WO1996032372A1

WO1996032372A1 - Serine derivatives and use thereof in cosmetics

Info

Publication number: WO1996032372A1
Application number: PCT/FR1996/000558
Authority: WO
Inventors: Akhtar Haider
Original assignee: Sochinaz S.A.
Priority date: 1995-04-12
Filing date: 1996-04-12
Publication date: 1996-10-17
Also published as: FR2732965B1; FR2732965A1; AU5652196A

Abstract

The invention relates to the field of organic chemistry and particularly to that of α-hydroxylated amino acids. Specifically, amides of serine with an α-hydroxylated organic acid of general formula (I), and hydroxyl or carboxylic function esters of such derivatives, are disclosed. In general formula (I), R1 is hydrogen or a C1-6 lower alkyl radical; R2 is hydrogen or the acyl residue of a C1-10 carboxylic organic acid; and R is hydrogen or a straight or branched saturated or unsaturated C1-10 alkyl radical. A method for preparing said amides, wherein a serine alkyl ester is reacted with a functional α-acetoxylated acid derivative by saponification or acid hydrolysis, is also disclosed. Furthermore, the use of said amides in cosmetics and dermatology is disclosed.

Description

SERINE DERIVATIVES AND THEIR USE IN COSMETICS

The present invention relates to the field of organic chemistry and more particularly to that of amides of α-hydroxylated acids.

More specifically, it relates to an amide chosen from the group corresponding to general formula I

COOR

in which R _x represents hydrogen or a lower alkyl radical having from 1 to 6 carbon atoms.

R represents hydrogen or the acyl residue of an organic carboxylic acid having from 1 to 10 carbon atoms and R represents hydrogen or a saturated or unsaturated alkyl radical having from 1 to 10 carbon atoms in a straight chain or branched.

Among these, mention will be made more particularly of the compounds of general formula I ′ (I ')

in which R and R2 are defined as above RI represents hydrogen or a methyl radical, in particular N-glycolyl-serine of formula (la), N-lactyl-serine of formula (Ib), the methyl ester of N - (O-acetyl-glycolyl) -serine of formula (Ie), the methyl ester of N- (0-acetyl-lactyl) -serine of formula (Id), the methyl ester of N-glycolyl-serine of formula (le) and the N-lactyl-serine methyl ester of formula (If).

The subject of the invention is also a process for preparing the compounds of general formula I, in which, firstly, the alcohol function of an α-hydroxylated acid of general formula II is esterified

GOLD,

in which R _x represents hydrogen or a lower alkyl radical having from 1 to 6 carbon atoms

R ₂ represents hydrogen

R ₃ represents hydrogen or an alkyl radical having from 1 to

6 carbon atoms using a functional derivative of carboxylic acid having

1 to 6 carbon atoms to form an ester of general formula II '

OR ₃

wherein R ₂ represents the acyl residue of an organic carboxylic acid.

Ri and R ₃ are defined as above

Then, this ester is condensed with a serine alkyl ester of general formula III:

wherein R represents a lower alkyl C _x to C ₄ .

The amide ester thus produced, of general formula I, is saponified, where appropriate, into free amide.

The attached synthetic schemes I and II describe, by way of example, the synthesis of N-glycolyl-serine [la] and N-lactyl-serine [Ib].

In the case where: R1 = H or R1 = CH3, one successively obtains the compounds of formula le, Id, then le, If, and finally la, Ib. Among the α-hydroxylated acids of general formula II, there may be mentioned more particularly glycolic acid, lactic acid, 2 - hydroxybutyric acid, 2 hydroxyvaleric acid, 2 - hydroxycaproic acid.

The acylation of the α-hydroxyl acid is carried out using a functional derivative of carboxylic acid having from 1 to 6 carbon atoms such as, for example, a halide, an anhydride or a mixed anhydride of a such acid. Among the acids concerned, mention will be made in particular of formic acid, acetic acid, isovaleric acid, pivalic acid.

Mention may more particularly be made, among the serine alkyl esters of general formula III, of methyl, ethyl, propyl, butyl, iobutyl, neopentyl ester or also unsaturated esters such as, for example, an ester of allyl alcohol, senecioic , tiglic or crotonic.

The synthesis is carried out more precisely in two stages using the alkyl ester of the serine of general formula III which is condensed with an acylated derivative of the α-hydroxylated acid of general formula II '(see synthesis schemes I and II attached).

Serine exists in racemic form or in split form. There are therefore two optically active forms, D-serine and L-serine. The same applies to the acylated derivatives of α-hydroxylated acids which exist in racemic form or in optically active form (such as for example 0-acetyl-D-lactic acid and O-acetyl-L-lactic acid).

The present application includes derivatives derived from form D, from form L and from any mixture of form D and from form L, of the two starting materials mentioned, namely serine and acyl derivatives of acid α- hydroxylated. The present application also describes, as new compounds, the O-acylated esters of hydroxyacyl serine, the alkyl esters of O-acyl hydroxyacyl serine as well as the alkyl esters of hydroxyacyl serine such as for example the O-acylated esters of lactyl- and glycolyl-serine, the alkyl esters of O-acetyl lactyl- and of O-acetylglycolyl serine as well as the alkyl esters of lactyl- and glycolyl serine.

The method according to the invention consists of a second step in condensing the amino function of the serine with the acid function of a cc-acyloxy alkanoic acid. This condensation can be carried out in particular in the following manner: one starts from a serine alkyl ester of general formula III or from its hydrochloride and from an organic base such as N-methylmorpholine in ethyl acetate. The reagents are introduced slowly into a mixture of α-acetoxy acid of general formula II '(for example, O-acetyl lactic acid or O-acetyl glycolic acid), in the presence of a carboxyl activating agent such as ethyl chloroformate and N-methylmorpholine cooled from -10 ° to 0 ° C. After stirring at room temperature for 16 to 20 hours, the mixture is hydrolyzed with water and extracted with ethyl acetate. The residue from the evaporation of the organic phase is purified. The products of general formula I, and more particularly of formula Ie and Id are recrystallized from ethyl acetate or ethyl ether or from a mixture of the two solvents.

The structures of the isolated products, in particular the alkyl esters of N- (O-acetyl-glycolyl) -serine [le] and the alkyl esters of N- (O-acetyl-lactyl) -serine [Id], are confirmed by their properties physico-chemical.

Examination of the IR (CH2C12) spectra of the compounds le and Id shows

-1 two intense bands at 1690 and 1740 cm- characteristic carbonyls of ^one amide and esters, respectively.

The molecular weights of the two products above are in perfect agreement with the structures proposed. At the final stage of the process, the compounds of formula le and Id, obtained above, for example, are hydrolyzed in a highly basic medium:

• the esters of formula le and Id purified, are hydrolyzed to the α-hydroxy amide of formula la and Ib, by saponification with a basic aqueous solution, such as soda or potash, then acidification and elimination of the salts.

• the products of formula la and Ib are isolated. These products are distinguished in IR (film) by 3 bands at 3380-3400, 1730 and

1660 cm, corresponding to the vibration of the N-H, 0-H connections

1 -1

(3380-3400 cm); carbonyl of the ester (1730 cm) and

-1 carbonyl of the amide (1660 cm).

The spectra [1H.RMN of the products la and Ib differ from those of the products le and Id by the absence of proton from the acetyl and ester methyl groups.

The products la and Ib can also be obtained from the corresponding esters le and If by basic hydrolysis.

The hydrolysis of the acyl group can also be carried out in an acid medium in the presence of an alkanol. Thus, the methyl ester of N-glycolyl-serine [le] and the methyl ester of N-lactyl-serine [If] are obtained by selective deprotection of the hydroxy group in the α position of corresponding amides le and Id , in a suitable solvent, for example in methanol in the presence of a catalytic amount of mineral acid

To our knowledge, the products of general formula I, namely the compounds of formula I ', la, Ib, le, Id, le and If, are not described in the literature.

The following nonlimiting examples illustrate the new compounds and the implementation of the methods according to the invention: Example 1: N- (LO-acetyl-lactyl) -L-serine methyl ester [Id] In a solution cooled in an ice bath containing 50 g of O-acetyl lactic acid, 42 ml of N-methylmorpholine in 250 ml of ethyl acetate, add a solution of 36 ml of ethyl chloroformate in 50 ml of ethyl acetate and leave to stir for 30 minutes. Then add a mixture of 56 g of hydrochloride of the serine methyl ester, 42 ml of N-methylmorpholine and 500 ml of ethyl acetate. After 16-20 hours of stirring at room temperature, hydrolyze with 500 ml of water, extract with ethyl acetate, evaporate the solvent in vacuo. Take up the residue in ethyl acetate, allow to crystallize. Weight 38 g - PF: 146-151 ° C

Example 2

N- (O-acety-glycolyl) -serine methyl ester [le]

The process is identical to that described above, except for the replacement of O-acetyl lactic acid by O-acetyl glycolic acid. O-acetyl glycolic acid 20 g; hydrochloride of serine methyl ester 25 g.

The isolated product is crystallized from ethyl acetate. Weight 18 g - P.F: 62-64 ° C

Example 3

N-glycolyl-serine from product le

To 15 g of N- (O-acetyl-glycolyl) -serine methyl ester in 150 ml of water, add a solution of 50.6 ml of sodium hydroxide in 112 ml of water. After 1 h 30, adjust the pH of the solution to 2. Concentrate under vacuum and add 150 ml of isopropanol. Filter the salts, and concentrate the filtrate under vacuum. Weight 6.3 g of product la

Example 4

N-lactyl-serine from the product Id

To a solution of methyl ester of N- (O-acetyl-lactyl) -serine (5g) in water (50 ml), add a solution of sodium hydroxide (16 ml) in water (35 ml). After 1 h of stirring at room temperature, acidify the solution to pH 2. Concentrate under vacuum and add 50 ml of isopropanol. Filter the salts, and concentrate the filtrate under vacuum. Weight 3 g of product Ib (oil).

Example 5

N-glycolyl-serine methyl ester [le]

To a solution of 9 g of N- (O-acetylglycolyl) -serine methyl ester in 180 ml of methanol, add 0.4 ml of hydrochloric acid. Heat to 60 ° C and keep there with vigorous stirring for 9 h. Concentrate under vacuum and purify the product obtained on a silica gel column. Weight 7 g of

Example 6

N-actyl-serine methyl ester [If]

Process identical to Example 5, with the exception of the raw material it is the methyl ester of N- (O-acetyl-lactyl) -serine (10 g) in 200 ml of methanol and 0.8 ml hydrochloric acid.

Product obtained: 6.4 g of If

Example 7

N-glycolyl-serine from

The process is identical to that of Example 3, except that product III is replaced by the methyl ester of N-glycolylserine (5.4 g). The hydrolysis is carried out with 8.5 ml of sodium hydroxide in 80 ml of water. Weight obtained: 4.5 g of the

Example 8

N-lactyl-serine from If

From N-lactyl-serine methyl ester (5 g) and sodium hydroxide (7 ml) in water (50 ml), according to the process described in Example 4. Weight obtained: 4.3 g of Ib

The compounds described in the present patent application find use in cosmetology, in particular as a principle active in the production of creams, ointments, anti-wrinkle or softening external formulations or as an active principle in moisturizing creams.

These compounds play a role in dermal preparations with exfoliating, and / or hydrating and / or kerato-regulating action.

Claims

R E V E N D I C A T I O N S

1. The amides of α-hydroxylated acids chosen from the group corresponding to general formula I

COOR

R ₂ represents hydrogen or the acyl residue of an organic carboxylic acid having from 1 to 10 carbon atoms and R represents hydrogen or a saturated or unsaturated alkyl radical having from 1 to 10 carbon atoms in chain straight or branched.

2. The α-hydroxylated acid amides according to claim 1 corresponding to the general formula I '

in which R ^ represents hydrogen or a methyl radical

R ₂ and R are defined as above

3.A compound according to claim 1, namely N-lactylserine of formula (Ib).

4.A compound according to claim 1, namely the N-glycolyl-serine of formula (la)

5.A compound according to claim 1, namely the methyl ester of N- (O-acetyl-lactyl) -serine of formula (Id)

6.A compound according to claim 1, namely the methyl ester of N- (O-acetyl-glycolyl) -serine of formula (Ie)

7.A compound according to claim 1, namely the methyl ester of N-lactyl-serine.

8.A compound according to claim 1, namely the methyl ester of N-glycolyl-serine.

9.The compounds according to one of claims 1 to 8 in which the serine is in one of the two optically active forms.

10.The compounds according to one of claims 1, 2, 3, 5, 7, 9, in which the O-acetyl-lactic acid is in an optically-active form.

11. A process for obtaining the compounds according to one of claims 1 to 10, which consists in reacting the amine function of an alkyl ester of serine of general formula III:

wherein R represents a lower alkyl C_ -C ₄ by condensation with an O-acyl acid of general formula II '

in which R _x represents a hydrogen or a lower alkyl radical having from 1 to 6 carbon atoms

R ₂ is the acyl residue of an organic carboxylic acid

R ₃ is a hydrogen or an alkyl radical having from 1 to 6 carbon atoms in the presence of an activating mixture, then hydrolyzes the amide derivative of α-hydroxy acid with an aqueous basic solution then acidification and elimination of salts.

12. A process for obtaining the compounds of general formula I according to claim 11, which consists in first esterifying the alcohol function of an α-hydroxylated acid of general formula II

in which R- represents hydrogen or a lower alkyl radical having from 1 to 6 carbon atoms

R ₂ represents hydrogen

R ₃ represents hydrogen or an alkyl radical having from 1 to

6 carbon atoms using a functional derivative of carboxylic acid having from 1 to 6 carbon atoms to form an ester of general formula (II ') which is then condensed with an alkyl ester of serine .

13. A process for obtaining the compounds of general formula I according to claim 12 in which the functional derivative of carboxylic acid is a halide, an anhydride or a mixed anhydride.

14.A process for obtaining the compounds according to one of claims 1 to 10 which consists in subjecting a 0-acyl-hydroxyacyl-serine to a deprotection selection of the hydroxy group at α, in the presence of a catalytic amount of strong acid to form an alkyl ester of N-hydroxyacyl-serine which is saponified to N-hydroxyacyl-serine by basic hydrolysis.

15. A process for obtaining the compounds of general formula I according to claim 14 in which the O-acyl hydroxyacyl-serine is an O-acetyl-glycolyl or an O-acetyl-lactyl-serine.

16. A process for obtaining the compounds of general formula I according to claim 14, in which the alkyl ester of N-hydroxyacyl-serine is a methyl ester of N-glycolyl-serine or of N-lactyl-serine.

17. Use of the compounds of general formula I according to claim 1, for the production of cosmetic compositions ensuring the improvement of the appearance of the skin.

18. Cosmetic compositions according to claim 17, in particular in the form of creams containing, as active principle, at least one compound according to one of claims 1 to 10.