NEW COMPOUNDS IN THE FAMILY OF N-ACYLAMINO-AMIDES, COMPOSITIONS COMPRISING THEM, AND USES

Abstract

The present application relates to new compounds in the family of N-acylamino-amides having formula (I), compositions, in particular cosmetic compositions comprising them, and their use to treat the signs of aging of skin of the body or face, whether chronobiological or photo-induced, and in particular aging generated by reduced skin elasticity.

##STR00001## in which p=1, 2 or 3 R independently denotes a cyano (—CN), hydroxy (—OH), CO.sub.2R′ group in which R′ denotes a hydrogen atom or linear or branched C.sub.1-C.sub.6 alkyl group, R.sub.1 denotes a hydrogen atom or a linear or branched C.sub.1-C.sub.6 alkyl group, and also the salts and/or isomers and/or solvates thereof.

Claims

1. A compound having formula (I): ##STR00021## in which p=1, 2 or 3 R independently denotes a cyano (—CN), hydroxy (—OH), CO.sub.2R′ group in which R′ denotes a hydrogen atom or a linear or branched C.sub.1-C.sub.6 alkyl group R.sub.1 denotes a hydrogen atom or a linear or branched C.sub.1-C.sub.6 alkyl group, salts thereof, isomers thereof, solvates thereof, and mixtures thereof.

2. The compound as claimed in claim 1, in which: p=1 or 2 and R independently denotes a cyano (—CN), hydroxy (—OH), CO.sub.2R′ group in which R′ denotes a hydrogen atom or a linear or branched C.sub.1-C.sub.4 alkyl group.

3. The compound as claimed in claim 1, in which: R.sub.1 denotes a hydrogen atom or a linear or branched C.sub.1-C.sub.6 alkyl group.

4. The compound as claimed in claim 1, in which: p=1 or 2, and R denotes independently a cyano (—CN), hydroxy (—OH), CO.sub.2R′ group in which R′ denotes a hydrogen atom or a linear or branched C.sub.1-C.sub.4 alkyl group and R.sub.1 denotes a hydrogen atom.

5. The compound as claimed in claim 1, in which the compound having formula (I) denotes a compound chosen from the following compounds (a) to (h), salts thereof, optical isomers thereof, and solvates thereof, and mixtures thereof, ##STR00022## ##STR00023##

6. The compound as claimed in claim 1, in which the compound having formula (I) denotes the following compound (a), salts thereof, optical isomers thereof, and solvates thereof, and mixtures thereof: ##STR00024##

7. A composition comprising at least one compound having formula (I) as defined in claim 1.

8. A cosmetic composition comprising at least one compound having formula (I) as defined in claim 1.

9. The composition as claimed in claim 7, in which the compound having formula (I) is present in a quantity between 0.00001 and 20% by weight relative to the total weight of the composition.

10. The composition as claimed in claim 7, presented in the form of a cosmetic composition intended for the care and/or treatment of areas having undergone skin stress or microstress.

11. The composition as claimed in claim 7, presented in the form of: a care, treatment, cleansing, or protecting product for skin of the body or face including the scalp; a mattifying composition for the face; a composition for irritated skin; a composition for sun protection, artificial tanning (self-tanning agent) or an after-sun care treatment; a haircare composition; a care composition for the scalp; a product for making up the skin of the face; an oral hygiene product.

12. The composition as claimed in claim 7, presented in the form of a care composition for the skin of the face, of the anti-wrinkle or anti-aging type, or a sun protection or after-sun composition.

13. A method of cosmetic treatment of signs of aging of skin of the body or face which comprises applying to said skin at least one compound having formula (I) as defined in claim 1 or a composition comprising said compound.

14. A method of cosmetic treatment of skin reduce wrinkles and/or fine lines, wizened skin, lack of skin elasticity and/or tone, dermal thinning, degradation of collagen fibers, flaccid skin, thinned skin; internal degradation of the skin caused by exposure to ultraviolet radiation which comprises applying to said skin at least one compound having formula (I) according to claim 1 or a composition comprising said compound.

15. A method of cosmetic treatment of skin to inhibit the activity of elastases and/or to limit and/or combat degradation of elastic fibers which comprises applying to said skin at least one compound having formula (I) according to claim 1 or a composition comprising said compound.

16. A method of cosmetic treatment for the skin of the body or face, including the scalp, in which a cosmetic composition as defined in claim 7 is applied to the skin.

17. The compound as claimed in claim 2, in which: R.sub.1 denotes a hydrogen atom or a linear or branched C.sub.1-C.sub.6 alkyl group.

18. A composition comprising at least one compound having formula (I) as defined in claim 2.

19. A composition comprising at least one compound having formula (I) as defined in claim 3.

20. A composition comprising at least one compound having formula (I) as defined in claim 4.

Description

EXAMPLE 1

Synthesis of N-acetyl-N-(4-carboxy-3-hydroxyphenyl)valylglycine 1 and its Ethyl Diester A

[0091] ##STR00005##

[0092] To a stirred solution of ethyl 4-amino-2-hydroxybenzoate (3.62 g, 20 mmol) and glacial acetic acid (1.2 g, 20 mmol) in 60 ml of methanol previously cooled to 10° C. under nitrogen, isobutyraldehyde is added (2.8 g, 40 mmol). After 5 min stirring at 10° C., ethyl isocyanoacetate (2.26 g, 20 mmol) is added dropwise then at the end of the addition, is held with stirring at 10° C. for 2 h then at room temperature for 12 hours. The reaction medium is concentrated under vacuum then purified by chromatography on a silica column twice to produce 1.8 g (Yield 22%) of intermediate A in the form of yellow oil. Intermediate A is purified again by preparative HPLC to produce 800 mg of pure diester A.

[0093] To a solution of 0.38 g of diester A (1 mmol) in 10 mL of methanol, 0.96 g (4 mmol) of an aqueous solution of 10% LiOH is added. The medium is held with stirring at room temperature for 15 h then the solvent is removed under vacuum. The resulting aqueous solution is acidified to pH=2 by an aqueous 10% HCl solution, then extracted 3 times by 20 mL of dichloromethane. After drying the combined organic phases on magnesium sulfate and concentrating under vacuum, the crude product is purified by chromatography (2:1 dichloromethane/methanol eluent) to produce 0.158 g of compound 1 in the form of a yellow solid (Yield=45%).

[0094] The NMR spectrum matches the expected structure.

EXAMPLE 2

Synthesis of N-acetyl-N-(3,4-dicarboxyphenyl)valylglycine 2 and its Triethyl Ester B

[0095] ##STR00006##

[0096] To a stirred solution of dimethyl 4-aminophthalate (1.05 g, 5 mmol) and glacial acetic acid (0.3 g, 5 mmol) in 30 mL of methanol previously cooled to 10° C. under nitrogen, isobutyraldehyde is added (0.72 g, 10 mmol). After 30 min stirring at 10° C., ethyl isocyanoacetate (0.57 g, 5 mmol) is added dropwise then at the end of the addition, is held with stirring at 10° C. for 2 h then at room temperature for 12 hours. The reaction medium is concentrated under vacuum then purified by chromatography on a silica column twice to produce 0.6 g (Yield 27%) of triester B in the form of a pale yellow solid.

[0097] To a solution of 2.2 g of diester B (5.05 mmol) in 20 mL of THF, 8.5 g (20.2 mmol) of an aqueous solution of 10% LiOH is added. The medium is held with stirring at room temperature for 15 h then the solvent is removed under vacuum. The resulting aqueous solution is acidified to pH=2 by an aqueous 10% HCl solution, then extracted 3 times by 30 mL of ethyl acetate. After drying the combined organic phases on magnesium sulfate and concentrating under vacuum, the crude product is purified by chromatography to produce 0.28 g of compound 2 in the form of a yellow solid (Yield=14.2%).

[0098] The NMR spectrum matches the expected structure.

EXAMPLE 3

Synthesis of N-acetyl-N-(3,5-dicarboxyphenyl)valylglycine 3 and its Triethyl Ester C

[0099] ##STR00007##

[0100] To a stirred solution of dimethyl 5-aminophthalate (2.09 g, 10 mmol) and glacial acetic acid (0.6 g, 10 mmol) in 30 mL of methanol under nitrogen, isobutyraldehyde is added (1.44 g, 20 mmol). The medium is brought to reflux for 30 min, then ethyl isocyanoacetate is added dropwise (1.13 g, 10 mmol). After addition, the medium is held at reflux for 4 h then cooled and concentrated under vacuum before being purified by column chromatography on silica to produce 1.89 g (Yield 43%) of triester C in the form of a white solid.

[0101] To a solution of 1.31 g of triester C (3 mmol) in 30 mL of methanol, 0.504 g (12 mmol) of LiOH is added. The medium is held with stirring at room temperature for 15 h then the solvent is removed under vacuum. The residue was poured into 30 mL of water, acidified to pH=2 by an aqueous 10% HCl solution, then left at 5° C. for 4 days. The crystals formed were filtered and dried to produce 0.8 g of compound 3 in the form of white crystals (yield=70%).

[0102] The NMR spectrum matches the expected structure.

EXAMPLE 4

Synthesis of N-acetyl-N-(3-hydroxyphenyl)valylglycine 4 and its Ethyl Ester D

[0103] ##STR00008##

[0104] In a reactor, 1.05 eq of 3-amino-benzonitrile (10 g, 84.65 mmoles) is solubilized in 40 mL of methanol. 1.05 eq of acetic acid (5.079 g, 84.65 mmoles) is added, then the mixture is brought to reflux. As soon as reflux is reached, 2 eq of isobutyraldehyde (12.2 g, 169.3 mmoles) is added and left to react for 30 min at reflux. Next 1 eq ethyl isocyanoacetate (9.25 g, 80.32 mmoles) is added and the mixture is left to react again for 3 h at reflux.

[0105] The reaction medium is then concentrated under vacuum and purified on a silica column (dichloromethane/methanol eluent), to produce 15 g of ester D (yield=50%).

[0106] The .sup.1H and .sup.13C NMR spectra and the mass spectrum are in accordance with the expected structure of the product D.

[0107] Ester D (5 g, 14.48 mmoles) is solubilized in 50 mL of methanol then 2 eq (1.16 g, 29 mmoles) of 1 N aqueous sodium hydroxide solution is added. The mixture is left with stirring for 1 h at room temperature then acidified to pH=2 by an aqueous 1 N HCl solution and the resulting product is purified on a silica column (dichloromethane/methanol eluent). 3.2 g (yield=70%) of compound 4 is produced.

[0108] The .sup.1H and .sup.13C NMR spectra and the mass spectrum are in accordance with the expected product 4.

EXAMPLE 5

Synthesis of N-acetyl-N-[3-(ethoxycarbonyl)-4-hydroxyphenyl]valylglycine 5 and its Ethyl Diester E

[0109] ##STR00009##

[0110] To a solution of 5-ethylaminosalicylate (1.8 g, 10 mmoles) and glacial acetic acid (0.6 g, 10 mmoles) in 30 mL of methanol, isobutyraldehyde is added (1.44 g, 20 mmoles) at 10° C. and under nitrogen.

[0111] After 10 min stirring, ethyl isocyanoacetate (1.13 g, 10 mmoles) is added dropwise. The reaction medium is then stirred for 2 h at 10° C., then 12 h at room temperature before being concentrated under vacuum and purified on a silica column (dichloromethane/methanol eluent) to produce diester E (1.4 g, yield=35%).

[0112] The .sup.1H and .sup.13C NMR spectra and the mass spectrum are in accordance with the expected structure of the product E.

[0113] Diester E (0.72 g, 1.8 mmoles) is saponified in 10 mL of methanol in the presence of LiOH (0.3 g, 7.2 mmoles) for 12 h. The reaction medium is concentrated under vacuum, acidified to pH=2 by a 10% aqueous HCl solution, extracted by 3×30 mL dichloromethane and purified on a silica column (dichloromethane/methanol eluent). 300 mg (50% yield) of compound 5 is thus obtained in the form of a pale yellow solid.

[0114] The .sup.1H and .sup.13C NMR and the mass spectrum are in accordance with the expected structure of the product 5.

EXAMPLE 6

Synthesis of N-acetyl-N-[3,5-bis(methoxycarboxy)phenyl]valylglycine 6 and its Triester F

[0115] To a solution of dimethyl 5-aminoisophthalate (10 g, 47.8 mmoles) and glacial acetic acid (2.87 g, 47.8 mmoles) in 100 mL of methanol, isobutyraldehyde is added (6.89 g, 95.6 mmoles) at 10° C. and under nitrogen.

[0116] After 10 min stirring, tert-butyl isocyanoacetate (6.84 g, 47.8 mmoles) is added dropwise. The reaction medium is then held with stirring for 2 h at 10° C., then 96 h at room temperature before being concentrated under vacuum and purified on a silica column (dichloromethane/methanol eluent) to produce 8.65 g of ester F.

[0117] The .sup.1H and .sup.13C NMR spectra and the mass spectrum are in accordance with the expected structure of the product F.

##STR00010##

[0118] Compound F (2.32 g, 5 mmoles) is saponified in 20 mL of toluene with TsOH.H.sub.2O (7.6 g, 18.9 mmole). After 16 h of reaction at room temperature, the medium is concentrated under vacuum then purified on a silica column (dichloromethane/methanol eluent) to produce 306 mg (yield=15%) of compound 6.

[0119] The .sup.1H and .sup.13C NMR and the mass spectrum are in accordance with the expected structure of the product 6.

EXAMPLE 7

Synthesis of N-acetyl-N-(3-hydroxyphenyl)valylglycine 7 and its Ethyl Ester G

[0120] To a solution of 3-aminophenol (1.09 g, 10.5 mmoles) and glacial acetic acid (0.63 g, 10.5 mmoles) in 30 mL of methanol, isobutyraldehyde is added (1.44 g, 20 mmoles) at 10° C. and under nitrogen.

[0121] After 10 min stirring, ethyl isocyanoacetate (1.13 g, 10 mmoles) is added dropwise then the reaction medium is held with stirring for 2 h at 10° C., then 12 h at room temperature.

[0122] The reaction medium is then concentrated under vacuum then purified on a silica column (dichloromethane/methanol eluent), to produce 2.3 g of intermediate ester G (yield=65%).

[0123] The .sup.1H and .sup.13C NMR spectra and the mass spectrum are in accordance with the expected structure of the product G.

##STR00011##

[0124] Compound G (0.6 g, 5.4mmoles) is then saponified in 10 mL of methanol in the presence of LiOH (0.22 g, 5.4 mmoles) in solution in 2 mL of water for 2 h. After acidification at pH=3 by a 5% HCl solution and extractions with 2×20 mL of dichloromethane, the product is purified by chromatography on a silica column (dichloromethane/methanol eluent), to produce 300 mg (yield=50%) of derivative 7.

[0125] The .sup.1H and .sup.13C NMR and the mass spectrum are in accordance with the expected structure of the product 7.

EXAMPLE 8

Synthesis of N-acetyl-N-(4-hydroxyphenyl)valylglycine and its Diethyl Ester H

[0126] ##STR00012##

[0127] To a solution of 4-ethylaminobenzoate (1.65 g, 10 mmoles) and glacial acetic acid (0.6 g, 10 mmoles) in 30 mL of methanol, isobutyraldehyde is added (1.44 g, 20 mmoles) at 10° C. and under nitrogen. After 10 min stirring, ethyl isocyanoacetate (1.13 g, 10 mmoles) is added dropwise then the stirring is held for 2 h at 10° C., then 12 h at room temperature.

[0128] The reaction medium is then concentrated under vacuum and purified on a silica column (dichloromethane/methanol eluent), to produce 1.4 g of intermediate ester H (yield=36%).

[0129] The .sup.1H and .sup.13C NMR spectra and the mass spectrum are in accordance with the expected structure of the product H.

[0130] Ester H (1 g, 2.5 mmoles) is saponified in 20 mL of ethanol in the presence of 40% aqueous KOH solution for 24 h. After purification on silica column (dichloromethane/methanol eluent), 380 mg (yield=45%) of compound 8 is isolated.

[0131] The .sup.1H and .sup.13C NMR spectra and the mass spectrum are in accordance with the expected structure of the product 8.

EXAMPLE 9

[0132] The molecules have been evaluated in vitro on a Human Elastase Assay test, available in the CEREP catalog.

[0133] The results are expressed as a percentage of activity versus a specific control (activity measured with compounds of the invention/control activity without the compound of the invention)×100.

[0134] The control is the enzymatic activity of human leukocyte elastase (HLE) on a reference substrate (MeOSAAPV-pNa at 0.1 mM).

[0135] The detection method used is photometry.

[0136] This method is described in the literature: Adeyemi et al 1990, J. Pharm. Pharmacol. 42, 487-490.

[0137] The results are as follows:

TABLE-US-00001 Elastase inhibition activity Test (conc compound Molecule 1 mM) Compound 4 (Example 4) [00013] 35% Compound 5 (Example 5) [00014] 62% Compound 6 (Example 6) [00015] 65% Compound 1 (Example 1) [00016] 98% Compound 7 (Example 7) [00017] 62% Compound 2 (Example 2) [00018] 98%

EXAMPLE 10

[0138] The activity of compound 4 of the invention was compared to that of the compound of the prior art, which differs by the presence of a CF3 group in the place of a CN group.

[0139] The concentration that produces 50% inhibition of the human elastase activity (IC50) was measured.

[0140] Compound of the invention:

##STR00019##

[0141] Compound outside the invention:

##STR00020##

[0142] Results were as follows:

TABLE-US-00002 Test compound IC50 Compound outside the 6.38 mM invention (Z) Compound 4 of the invention  5.6 mM (Example 4)

[0143] Compound 4 is clearly more effective than the compound of the prior art for inhibiting elastase activity.

EXAMPLE 11

Composition for Topical Application

[0144] The following emulsion is prepared conventionally (% by weight):

TABLE-US-00003 compound of example 4 1% propylene glycol isostearate 13%  polyethylene glycol (8 OE) 5% propylene glycol 3% pentylene glycol 3% glyceryl stearate and polyethylene glycol stearate (100 OE) 5% oxyethylenated sorbitan monostearate (20 OE) 0.5%   oxyethylenated (20 OE) and oxypropylenated (5 OP) cetyl 1% alcohol gellants 0.5%   C.sub.12-15 alkyl benzoates 4% ethanol 3% sodium hydroxide 0.12%   preservatives qs water q.s. 100%

[0145] Applied to skin, this composition improves its elasticity.

EXAMPLE 12

Facial Care Cream

[0146] The following oil-in-water emulsion is prepared conventionally (% by weight):

TABLE-US-00004 Compound of example 2   1% Glyceryl stearate   2% Polysorbate 60 (Tween 60 ® sold   1% by the company ICI) Stearic acid 1.4% Triethanolamine 0.7% Carbomer 0.4% Liquid fraction of shea butter  12% Perhydrosqualene  12% Antioxidant qs Fragrance qs Preservative qs Water q.s. 100%

EXAMPLE 13

Facial Lotion

[0147] The following lotion is prepared conventionally (% by weight):

TABLE-US-00005 Liquid petroleum jelly 7% Compound of example 4 1% Glyceryl stearate, polyethylene 3% glycol stearate (100 EO) Carboxyvinyl polymer 0.4%   Stearyl alcohol 0.7%   Soya extract 3% NaOH 0.4%   Preservative qs Water q.s. 100%

EXAMPLE 14

Hair Lotion

[0148] The following lotion is prepared conventionally (% by weight):

TABLE-US-00006 compound of example 4  1% propylene glycol 23% ethanol 55% water q.s. 100%

[0149] This lotion can be applied to the scalp, to prevent the effects of UV, before and/or after sun exposure.

EXAMPLE 15

Anti-Hair Loss Lotion

[0150] The following lotion is prepared conventionally (% by weight):

TABLE-US-00007 compound of example 2  1% propylene glycol 23% ethanol 55% Aminexil 1.5%  water q.s. 100%

[0151] This anti-hair loss lotion can be applied to the scalp.