FR2706889A1 - Use of N-(arylmethylene)ethylenediaminetriacetate, N-(arylmethylene)iminodiacetate or N,N'-di(arylmethylene)ethylenediaminediacetate compounds against oxidative stress - Google Patents

Abstract

The present invention relates to compounds of the N-(arylmethylene)ethylenediaminetriacetate, N-(arylmethylene)iminodiacetate or N,N'-di(arylmethylene)ethylenediaminediacetate type and to their use against oxidative stress, as well as to the pharmaceutical and cosmetic compositions containing such compounds. It also relates to the process for the preparation of these compounds.

Description

The present invention relates to N-arylmethylene derivatives

  ethylenediaminetriacetate, N-arylmethylene iminodiacetate or N, N'-

  diarylmethylene ethylenediaminediacetate, useful in particular for protecting the organism against oxidative stress, their process of preparation as well as pharmaceutical and cosmetic compositions

containing such compounds.

  In the field of health and cosmetics, the concept of oxidative stress is known, oxidative stress which appears in particular as soon as there is an imbalance in the antioxidant-prooxidant balance. This imbalance is reflected 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).

  it is known that various situations cause, promote or accompany oxidative stress; these include exposure to ultraviolet rays and ionizing radiation, aging, inflammation, carcinogenesis, ischemia reperfusion situations, toxicity and / or mode

of certain drugs.

  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 the reactions of Fenton (1) and Haber-Weiss (2 ) which results in the formation of hydroxyl radicals, radicals known to be responsible for numerous oxidative damage (Reif, DW, Free Rad. Biol. Med. 12, 417-427,

1992).

  Oxygen is essential for the respiration of aerobic living beings, but can be reduced to superoxide radical 02 - in all aerobic cells. This radical can undergo a disproportionation reaction giving rise to hydrogen peroxide:

2 02- + 2H +> - H202 + 02

  In the presence of traces of iron, this superoxide radical can also reduce the ion Fe3 + 0 2- + Fe3 + - Fe2 + + 02 02> - Fe2 + 02 The Fe2 + ions thus produced can give rise to the Fenton reaction which produces the hydroxyl radical : H202 + Fe2 +> OH H + OH- + Fe3 + (1) - The Haber-Weiss reaction also produces hydroxyl radicals: [151202 + 02- Fe3 + OH + OH- + 02 (2) The hydroxyl radical OH can cause very significant damage in the body. It is able to break strands of DNA

  and alter the genetic heritage of the living cell.

  Unlike H202 and the superoxide radical O2-, it is also capable of causing peroxidation of unsaturated fatty acids. he

  plays an important role in aging skin.

  The protection of living tissue from attack is known

of the hydroxyl radical is difficult.

  One of the known approaches for protecting oneself is by using molecules, in particular D-mannitol or DMSO

  (dimethylsulfoxide), capable of trapping hydroxyl radicals.

  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 (Halliwell, B., Free Rad. Res Comms., 9 (1), 1-32, 1990). The use of large amounts of these

  trappers pose toxicity problems.

  The other known approach to protect against hydroxyl radicals is to use iron chelators, in particular deferoxamine or diethylene triamine pentaacetic acid (DTPA).

  to prevent him from participating in the reactions of Fenton and Haber-Weiss.

  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.

  Deferoxamine has a chronic toxicity supposed linked to its ability to chelate metals from active sites of metalloenzymes

  or hemoproteins like hemoglobin.

  In addition, strong chelators, which can complex iron, such as EHPG (ethylene bis-O-hydroxy phenyl glycine), are

  also known to have significant acute toxicities.

  - Finally, HBED [N, N'-bis (2-hydroxybenzyl) -ethylene diamine diacetic acid] which is an exceptionally effective iron chelator (cf. US-4,528,196), also presents risks of toxicity because it forms a very stable complex, all the coordination sites of the

  iron being occupied due to the presence of the OH groups in position 2.

  The Applicant has discovered that derivatives of N-arylmethylene

  ethylenediaminetriacetate, N-arylmethylene iminodiacetate or N, N'-

  diarylmethylene ethylenediaminediacetate, were particularly

  effective in protecting the body against oxidative stress.

  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. In fact, the compounds according to the invention form complexes with the Fe2 + ion and these complexes are capable of breaking down 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.

  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. 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

  prevent it from catalyzing the formation of other hydroxyl radicals.

  The subject of the invention is the use for protection against oxidative stress, and in particular as scavengers for hydroxyl free radicals and iron chelators, of N-arylmethylene derivatives

  ethylenediaminetriacetate, N-arylmethylene iminodiacetate or N, N'-

  diarylmethylene ethylenediaminediacetate.

  Another object is constituted by cosmetic compositions and

  pharmaceuticals using them.

  A subject of the invention is also the new compounds of the

  family of N-arylmethylene ethylenediaminetriacetate, N-aryl-

  methylene iminodiacetate or N, N'-diarylmethylene ethylenediamine-

diacetate and their preparation.

  Other objects of the invention will appear on reading the

  description and examples which follow.

  The compounds used in accordance with the invention for protection against oxidative stress, in particular by trapping hydroxyl free radicals and complexing of iron, are the compounds of formula (I): z5 N / COOR

Z4

Z3-X3 H (I)

  Xl = Z2x / Z z2 / in which Z1, Z2, Z3, independently of one another, represent COOH, CF3, a halogen atom or a group R1, OR1, SR1 or NR1R2, Z4 represents H or a group R1; o R, R1 and R2, independently of one another, represent H or a linear or branched C1-C8 alkyl group, X1, X2, X3 represent: -Y = or -N =, provided that if X1 = N, then X2 = X3 = C and there is no Z1 substituent on X1, if X2 = N, then X1 = X3 = C and there is no Z2 substituent on X2, if X3 = N , then X2 = X1 = C and there is no substituent Z3 on X3, that is to say that it is a benzene or pyridine ring; Z5 represents the grouping: -COOR (a)

COOR

r COOR or the group:

OOR

CH2N z3-X3 H (c)

X \ 2 = X

  z2 / Z1 in which Z1, Z2, Z3, Z4, X1, X2, X3, R, R1 and R2 have the same meanings as above; provided that when Z5 is: COOR CH2Z4

Z3-X H

Z2 /

  and X1 = X2 = X3 = C, then Z4 is not H;

  as well as their salts and their metal complexes.

  The linear or branched C1-C8 alkyl groups are preferably C1-C4 alkyl groups, such as methyl, ethyl,

isopropyl, tert-butyl.

  As salts, mention may be made of addition salts with a mineral acid such as acids H2SO4, HC1, HNO3 or H3PO4, for example,

  and addition salts with a mineral base such as NaOH or KOH.

  As metal complexes, mention may be made of the complexes formed

  by adding ZnC12 or CaC12, for example.

  The new compounds are the compounds of formula (I), in which Z1, Z2, Z3, Z4, Z5, X1, X2, X3, R, R1, R2 have the meanings indicated above, as well as their salts and metal complexes, the exclusion of the products below which are already known: NH2 sN X \ COOH SN - / \ COeH

-OOH OOH

O10

  benzyl imino acid 3-aminobenzyl imino acid

diacetic diacetic

NI-2 OH H3C \ / CH3

7H, OH

-N-COOH, - '/ COOH -N -'COOH

- CO NOOH 'CO

  4-aminobenzyl acid 4-hydroxybenzyl acid 4-dimethyl-

  iminodiacetic iminodiacetic aminobenzyl imino-

diacetic

CH3 F

N --COOH -N-COOH

00O OOH

  4-methylbenzyl imino acid 4-fluorobenzyl imino acid

  diacetic diacetic COOH EN - / \ X soC00H ÉN X \ COOH

OH 00O

  benzyl ethylenediamine acid 3-pyridylmethylene triacetic iminodiacetic acid The compounds defined by formula (I) are used as medicaments, in particular for protecting the organism 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. 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 topically

  for their cosmetic effect on the skin or hair.

  The cosmetic and pharmaceutical compositions using the compounds of formula (I) comprise a compound of formula (I) or one of its salts or metal complexes, in a medium

  cosmetically or pharmaceutically acceptable.

  These compositions contain the compounds of formula (I) in

  proportions of 0.001 to 10% by weight.

  The cosmetic and pharmaceutical compositions can be in various forms usually used in this field, and in particular in the form of an ointment, cream, ointment, tablet, oral suspension, injection or gel for pharmaceutical compositions. and in the form of a gel, spray, lotion, emulsion or vesicular dispersion for

cosmetic compositions.

  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 dosage is generally between

1 and 100 mg / kg / day.

  The cosmetically or pharmaceutically acceptable medium is

  a usual medium in the cosmetic or pharmaceutical field.

  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: - the 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 sensor for singlet oxygen as a carotenoid such as [3-carotene, a system capable of breaking down hydrogen peroxide such as enzymes like catalase or peroxidases in the presence of their co-substrate, - an anion protection system superoxide like

  SOD or analogues such as the Mn-desferal complex or the di-

  copper isopropyl 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,

  and combinations of these compounds.

  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 shifted or not, in time, using

  of a cosmetic or pharmaceutical composition containing them.

  Furthermore, the applicant has found that the compounds (I) according to the invention can be used as antioxidants for preserving

the compositions containing them.

  The present invention also relates to the method of

  preparation of the compounds (I) of the invention.

l

  The process varies depending on the nature of Z5.

  When Z5 = - COOR (a), according to method (A), the aldehyde of formula (II) (1 mole):

H Z

C (IZ2I)

z4

Z3

  o X1, X2, X3, Z1, Z2, Z3 and Z4 have the meanings already indicated, is placed in the presence of the ethyl ester of glycine (1 mole) to

get the corresponding imine.

  When Z5 denotes COOR (b) OOR according to method (B), the aldehyde of formula (II) (1 mole) is placed in the presence of N-acetyl ethylenediamine (1 mole) to obtain the corresponding imine. When Z5 designates OOR

CH2-N / C

Z3-X3 H (c) Xi = X1 xV5x

Z2 / "Z1

  according to method (C), the aldehyde of formula (II) (2 moles) is placed in the presence of ethylenediamine (1 mole) to obtain the corresponding diimine. In each of the three processes, the imine or diimine obtained, isolated or not, is placed in the presence of sodium borohydride or is reduced by catalytic hydrogenation, to give rise to the amine

or to the corresponding diamine.

  According to method (B), the diamine obtained is then treated with

  hydrochloric acid to hydrolyze the acetyl function.

  According to method (A), the amine obtained is treated with sodium hydroxide to

saponify the ethyl ester.

  In a subsequent step, the amine or diamine obtained by methods (A), (B) or (C) is treated in basic medium, for example in the presence of sodium hydroxide, with bromoacetic acid or l 'one of its esters, in the presence of sodium monohydrogencarbonate. The corresponding product of formula (I) is then recovered. These processes are schematized as follows:

GENERAL SYNTHESIS DIAGRAM

Z3 Z4

Z1 / 5N

2- HO H2N -'- Z5 C

Z2 0I) H

Z5 N Z5 N

  > \ <Z4 NaBH4 x <i3 Z "Z2 COOH H Z5N" ... BrCH2COOR NaOH Z23 NaEH CO3 xk \ Z3 Z 3 2 Z2 'Depending on the nature of Z1, Z2 and Z3, a protection / deprotection step may be necessary , especially in the case where one of these substituents is NH2. This additional step is carried out according to the usual techniques of organic chemistry, as well as the final esterification of the compounds according to formula (I) for which

  R is H, if free bromo-acetic acid is used.

  Other characteristics and advantages of the invention will appear

reading the examples below.

PREPARATION EXAMPLES

  OMe Example 1 MeO COOH 3, 4,5-trimethoxybenzyl iminodiacetic acid MeO 2OOH COOH

Example 2

  benzyl iminodiacetic acid OOH OH Example 3 COOH 3-hydroxybenzyl ninodiacetic acid COOH HO0C Example 4 COOH N-benzyl ethylene N diaminetriacetic acid

00OH

  Example 5 HOOC N, N '- (2-methylbenzyl) 3 ethylenediarninediacetic acid H3C

GENERAL PROCEDURE

  First step mmoles of the starting benzaldehyde are dissolved in 30 ml of methanol. 40 mmol of the amine (20 mmol in the case of ethylenediamine) are added, then the mixture is heated for 30 minutes to C. The precipitate obtained is filtered and washed with ethyl ether. We obtain

a white product.

  Example starting amine starting benzaldehyde N 1 ethyl ester of glycine 3,4,5-trimethoxy benzaldehyde N 2 ethyl ester of glycine benzaldehyde N 3 ethyl ester of glycine 3-hydroxy benzaldehyde N 4 N-acetyl ethylenediamine benzaldehyde N 5 ethylenediamine 2-methyl benzaldehyde Second step 17 mmol of the imine or of the diimine are suspended in 100 ml of absolute ethanol. 1 equivalent of sodium borohydride is added little by little and the mixture is stirred for 1 hour at temperature.

ambient.

  After evaporation, 20 ml of water are added to the residue and the

  pH at 8 by addition of hydrochloric acid.

  The precipitate is filtered, washed with water and then dried.

  The product is recrystallized from a water / ethanol mixture. We

obtains a white product.

  Third step According to method (C) (Example No. 5), 10 mmol of the diamine are dissolved in 15 ml of water containing 10 mmol of hydroxide

sodium.

  mmol of bromoacetic acid are dissolved in 25 ml of water at 0 C containing 20 mmol of sodium monohydrogencarbonate. The two solutions are mixed and heated at 40 C for 6

  hours keeping the pH around 12 by adding 30% sodium hydroxide.

  After standing overnight at room temperature, the mixture is

  acidified with concentrated hydrochloric acid to pH 4.5.

  The solution is concentrated under vacuum and the precipitate obtained is filtered then recrystallized from a water / ethanol mixture. We recover a

White powder.

  According to method (A) (Examples 1, 2, and 3), 10 mmol of amine in 20 ml of water are previously stirred for 30 minutes at room temperature in the presence of 10 mmol of NaOH. The crude mixture obtained is then treated with 10 mmol of bromoacetic acid dissolved in

  ml of water containing 10 mmol of NaHCO3, as indicated above

above for process (C).

  According to method (B) (Example No. 4), 10 mmol of diamine in 20 ml of 4N HCl are brought to reflux for 24 hours. The crude mixture obtained is then brought to basic pH and treated with 30 mmol of bromoacetic acid dissolved in 30 ml of water containing 30 mmol of NaHCO3 to obtain the N-benzylethylene diamine derivative

  corresponding, as indicated above for process (C).

  Example overall yield melting point NMR 13 C or 1H and SM N 1 21% 206-208 C compliant N 2 33% 200 C compliant N 3 41% 222 C compliant N 4 8% 250 C compliant N 5 40% 198 C compliant

COSMETIOUE FORMULATION EXAMPLES

EXAMPLE A

  The following emulsion is prepared according to conventional techniques using the constituents below. - Compound of Example 1 0.1 g Polyethylene glycol oxyethylenated to 50 moles of ethylene oxide 3 g Monodiglyceryl stearate 3 - Vaseline oil 24 g - Cetyl alcohol 5 Water qs 100 g A white emulsion intended to be applied is obtained

  topically on the area of the skin to be protected.

EXAMPLE B

  The following emulsion is prepared according to conventional techniques by

  using the constituents below.

  - Compound of Example 2 0.02 - Octylpalmitate 10 - Glyceryl isostearate 4 g - Vaseline oil 24 C - Vitamin E 1 - Glycerol 3 g - Water qs 100 b We obtain a white emulsion intended to be applied

  topically on the area of the skin to be protected.

EXAMPLE C

  The following formulation is prepared according to conventional techniques

  using the constituents below.

  - Compound of Example 2 0.02 g - Jojoba oil 13 g Methyl and isopropyl parahydroxybenzoates 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 We obtain a white emulsion intended to be applied

  topically on the area of the skin to be protected.

  EXAMPLES OF PHARMACEUTICAL FORMULATION

D - ORAL ROUTE

  1) Tablet - Compound of Example 2 0.001 g - Starch 0.114 g - Dicalcium phosphate 0.020 g - Lactose 0.060 g - Magnesium stearate 0.005 g

  After compacting, a 0.2 g tablet is obtained.

  2) Oral suspension - Compound of Example 2 0.001 g - Glycerol 0.500 g - Sorbitol at 70% 0.500 g - Sodium saccharinate 0.010 g Methyl parahydroxybenzoate 0.040 g - Flavor qs - Purified water qs 5 ml

E- ADMINISTRATION BY INJECTION

  3 ml ampoule for injection - Compound of Example 2 0.002 g - Sodium hydroxide 0.0007 g - Water for injectable preparation qs 3 ml

Claims (14)

  1. Use of a compound of formula (I): z5 \ W COOR z4 Z3-X3 H (I)   z2 / \ Z in which Z1, Z2, Z3, independently of one another, represent COOH, CF3, an halogen atom or a group R1, OR1, SR1 or NR1R2, Z4 represents H or a group R1; o R, R1 and R2, independently of each other, represent H or a linear or branched aikyl group in C1 to C8, X1, X2, X3 represent: -Y = or - N =, provided that if X1 = N, then X2 = X3 = C and there is no substituent Z1 on X1, if X2 = N, then Xi = X3 = C and there is no substituent Z2 on X2, if X3 = N , then X2 = X1 = C and there is no substituent Z3 on X3, that is to say that it is a benzene or pyridine ring; Z5 represents: the group: -COOR (a) COOR or the group: (b) C2 OOR or the group: COOR -CH2-N /   z4 Z3 -X H (c) Zz2 / \ 1 in which Z1, Z2, Z3, Z4, X1, X2, X3, R, R1 and R2 have the same meanings as above; provided that when Z5 is COOR -CH2- Nr Z4 Z3-X3x> 3i = Xj Z2 \ z and X1 = X2 = X3 = C, then Z4 is not H; or its salts and metal complexes, for the cosmetic treatment of the skin or hair, with a view to protecting them against oxidative stress. 2. Cosmetic composition, characterized in that it contains at least one compound of formula (I) as defined in   claim 1, in a cosmetically acceptable medium.   3. Composition according to claim 2, characterized in that it contains 0.001 to 10% by weight of at least one compound of   formula (I) as defined in claim 1.   4. Composition intended for the cosmetic treatment of the effects of oxidative stress or for protection against these effects, characterized in that it comprises two components (A) and (B): component (A) consisting of the compound of formula (1) as defined in claim 1, component (B) being chosen from antilipoperoxidants, biological reducers, singlet oxygen sensors, systems capable of decomposing hydrogen peroxide, protection systems against superoxide anion, systems capable of decomposing organic hydroperoxides, UV filters, penetration promoters or their associations, and being present in the same composition as component (A) or intended to be used   separately, delayed or not in time.   5. Composition according to claim 4, characterized in that the antilipoperoxidizing agent is chosen from vitamin E, trolox, BHT; the biological reducing agent is chosen from reduced glutathione or vitamin C; the singlet oxygen sensor is a carotenoid; the system capable of breaking down hydrogen peroxide is a catalase or peroxidase enzyme; the superoxide anion protection system consists of SODs, the Mn-desferal complex, copper di-isopropyl salicylate; the system capable of breaking down organic hydroperoxides is the   glutathione peroxidase or a selenium-based system.   6. Compound of formula (I): z5 N COOR Z4 Z3-X3 H (I)   z2 / in which Z1, Z2, Z3, independently of one another, represent COOH, CF3, a halogen atom or a group R1, OR1, SR1 or NR1R2, Z4 represents H or a group R1; o R, R1 and R2, independently of each other, represent H or a linear or branched C1-C8 alkyl group, X1, X2, X3 represent - = or - N =, provided that if X1 = N , then X2 = X3 = C and there is no substituent Z1 on X1, if X2 = N, then X1 = X3 = C and there is no substituent Z2 on X2, if X3 = N, then X2 = X1 = C and there is no substituent Z3 on X3, that is to say that it is a nucleus of benzene or pyridine; Z5 represents: the group: -COOR (a) COOR or the group: (b) xC11 _OOR or the group: COOR CH2-N   z4 Z3-X3 / H (c) X = XI z2 / "Zx in which Z1, Z2, Z3, Z4, X1, X2, X3, R, R1 and R2 have the same meanings as above; provided that when Z5 is CH2N // COOR -CH, -8 Z4 H Z3 ---- X H   Z2 / \ z1 xV = xî and X! = X2 = X3 = C, then Z4 is not H; or its salts or metal complexes, for its use in a method of therapeutic treatment of human or animal body.   7. Compound corresponding to formula (I) as defined in claim 6, for its use in the protection of the organism human against oxidative stress.   8. Pharmaceutical composition, characterized in that it contains in a pharmaceutically acceptable medium, at least one   compound of formula (I) as defined in claim 6.   9. Pharmaceutical composition according to claim 8, characterized in that it contains 0.001 to 10% by weight of at least one compound of formula (I) as defined in claim 6.   10. Composition intended for the therapeutic treatment of the effects of oxidative stress or for protection against these effects, characterized in that it comprises two components (A) and (B): component (A) consisting of the compound of formula (I) as defined in claim 6, component (B) being chosen from antilipoperoxidants, biological reducers, singlet oxygen sensors, systems capable of decomposing hydrogen peroxide, protection systems against superoxide anion, systems capable of   decompose organic hydroperoxides, anti-   inflammatory, penetration promoters or their associations, and being present in the same composition as component (A) or   intended to be used separately, staggered or not in time.   11. Compound of formula (I): z5 COOR Z4 Z3-X3 \ H (I)   z2 / \ 1 in which Z1, Z2, Z3, independently of one another, represent COOH, CF3, a halogen atom or a group R1, OR1, SR1 or NR1R2, Z4 represents H or a group R1; o R, R1 and R2, independently of each other, represent H or a linear or branched C1-C8 alkyl group, X1, X2, X3 represent: -d = or -N =, provided that if X1 = N, then X2 = X3 = C and there is no Z1 substituent on X1, if X2 = N, then X1 = X3 = C and there is no Z2 substituent on X2, if X3 = N , then X2 = X1 = C and there is no substituent Z3 on X3, that is to say that it is a benzene or pyridine ring; Z5 represents: the group: -COOR (a) COOR or the group: (b) \ Cg2 N)% cFf OO) R or the group: /.COOR -CH2-N   Z4 Z3-X3 H (c) kX = X1 z2 / \ Z1 in which Z1, Z2, Z3, Z4, X1, X2, X3, R, R1 and R2 have the same meanings as above; provided that when Z5 is: COOR CH2 -N Z4 Z3 - X H   z2 / \ Z1 and X1 = X2 = X3 = C, then Z4 is not H, excluding the compounds   following: benzyl iminodiacetic acid, 3-aminobenzyl imino acid   diacetic, 4-aminobenzyl iminodiacetic acid, 4-hydroxy acid   benzyl iminodiacetic, 4-dimethylaminobenzyl imino- acid   diacetic, 4-methylbenzyl iminodiacetic acid, 4-fluoro- acid   benzyl iminodiacetic, benzyl ethylenediaminetriacetic acid, 3pyridylmethylene iminodiacetic acid, and its salts and metal complexes.   12. Compound of formula (I) according to claim 11, characterized   by the fact that it is chosen from 3,4,5-trimethoxybenzyl imino-   diacetic, 3-hydroxybenzyl iminodiacetic acid and N, N '- (2-   methylbenzyl) ethylenediaminediacetic.   13. Process for the preparation of the compound of formula (I) according to claim 11, characterized in that the following steps are carried out 1) the aldehyde of formula (H) is reacted: H Z   c> / e (IH) z4 (A) with the ethyl ester of glycine when Z5 denotes the group (a), (B) with N-acetyl ethylenediamine when Z5 denotes the group (b), or (C) with ethylenediamine when Z5 denotes the group (c), 2) the corresponding imine or diimine obtained is reduced with sodium borohydride or by catalytic hydrogenation, 3) the amine obtained by process (A) is treated with NaOH to saponify the ethyl ester and the diamine obtained by process (B) with HCl to hydrolyze the acetyl function, 4) the amine or diamine obtained in basic medium is treated with bromoacetic acid in the presence of sodium monohydrogencarbonate , to obtain the corresponding compound of formula (I) and we recovers the product obtained.   14. Use as an antioxidant of the compound as defined in   any one of claims 1, 11 and 12.