FR2685324A1 - Hydroquinone esters and pharmaceutical or cosmetic compositions having a regulatory activity on cutaneous (skin) pigmentation containing them - Google Patents

Abstract

The invention relates to hydroquinone alpha amino acid esters and cosmetic or pharmaceutical compositions containing them. These new hydroquinone derivatives are useful for the preparation of pharmaceutical compositions, in particular dermatological compositions, with depigmenting activity or cosmetic compositions, which are stable and non-irritating.

Description

 The present invention relates to novel amino acid esters of hydroquinone. pharmaceutical or cosmetic compositlons containing them. It is more specifically related to pharmaceutical or cosmetic compositions with regulatory activity of cutaneous pIgmentation, for a pharmaceutical, cosmetic or aesthetic application.

The mechanism of formation of the pigment responsible for the coloration of the skin, regional or local hyperpigmentotlons, is a complex mechanism of oxidation which responds very schematically to the following representation:
Tyrosine -> Dopa -> Dopachrome -> Melonine
The consequent Irregular Brown spots can be induced by the use of poorly tolerated solar products, contact with photosensitizing substances. the use of oral contraceptives senescence, pregnancy.

 The present invention aims to prevent the formation of such spots or facilitate their disappearance, by providing a pharmaceutical or cosmetic composition characterized in that it comprises, as active substance, one or more chemical compounds having an inhibitory activity of peroxidase and tyrosinase.

 Many substances have been proposed before, in particular kolic acid. ascorbic acid and derivatives, cystine and derivatives, hydroquinone. However, the compositions containing them have certain major disadvantages, both in terms of stability with uncontrolled browning or untimely oxidation, as well as toxicity with the induction of contact allergies and irritations which contraindicate repeated local use.

 The present invention aims to provide hydroquinone derivatives which do not induce the disadvantages mentioned above.

dans laquelle. The present invention has as its object natural amino acid esters of hydroquinone and the formulations or compositions containing them. These products correspond to the following general formula (1):

in which.

X represents the residue of a natural alpha amino acid or a simple derivative thereof, such as a methyl or ethyl monoester, or a primary amide in the case of dicarboxylic amino acids, which may or may not be substituted with nitrogen by an alkylcarbonyl radical having 1 to 20 hydrocarbon sequences
Y, which is identical to or different from X, represents the residue of a natural alpha aminoocide or a simple derivative thereof, such as a methyl or ethyl monoester or a primary amide in the case of dicarboxylic amino acids, whether or not substituted with nitrogen by an alkylcarbonyl radical having 1 to 20 hydrocarbon groups. or represents an alicylcarbonyl radical with 1 to 20 hydrocarbon sequences
In more precise terms, X and Y may thus represent the remainder of a naturally occurring alpha aminoocide chosen in particular porml alanine. the originine.

asparagine, glutamine, pyroglutamic acid, cysteine, aspartic acid.

glutamic acid, glycine, histidine, isoleucine. rhydroxy4 proline, leucine, lysine. methionine, ornithine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.

 By natural amino acids is meant in the sense of the present invention, the alpha amino acids constituting proteins. The chiral site in the alpha position determines isomers (I) and (d). The general formula (I) includes the isomer (I) and the racemic form of the amino acid.

 For the purposes of the present invention, the term "allyl" especially encompasses methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, hepladecyl and octodecyl radicals. nonadecyl and elcosyl.

The Applicant has found that, surprisingly, the products according to the general formula (I) were peroxidase and tyrosinase inhibitors, and exhibited at least a compelling and in most cases depigmenting activity superior to that of the hydroquinone and other derivatives, that they had an excellent margin of safety unlike the products of the prior art, that they could be mixed with any ingredient commonly used in cosmetic compositions or pharmaceutical preparations for the treatment of skin
According to an advantageous arrangement of the present invention, X or
X and Y more particularly determine a pyrrolidinone-2 ring. substituted or unsubstituted, thus representing derivatives of pyroglutamic acidf corresponding to the general formulas (II) and (III).

in which
R1 and R2, identical or different, represent a hydrogen atom, an alkylcarbonyl radical having 1 to 20 hydrocarbon sequences,
Y has the same meaning as previously defined for the general formula (I).

 The interest of the pyroglutamic residue in the dermatological and cosmetic field is no longer to be demonstrated. For example, it is known that the sodium salt of (I) pyroglutamic acid prevents the dryness of the skin by imparting softness, elasticity and flexibility.

 The present invention also provides a depigmenting agent, characterized in that it consists of a natural amino acid ester of hydroquinone of general formula (1), the groups X and Y having the previously defined specifications, and a method of treatment for modifying skin pigmentation, comprising the topical administration of an appropriate amount of depigmenting agent in accordance with the invention.

The products of the present invention have their optimal applications as depigmenting agents and skin beautifying agents, particularly effective in the treatment of melanic hyperpigmentations.
Undesirable and especially the pregnancy mask (chloasma), age spots or senile lentigo, post-traumatic or post-lesion hyperpigmentations, phototoxicity reactions Induced especially by perfumes.

 The pharmaceutical or cosmetic compositions containing them do not have the defects inherent in conventional preparations of this type, which do not cause significant irritation of the skin and do not sensitize it, and are not subject to any particular restrictions concerning the rating or the proportions of the ingredients generally used.

 The skin treatment compositions according to the present invention may be in any conventional form suitable for application on the skin, such as, for example, creams, liquid creams, ointments, milks, lotions, jellies, powders, powders, aerosols. , dyes, powders. The corresponding preparations have as active ingredient only one or more of the compounds of general formula O, as such, or a pharmaceutically acceptable salt form. These active ingredients are usually used in amounts of from 0.01% to about 20% by weight, preferably from about 0.1% to about 4% by weight.

 The basic materials used may be indifferently selected from the conventional ingredients generally used in the usual skin treatment compositions. cosmetic or pharmaceutical compositions.

There may be mentioned, for example, the various types of alcohols, animal or vegetable fats, mineral or vegetable oils, antioxidants, surfactants. waxes, humectants. filled, film-forming agents, preservatives, pigments and coloring agents, plasticizers, radiation
UV, perfumes.

The compounds corresponding to b general formula (I) can be prepared according to known techniques, including, for example, the activation of the corboxpic acid function defined by X and / or Y. The activating reagents of the carboxylic acid function are chosen from 1,1'-carbonyldiimidazole. 1,1'-carbonyldl (1,2,4-triazole), N-hydroxyphthalimide, N-hydroxysuccinimide, p-nitro phenol, pentochlorophenol, thionyl chloride. The condensation on the hydroquinone unit can be carried out in one stage, when X and Y are identical, in particular with pentachlorophenol as activation agent, in a solvent
Inert and a deficit in hydroquinone.

 The reaction can be carried out in two stages, with, for example, condensing between an N-substituted amino acid residue, or N-protected by an activated benzyloxycarbonyl radical, and the benzyl monoether of hydroquinone, hydrogenolysis, and reoction with another N amino acid residue. -substituted activated. or a carboxylic acid having 2 to 21 carbon atoms, previously subjected to activation. In this case the activating reagent is preferably 1,1'carbonyldiimidazle or thionyl chloride.

 The following examples are illustrations of the compounds of general formula (I), the various routes detailed above pharmaceutical or cosmetic compositions containing them and evaluation tests of these compositions.

 It should be understood that these examples of implementation and experimental report are given solely by way of illustration of the subject of the invention, of which they in no way constitute a limitation.

All the products obtained were subjected to analysis by thin layer chromatography (MLC) and have only one spot. The
TLC were produced on Kieselgel F 254 plates and developed in the following systems:
(a): toluene 10; ethyl formate 10; formic acid 1.

 (b): n-butanol 8; acetic acid 1; water 1.

 The results of the centesimal analyzes performed on all the products are in accordance with the theoretical formulas.

EXAMPLE 1: (L) PROLINE, 6-OXO, 4 - (((L) PROLYL, 5-OXO) OXY) PHENYL ESTER:
7.5 g (0.02 moles) of pentachlorophenol (I) pyroglutamate (prepared according to J. Med Chem (1970) 13: 843) and 4 g (0.02 moles) of 4- in the presence of 0.7 g (0.01 mol) of imidazole, which is reacted at room temperature for 12 hours, evaporated, taken up in isopropyl ether to eliminate the by-products of which pentachlorophenol is subjected, the residue is hydrogenolyzed and the crude product (a) obtained is reacted with 3.95 g (0.014 mol) of N-benzyloxycarbonyl (I) pyroglutamic acid chloride (prepared according to Ann (1961), 640, p. 145) in 40 ml of pyridine. The mixture is stirred for 6 hours at 400 ° C., evaporated, taken up in chloroform for careful washings in water, diluted hydrochloric acid, with water and then with dilute sodium bicarbonate, and finally to the water. After drying and evaporation, a crude product (b) is obtained having only one CcM spot (Rfa = 0.21) which is subjected directly to a hydrogenolysis in 50 ml of acetic acid, in the presence of 0, 8 g of Pd! C. After partial evaporation of the acetic acid, a dilution with ether makes it possible to crystallize the title product, of pF = 191 3, having only one spot in TLC, Rflo = 0.49.

EXAMPLE N: (L) PROLINE, 5-OXO, 4- (DECANOYLOXY) PHENYL ESTER:
5.7 g (0.03 mol) of the decanoic acid chloride are poured at room temperature over a solution of 6 g (0.027 mol) of the product (a) prepared according to Example (I) in 60 ml. of pyridine, stirred for 3 hours, evaporated, taken up in ether, filtered. The resulting whitish product is washed with water to give pure title product, pF = 103/4, with only one TLC spot, Rfa = 0.54.

EXAMPLE III (L) VALINE, N-DECANOYL, 4- (PALMITOYLOXY) PHENYL ESTER:
16.3 g (0.06 mol) of N-decanoyl (i) valine (prepared by direct acylation of (I) valine by decanolic acid chloride in medium biphasic water / ethyl ether) are dissolved in 100 ml. ml of dimethylformamide, 9.75 g (0.06 mol) of 1,1'-carbonyldiimidazole dissolved in 50 ml of dimethylformamide, stirred for 1 hour, poured 12 g of 4-benzyloxyphenol dissolved in 70 ml of dimethylformamide stirred at room temperature for 18 hours, evaporated, taken up in chloroform for washing with water and diluted sodium bicarbonate. After drying and evaporation, the crude residue is subjected to hydrogenolysis to yield product (c) having only one TLC spot. Rfa = 0.65. 16.5 g (0.06 mol) of the hexadecanoic acid chloride is poured onto the product (c) in solution in 100 ml of pyridine, stirred for 4 hours, evaporated, taken up in ether. The cream product obtained is washed extensively with water to yield the title product, pF = 82/3, with only one TLC spot, Rfa = 0.88.

EXAMPLE IV (1) PROLINE, 5-OXO, 4 - ((DECANOYLAMINO ACETYL) OXY) PHENYL ESTER:
4.85 g (0.03 mol) of 1,1'-carbonyldiimidazole in solution in 35 ml of dimethylformamide are poured into a solution of 6.9 g (0.03 mol) of
N-decanoyl glycine, prepared as explained in Example III, in 75 ml of dimethylformamide, stirred for 1 hour, poured 5.6 g (0.025 mol) of the product (a), prepared according to Example I, in solution 35 ml of dimethylformamide. stirred for 18 hours at room temperature, evaporated, taken up in chloroform for abundant washing with water and diluted bicarbonate. After drying and evaporation, the crude product is crystallized from isopropyl ether to give the title product of the crystallized state, pF = 172/4 having only one single spot.
TLC, Rfb = 0.68.

EXAMPLE V DEPIGMENTING COMPOSITION n á1
Ingredients

Beeswax ...... 10
Ceresin ... ... .... . ... 8
White Vaseline 3
Lanolin hydrated .. .. 2
Isopropyl myristate .................. 2
Squoione ............ 2
Liquid paraffin .... 40
Polyoxyethylene cetyl ether .... .. 2
Product according to Example 1. ... 6
Glycerol monostearate ........... 2
Propylene glycol .................... 2
Water, perfume, preservative ..... qsp..100 EXAMPLE V: DEPIGMENTING COMPOSITION n2:
ingredients ........

Polyoxyethylene monostearate ... 2
Glycerol monostearate ... 5
Stearic acid ....... 6
Docosanol ............. 1
Liquid paraffin ..... 6
Glycerol trioctanoate ... 10
Produced according to the example li ... 7
1,3-Butylene glycol .... ... .. 4
Glycine ........................... 2
Water, perfume, preservative ... qsp ... 100 EXAMPLE VII: EVAWATION TESTS OF THE COMPOSITIONS ACCORDING TO EXAMPLES V AND VI
a) Depigmenting activity:
Twenty-five women, aged between 20 and 40 years old and with persistent chloasma, and 25 people between the ages of 45 and 75 years, with melanoma hyperplastic hats are selected. In all cases, very clearly three areas, rune to treat with a placebo composition, one to be treated with a composition according to the invention, the third to be treated with a composition engaging hydroquinone. In the morning and evening, the three subjects were applied to the three zones at the rate of 0.2 g each, each zone always receiving the same product for the duration of the treatment, ie 10 weeks.

 The improvements are observed visually each week, the experimenter also appreciating the tolerance to treatment by noting any skin manifestations or other may be the consequence. It was thus noted the particular interest of the compositions according to the invention, perfectly tolerated and dated a very significant depigmenting activity.

 Table I below groups together the results obtained at the end of the experiment. The compositions n03 and n04 are prepared according to example V, without active ingredient for the first, and 2% hydroquinone instead of the product according to example I for the second.

Table I

<SEP> CHLOASMA <SEP> TASKS <SEP> FROM <SEP> SENESCENCE
<tb><SEP> NOTATION <SEP> CP <SEP> CP <SEP> CP <SEP> CP <SEP> CP <SEP> CP
<tb> (*) <SEP> n 1 <SEP> n 3 <SEP> n 4 <SEP> n 2 <SEP> n 3 <SEP> n 4
<tb><SEP> xxx <SEP> 7 <SEP> 0 <SEP> 4 <SEP> 6 <SEP> 0 <SEP> 6
<tb><SEP> xx <SEP> 13 <SEP> 0 <SEP> 10 <SEP> 12 <SEP> 0 <SEP> 11
<tb><SEP> x <SEP> 9 <SEP> 2 <SEP> 10 <SEP> 6 <SEP> 3 <SEP> 8
<tb> (*) xxx: Remarkable improvement
xx: Significant improvement
x: Slight improvement
o No improvement
b) Stability:
The color change of the compositions is monitored by storing the 370 samples for 12 weeks. The modifications are visually evaluated and reported in Table II hereafter, confirming the remarkable stability of the compositions according to the invention.

Table II

<tb><SEP> COMPOSITION <SEP> Time <SEP> of <SEP> storage <SEP> (weeks)
<tb><SEP> 1 <SEP> 3 <SEP> 6 <SEP> 9 <SEP> 12
<tb> O <SEP> O <SEP> O <SEP> O <SEP> O
<tb><SEP> 2 <SEP> o <SEP> o <SEP> o <SEP> o <SEP> o
<tb><SEP> 4 <SEP> O <SEP> x <SEP> xx <SEP> xx <SEP> xxx
<tb> (t) o: No change
x: Light browning
Sensitive browning
Considerable browning

Claims (9)

 1): Derivative of hydroquinone, characterized in that it corresponds to an ester of hydroquinone and that it corresponds to the following formula (I):

 X is the residue of a natural alpha amino acid, or a simple derivative thereof, such as a methyl, ethyl, or a primary amide in the case of dicarboxylic amino acids. substituted or not with nitrogen by an alkylcarbonyl radical having 1 to 20 hydrocarbon sequences.  in which:  Y identical or different from X represents the residue of a natural alpha amino acid, or a simple derivative thereof. as an ethyl methyl monoester or a primary amide in the case of dicarboxylic amino acids. substituted or not with nitrogen by an alkylcarbonyl radical having 1 to 20 hydrocarbon groups, or represents an alkylcarbonyl rodical with 1 to 20 hydrocarbon groups.  2): Derivative according to claim 1, characterized in that the natural alpha amino acid is chosen from alanine, arginine. asparagine glutamine, pyraglutamic acid, cysteine, aspartic acid, glutamic acid, glycine, histidine, isoleucine, 4-hydroxyproline, leucine, lysine, methionine , ornithinine, phenylalanine. proline, serine, threonine, tryptophan, tyrosine.  3): Derivative according to claims 1 and 2, characterized in that X and Y represent the remainder of the pyroglutamic acid (I). substituted or not with nitrogen by an alicylcarbonyl radical having 1 to 20 hydrocarbon chains;  4): depigmenting agent characterized in that it consists of a hydroquinone ester spreading to the formula (I). according to claim 1,  in which::  X represents the residue of a natural alpha amino acid, or a simple derivative thereof, such as a methyl, ethyl monoester. or a primary amide in the case of dicarboxylic amino acids. substituted or not with nitrogen by an alkylcarbonyl radical having from 1 to 20 hydrocarbon sequences,  Y represents the residue of a natural alpha amino acid or of a simple derivative thereof, such as a methyl, ethyl or primary amide monocrystalline in the cos of the dicarboxylic amino acids, substituted or not with nitrogen by an alkpiecorbonyl radical comprising 1 to 20 hydrocarbon chains. or represents an alkylcarbonyl radical with 1 to 20 hydrocorbonated rings.  5): Pharmaceutical composition, characterized in that it comprises at least one depigmenting agent according to claim 4, optionally associated with at least one pharmaceutically acceptable vehicle.  6) Cosmetic composition, characterized in that it comprises at least one depigmenting agent according to claim 4, optionally combined with at least one pharmaceutically acceptable vehicle.  7): A composition according to claim 5 or claim 6, characterized in that the content of the compound corresponding to the general formula (I) is in the range of 0.01 to 20% by weight.  8): Composition according to Claim 7, characterized in that the content of compound corresponding to the general formula (I) is in the range of 0.1 to 10 Qb by weight.  9) A cosmetic treatment method for modifying skin pigmentation, comprising the topical administration of an appropriate amount of depigmenting agent according to claim 4.