# US 5,703,095 A · Use of N-arylmethylene, ethylenediaminetriacetates, N-arymethylene iminodiacetates or N,N'-diarylmethylene ethylenediamineacetates against oxidative stress

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- Number: US 5,703,095 A
- Document ID: US5703095A
- Status: Granted
- Kind: A
- Application number: 08/436,203
- Filed: 1995-06-27
- Granted: 1997-12-30
- Earliest claimed: 1992-11-13
- Assignees: L'oreal
- Inventors: Jean Baptiste Galey; Jacqueline Dumats
- Web page: https://patentgrep.com/patent/US5703095A

## CPC

- C07D 213/38: having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
- A61K 8/44: Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
- A61K 31/195: having an amino group
- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 31/4406: only substituted in position 3, e.g. zimeldine (nicotinic acid A61K31/455)
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61Q 5/00: Preparations for care of the hair
- A61Q 17/00: Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
- A61Q 19/00: Preparations for care of the skin
- C07C 229/16: to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
- A61Q 19/08: Anti-ageing preparations
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61Q: SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

N-arylmethylene ethylenediaminetriacetate, N-arylmethylene iminodiacetate or N,N'-diarylmethylene ethylenediaminediacetate type compounds and their use in combatting oxidative stress, and pharmaceutical and cosmetic compositions comprising said compounds. The invention also concerns a process for the preparation of said compounds.

## Claims

### Claim 1

Process for protecting the human body against oxidative stress which comprises administering to it an effective amount of a compound of formula (I): ##STR18## in which: Z.sub.1, Z.sub.2 and Z.sub.3, independently of one another, represent NO.sub.2, COOH, CF.sub.3, a halogen atom or an R.sub.1, OR.sub.1, SR.sub.1 or NR.sub.1 R.sub.2 group,
Z.sub.4 represents an R.sub.1 group;
where R, R.sub.1 and R.sub.2, independently of one another, represent H or a linear or branched C.sub.1 to C.sub.8 alkyl group,
X.sub.1, X.sub.2 and X.sub.3 represent: ##STR19## or --N.dbd., provided that if X.sub.1 =N, then X.sub.2 --X.sub.3 =C and there is no Z.sub.1 substituent at X.sub.1,
if X.sub.1 =N, then X.sub.1 .dbd.X.sub.3 =C and there is no Z.sub.2 substituent at X.sub.2,
if X.sub.3 =N, then X.sub.2 .dbd.X.sub.1 =C and there is no Z.sub.3 substituent at X.sub.3, that is to say that it is a pyridine ring;
if X.sub.1, X.sub.2 and X.sub.3 all represent C, it is then a benzene ring;
Z.sub.5 represents:
the group: --COOR (a)
or the group: ##STR20## or the group: ##STR21## in which Z.sub.1, Z.sub.2, Z.sub.3, Z.sub.4, X.sub.1, X.sub.2, X.sub.3, R, R.sub.1 and R.sub.2 have the same meanings as above;
or of its salts and metal complexes.

### Claim 2

Cosmetic composition comprising at least one compound of formula (I): ##STR22## in which: Z.sub.1, Z.sub.2 and Z.sub.3, independently of one another, represent NO.sub.2, COOH, CF.sub.3, a halogen atom or an R.sub.1, OR.sub.1, SR.sub.1 or NR.sub.1 R.sub.2 group,
Z.sub.4 represents an R.sub.1 group;
where R, R.sub.1 and R.sub.2, independently of one another, represent H or a linear or branched C.sub.1 to C.sub.8 alkyl group,
X.sub.1, X.sub.2 and X.sub.3 represent: ##STR23## or --N.dbd., provided that if X.sub.1 =N, then X.sub.2 .dbd.X.sub.3 =C and there is no Z.sub.1 substituent at X.sub.1,
if X.sub.2 =N, then X.sub.1 .dbd.X.sub.3 =C and there is no Z.sub.2 substituent at X.sub.2,
if X.sub.3 =N, then X.sub.2 .dbd.X.sub.1 =C and there is no Z.sub.3 substituent at X.sub.3, that is to say that it is a pyridine ring;
if X.sub.1, X.sub.2 and X.sub.3 all represent C, it is then a benzene ring;
Z.sub.5 represents:
the group: --COOR (a)
or the group: ##STR24## or the group: ##STR25## in which Z.sub.1, Z.sub.2, Z.sub.3, Z.sub.4, X.sub.1, X.sub.2, X.sub.3, R, R.sub.1 and R.sub.2 have the same meanings as above; or its salts or metal complexes, in a cosmetically acceptable medium.

### Claim 3 (depends on 2)

Composition according to claim 2, which contains 0.001 to 10% by weight of at the least one compound of formula (I).

### Claim 4 (depends on 2)

Composition intended for the cosmetic treatment of the effects of oxidative stress or for protecting against these effects, which it comprises two components (A) and (B):
the component (A) consisting of the compound of formula (I) as defined in claim 2,
the component (B) being selected from the group consisting of antilipoperoxidants, biological reducing agents, singlet oxygen scavengers, systems capable of decomposing hydrogen peroxide, systems for protecting against the superoxide anion, systems capable of decomposing organic hydroperoxides, UV screening agents, penetration promoters and their combinations and being present in the same composition as the component (A) or intended to be used separately, optionally separated in time.

### Claim 5 (depends on 4)

Composition according to claim 4, wherein the antilipoperoxidant agent is selected from the group consisting of vitamin E, trolox and BHT; the biological reducing agent is selected from reduced glutathione and vitamin C; the singlet oxygen scavenger is a carotenoid; the system capable of decomposing hydrogen peroxide is a catalase or peroxidase enzyme; the system for protecting against the superoxide anion consists of the SODs, the Mn-desferal complex or copper diisopropylsalicylate; and the system capable of decomposing organic hydroperoxides is glutathione peroxidase or a selenium-based system.

### Claim 6

Pharmaceutical composition comprising, in a pharmaceutically acceptable medium, at least one compound of formula (I): ##STR26## in which: Z.sub.1, Z.sub.2 and Z.sub.3, independently of one another, represent NO.sub.2, COOH, CF.sub.3, a halogen atom or an R.sub.1, OR.sub.1, SR.sub.1 or NR.sub.1 R.sub.2 group,
Z.sub.4 represents an R.sub.1 group;
where R, R.sub.1 and R.sub.2, independently of one another, represent H or a linear or branched C.sub.1 to C.sub.8 alkyl group,
X.sub.1, X.sub.2 and X.sub.3 represent: ##STR27## or --N.dbd., provided that if X.sub.1 =N, then X.sub.2 .dbd.X.sub.3 =C and there is no Z.sub.1 substituent at X.sub.1,
if X.sub.2 =N, then X.sub.1 .dbd.X.sub.3 =C and there is no Z.sub.2 substituent at X.sub.2,
if X.sub.3 =N, then X.sub.2 .dbd.X.sub.1 =C and there is no Z.sub.3 substituent at X.sub.3, that is to say that it is a pyridine ring;
if X.sub.1, X.sub.2 and X.sub.3 all represent C, it is then a benzene ring;
Z.sub.5 represents:
the group: --COOR (a)
or the group: ##STR28## or the group: ##STR29## in which Z.sub.1, Z.sub.2, Z.sub.3, Z.sub.4, X.sub.1, X.sub.2, X.sub.3, R, R.sub.1 and R.sub.2 have the same meanings as above; or its salts or metal complexes.

### Claim 7 (depends on 6)

Pharmaceutical composition according to claim 6, which contains 0.001 to 10% by weight of at least one compound of formula (I).

### Claim 8 (depends on 6)

Composition intended for the therapeutic treatment of the effects of oxidative stress or for protecting against these effects, which comprises two components (A) and (B):
the component (A) consisting of the compound of formula (I) and defined in claim 6,
the component (B) being selected from the group consisting of antilipoperoxidants, biological reducing agents, singlet oxygen scavengers, systems capable of decomposing hydrogen peroxide, systems for protecting against the superoxide anion, systems capable of decomposing organic hydroperoxides, anti-inflammatory agents, penetration promoters and their combinations and being present in the same composition as the component (A) or intended to be used separately, optionally separated in time.

### Claim 9

Compound of formula (I): ##STR30## in which: Z.sub.1, Z.sub.2 and Z.sub.3, independently of one another, represent NO.sub.2, COOH, CF.sub.3, a halogen atom or an R.sub.1, OR.sub.1, SR.sub.1 or NR.sub.1 R.sub.2 group, Z.sub.4 represents an R.sub.1 group;
where R, R.sub.1 and R.sub.2, independently of one another, represent H or a linear or branched C.sub.1 to C.sub.8 alkyl group,
X.sub.1, X.sub.2 and X.sub.3 represent: ##STR31## or --N.dbd., provided that if X.sub.1 =N, then X.sub.2 .dbd.X.sub.3 =C and there is no Z.sub.1 substituent at X.sub.1,
if X.sub.2 =N, then X.sub.1 .dbd.X.sub.3 =C and there is no Z.sub.2 substituent at X.sub.2,
if X.sub.3 =N, then X.sub.2 .dbd.X.sub.1 =C and there is no Z.sub.3 substituent at X.sub.3, that is to say that it is a pyridine ring;
if X.sub.1, X.sub.2 and X.sub.3 all represent C, it is then a benzene ring;
Z.sub.5 represents:
the group: --COOR (a)
or the group ##STR32## or the group: ##STR33## in which Z.sub.1, Z.sub.2, Z.sub.3, Z.sub.4, X.sub.1, X.sub.2, X.sub.3, R, R.sub.1 and R.sub.2 have the same meanings as above provided that when X.sub.1, X.sub.2 and X.sub.3 all represent C, Z.sub.5 does not represent the group (c);
with the exception of the following compounds: benzyliminodiacetic acid and its dimethyl ester, diethyl ester, monoethyl ester and ethyl-tert.-butyl ester, (3-aminobenzyl)iminodiacetic acid, (3-nitrobenzyl)iminodiacetic acid, (4-nitrobenzyl)iminodiacetic acid, (4-aminobenzyl)iminodiacetic acid, (4-hydroxybenzyl)iminodiacetic acid, (4-dimethylaminobenzyl)iminodiacetic acid, (4-methylbenzyl)-iminodiacetic acid, (4-fluorobenzyl)iminodiacetic acid, (3-nitro-4-chlorobenzyl)iminodiacetic acid, benzylethylenediaminetriacetic acid and (3-pyridylmethylene)iminodiacetic acid, N,N'-bis(3-hydroxy-2,5-dimethyl-4-pyridylmethylene)ethylenediamine diacetic acid; or its salts or metal complexes.

### Claim 10 (depends on 9)

Compound of formula (I) according to claim 9, selected from the group consisting of (3,4,5-trimethoxybenzyl)iminodiacetic acid, (3-hydroxybenzyl)iminodiacetic acid, and N,N'-di(3-pyridylmethylene)-ethylenediaminediacetic acid, and their salts and metal complexes.

### Claim 11 (depends on 10)

Process for the preparation of a compound of formula (I) according to claim 10, wherein the following stages are carried out:
1) the aldehyde of formula (II): ##STR34## is reacted (A) with the ethyl ester of glycine when Z.sub.5 denotes the group (a), (B) with N-acetylethylenediamine when Z.sub.5 denotes the group (b) or (C) with ethylenediamine when Z.sub.5 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 in order to saponify the ethyl ester and the diamine obtained by process (B) is treated with HCl in order to hydrolyse the acetyl functional group,
4) the amine or diamine obtained is treated in basic medium with bromoacetic acid in the presence of sodium monohydrogencarbonate in order to obtain the corresponding compound of formula (I) and the product obtained is recovered.

### Claim 12

A compound of the formula: ##STR35## wherein Z.sub.2 and Z.sub.4 represent H and Z.sub.1 and Z.sub.3 are independently of each other CH.sub.3, OCH.sub.3, CF.sub.3, NO.sub.2 or a halogen atom.