
JOURNAL OF MEDICINAL CHEMISTRY vol. 29, no. 7, Juillet 1986, WASHINGTON US pages 1231 - 1237 C.G. PITT ET AL. 'ESTERS AND LACTONES OF PHENOLIC AMINO CARBOXYLIC ACIDS: PRODURUGS FOR IRON CHELATION' * |
Cited By (11)
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EP0700896A1 (en) * | 1994-09-08 | 1996-03-13 | L'oreal | Photochemically cleavable metal chelating agents and compositions containing them |
FR2724317A1 (en) * | 1994-09-08 | 1996-03-15 | Oreal | PHOTOCLEADABLE METAL CHELATORS AND COMPOSITIONS CONTAINING SAME |
US5709848A (en) * | 1994-09-08 | 1998-01-20 | L'oreal | Photocleavable metal-chelating agents and compositions containing the same |
EP2204164A1 (en) | 2008-12-30 | 2010-07-07 | L'oreal | Combination of monosaccharides with antioxidizing agents and cosmetic use thereof |
WO2018159139A1 (en) | 2017-02-28 | 2018-09-07 | L'oreal | Composition comprising resorcinol or derivative thereof |
WO2020218022A1 (en) | 2019-04-26 | 2020-10-29 | L'oreal | Combination of specific particle and lipophilic antioxidant agent |
WO2021125070A1 (en) | 2019-12-16 | 2021-06-24 | L'oreal | Stable composition comprising combination of cinnamic acid derivatives with specific ingredients |
WO2023120259A1 (en) | 2021-12-20 | 2023-06-29 | Oreal | Stable composition comprising retinoid |
WO2023120390A1 (en) | 2021-12-20 | 2023-06-29 | L'oreal | Stable composition comprising retinoid and ascorbic acid compound |
FR3131837A1 (en) | 2022-01-19 | 2023-07-21 | L'oreal | STABLE COMPOSITION COMPRISING A RETINOID AND AN ASCORBIC ACID COMPOUND |
FR3131845A1 (en) | 2022-01-19 | 2023-07-21 | L'oreal | STABLE COMPOSITION COMPRISING RETINOID |
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