FR2480600A1 - Use of aroyl-alkanoic acid in cosmetics - for reducing secretion of sebaceous glands - Google Patents

Abstract

The use in cosmetics of cpds. of formula (I) and their salts with acceptable inorganic or organic bases is new. (A is 2-4C opt. branched, satd. or unsatd. alkylene; R1 and R2 are each H, halo, alkoxy, alkyl, cycloalkyl, phenoxy or R3-substd. phenyl (R3 is H, alkyl or alkoxy), or R1 and R2 together complete naphthyl or 1,2,3,4-tetrahydro naphthyl). Pref. A is -CH2.C(:CH )-, -CH:C(CH3)-, -CH2.CH(CH3)- or CH2CH2 and pref. salts are of Na, K, Co, Zn, Al, Mn, triethanolamine, dimethylaminoethanol, pyridoxine, guanidine or imidazole. Specifically claimed are 17 cpds. e.g. 4-(p-Z-phenyl)-4-oxo 2- methylenebutyric acid (Z is phenyl, cyclohexyl, chloro or phenoxy) or the Na, Ca or Zn salts of 4-(4-phenyl phenyl)-4-oxo- 2-methylbutyrate. (I) reduce the formation of sebum by sebaceous glands so are useful in skin care formulations, esp. for control of acne and seborrhoea.

Description

The present invention, carried out at the Pierre FABRE Research Center concerns the application in cosmetology of derivatives of general formula

R1 et R2 sont identiques ou différents. Ils représentent plus particulièrement un hydrogène, un halogène, un alcoxy, un alcoyle, un cycloalcoyle, un phenoxy, un phenyl substitue de type

A is a linear or branched, saturated or unsaturated alkyl of 2 to 4 carbon atoms, for example

R1 and R2 are the same or different. They more particularly represent a hydrogen, a halogen, an alkoxy, an alkyl, a cycloalkyl, a phenoxy, a phenyl substitute of type

R3 = hydrogen, halogen, alkyl, alkoxy.

R1 and R2 can with the aromatic ring form a bicylic system

 These compounds are endowed with regulating properties in the glands, which reduce sebum formation and are therefore usable in cosmetological preparations.

The invention relates to the use in cosmetology of the compounds defined above and their therapeutically acceptable salts.

The salts are obtained by neutralization of the carboxylic function with mineral or organic bases.

By way of nonlimiting example, are mentioned some salts obtained: sodium, potassium, calcium, triethanolamine, dimethylamino ethanol, pyridoxine, guanidine, imidazole.

From the sodium or calcium salts, salts or metal complexes have been obtained by treating with metal sulphates or chlorides according to the scheme

The invention therefore also includes the application in cosmetology of the acid derivatives defined above with the acceptable metals for their good local tolerance or low toxicity; the derivatives of zinc, manganese, copper, aluminum and magnesium have been particularly selected.

The chemical compounds used in the context of the invention have been the subject of patents filed by the applicant; these patents also describe the methods for obtaining certain compounds according to the general formula.

These are the following patents
1) "aromatic ketoacids with analgesic and anti-inflammatory action", No. 74.10196, of March 25, 1974, published under No. 2,265,409, inventors
H. COUSSE, G. MOUZIN and JP RIEU.

 2) Addiction certification of 17/2175 n 75.04912.

3) "Oresoaryl oxo isovaleric compounds endowed with antiphogistic properties" n 77.02959, of February 1, 1977, published under No. 2,378,741, inventors
H. COUSSE; G. MOUZIN, JP RIEU and JP TARARE.

By way of nonlimiting example, the formulas and the codes of the chemical compounds having the cosmetological properties, object of the present invention, are recalled below:

The salts will be designated F 1594 Zn, F 1594 Na, respectively for the zinc or sodium salts.

The synthesis and characteristics of some compounds are described below; these techniques are generalizable to obtain all the derivatives of the invention defined in the general formula:
A. Friedel and Crafts Reaction Example 18: Preparation of 4- (4-phenylphenyl) -4-oxo-2-methylene
butyric (F 1377)
A suspension of 100 g (0.74 mol) of aluminum chloride in 150 ml of s-tetrachloroethane is stirred at room temperature. To this suspension, add a solution of 39 g (0.35-mole) of itaconic anhydride and 52.25 g (0.34 mole) of biphenyl in 250 ml of s-tetrachloroethane. The addition lasts two hours, then the reaction mixture is heated at 500C for 5 hours.

Allow to come to room temperature and hydrolyze with 300 ml of hydrochloric acid and 1 kg of crushed ice.

The product is recovered which is recrystallized from THF, the product of formula is obtained with a yield of 80%.

Crude formula: C17-H14 03 Molecular mass: 266.3
Crystals: yellow
Melting point: 2400 C
Plate chromatography
- support: silica gel 60 F 254 Merck
- solvent: acetic acid - dioxane - toluene 4/25 / 9o
- revelation: UV and iodine
- Rf: 0.65
Example 2 A: Preparation of (p-cyclohexylphenyl) -4-methylene-2-acid
oxo-4 butyric
In a manner similar to that described in Example 1A, but using phenylcyclohexane, the product of formula

Gross formula: C17 H20 03
Molecular weight: 272.3
Crystals: straw yellow
Melting point: 150 ° C
Plate chromatography
- support: silica gel
- solvent: acetic acid - dioxane - toluene 2/8/90
- revelation: UV and iodine
- Rf: 0.43
Example 3 A: Preparation of 4-phenyl-2-methylene-4-oxo-butyric acid
In a manner similar to that described in Example 1A, but using benzene, the product of formula

Gross formula: C11 H10 03
Molecular weight: 190.2
Crystals: white
Melting point: 163 C
Plate chromatography
- support: silica gel 60 F 254 Merck
- solvent: acetic acid-dioxane-toluene 2/8/90
- revelation: UV and iodine
- Rf: 0.48
Example 4 A: Preparation of 4-p-chlorophenyl-2-methylene-4-oxoic acid
butyric
In a manner similar to Example 1 As but using chlorobenzene as an aromatic substrate, the product of formula

Crude formula t Cll Hg C1 03 molecular mass: 224.6
Crystals: yellow
Melting point: 1800C
Plate chromatography
- support: silica gel 60 F 254 Merck
- solvent: acetic acid - dioxane - toluene 2/8/90
- revelation: W and iodine
- Rf: 0.46
Example 5 A: Preparation of 4-p-phenoxy phenyl-4-oxo-2-methylene
butyric
In a manner similar to that described in Example 1A, but using biphenyloxide as an aromatic substrate, the product of formula:

Gross formula: C17 H14 04
Molecular weight: 282.3
Crystals: white
Melting point: 1500 C
Plate chromatography
- support: silica gel 60 F 254 Merck
- solvent: acetic acid - dioxane - toluene 2/8/90
- revelation: W and iodine
Rf: 0.45) Example 6 A: Preparation of (4-orthochlorophenylphenyl) -4-oxo-4-acid
2-methylene butyric
In a manner similar to that described in Example 1A, but using 2-chlorobiphenyl as an aromatic substrate, the product of formula

Gross formula: C17 H13 C1 03
Molecular weight: 300.7
Crystals: white
Melting point: 206 ° C
Plate chromatography
- support: silica gel 60 F 254- Merck
- solvent: acetic acid - dioxane - toluene 2/8/90
- revelation: UV and iodine
- Rf: 0.42.

Example 7 A: Preparation of (4-p-phenyl) -4-butyric acid In a manner similar to that described in Example 1A, but using succinic anhydride, the product of formula

Gross formula: C16 H14 03
Molecular weight: 259.1
Melting point: 186 C
EXAMPLE 8 A Preparation of 4-naphthalen-4-oxo-2-methylenebutanate in a manner similar to that described in Example 1A, but using naphthalene as an aromatic substrate, the product of formula is obtained

Gross formula: C, s H12 03
Molecular weight: 240.26
Crystals: white
Melting point: 142 ° C
Plate chromatography
- support: silica gel 60 F 254 Merck
- solvent: acetic acid - dioxane - toluene 2/8/90
- revelation: UV and iodine
- Rf: 0.36
Example 9 A: Preparation of acid (11-2'-3r-4'tetrahydro naphthalene)
4-oxo-4-methylene-2-butyric (F 1495) In a manner similar to that described in Example 1A, but using tetralin as an aromatic substrate, the product of formula is obtained

Gross formula: C15 H16 03
Molecular weight: 244.29
Crystals: white
Melting point: 123 C
Plate chromatography
- support: silica gel 60 F 254 Merck
- solvent: acetic acid - dioxane - toluene 2/8/90
- revelation: W and iodine
- Rf: 0.41
Example 10 A: Preparation of 4- (4-phenyl-3'-methoxyphenyl) -4-oxoacidic acid
2-methylene butyric
In a manner similar to that described in Example 1A, but using 2-methoxybiphenyl as an aromatic substrate, the product of formula

sont obtenus à partir des dérivés précédents de formule générale

par isomérieation de la double liaison.A titre d'exemple non limitatif, nous décrivons le produit suivant
Exemple 1 B : Préparation de l'acide (0-chlorophényl-4' phényl)-4 oxo-4
méthyl-2 buten-2 olque (F 1439)
Une suspension de 30 g (0,1 mole) d'acide (ortho chlorophényl-4' phényl)
-4 oxoe4méthylène-2 butyrique dans 300 ml d'éther est agitée pendant 70
heures à 25 C avec 85 ml (0,6 mole) de triéthyl amine. Gross formula: C18 H16 04
Molecular weight: 296.3
Crystals: white
Melting point: 145 ° C
Plate chromatography
- support: silica gel 60 F 254 Merck
- solvent: acetic acid - dioxane - toluene 2/8/90
- revelation: W and iodine
- Rf: 0.36
B. Isomerization
Derivatives of formula

are obtained from the previous derivatives of general formula

by isomerization of the double bond. As a non-limiting example, we describe the following product
Example 1 B: Preparation of (4-chlorophenyl-4'-phenyl) -4-oxo-4-oxoic acid
2-methyl buten-2-ol (F 1439)
A suspension of 30 g (0.1 mol) of acid (ortho-chlorophenyl-4 'phenyl)
4-oxo-2-butyric methylene in 300 ml of ether is stirred for 70 minutes.
hours at 25 C with 85 ml (0.6 mol) of triethylamine.

300 ml of water are added to the reaction mixture and the phases are separated.

The organic phase is washed with water. Combine the aqueous phases and acidify while chilling; 85% of formula product is recovered after filtration and drying.

Gross formula: C17 H13 03
Molecular weight: 300.7
Yellow crystals
Melting point: 19600
Plate chromatography
- support: silica gel 60 F 254 Merck
- solvent: acetic acid - dioxane - toluene 2/8/90
- revelation: UV and iodine
- Rf: 0.43
Example 2 B: Preparation of 4-phenylphenyl-4-oxo-4-oxo-2-methyl
buten-2 oSque
In a manner similar to that described in Example 1B but using (4-p-phenylphenyl) -4-oxo-2-methylene-butyric acid, the product of formula is obtained

Gross formula: C17 H14 03
Molecular weight: 266.3
Crystals: light yellow
Melting point: 182 ° C
Plate chromatography
- support: silica gel 60 F 254 Merck
- solvent: acetic acid - dioxane - toluene 4/25/90
- revelation: W and iodine
- Rf: 0.61
C. Reduction
Example 1 C: Preparation of orthochloro-phenyl-4'-phenyl-4-oxo-4
2-methyl butyric
A suspension of 13 g of 10% palladium on carbon and 270 g of 4-ortho-chloro-phenylphenyl-4-oxo-4-methylene-butyric acid in 5 liters of dioxane and 1.8 liters of Acetic acid is treated with stirring with hydrogen at ambient pressure.

After removal of the catalyst, the reaction mixture is distilled to dryness.

The residue is solubilized in absolute alcohol while hot and then gradually cooled; the product of formula is recovered with a yield of 70%

Crude formula: C17 H15 C1 03 - Molecular mass: 302.7
Crystals: light yellow
Melting point: 172 ° C
Plate chromatography
- support: silica gel 60 F 254 Merck
- solvent: methanol - chloroform 20/80
- revelation: UV and iodine
- Rf: 0.79
EXAMPLE 2 Preparation of 4'-phenyl-4'-phenyl-4-oxo-2-methyl-2-methyl
butyric (F 1594)
In a manner similar to that described in Example 1C, but using p-biphenyl-4-oxo-4-methylene-2-butyric acid, the product of formula is obtained

F 1594
Gross formula: C17 H16 03
Molecular weight: 268.3
Crystals: white
Melting point: 216 ° C
Plate chromatography
- support: silica gel 60 F 254 Merck
- solvent: acetic acid - dioxane - toluene 2/8/90
- revelation: UV and iodine
- Rf: 0.38
D. Salification
Example 1 D: Preparation of 4-phenyl-4-phenyl-4-oxo-2-methyl-butyrate
sodium
One mole of 4'-phenyl-4-phenyl-4-oxo-2-methyl butyric acid is treated with the stoichiometric amount of a sodium hydroxide solution (N). After stirring, filter and evaporate to dryness.

The product of formula is recovered with a quantitative yield

White crystals
Melting point: 2100C
Solubility characteristics: 25% soluble in water.

E. Transalification
Example I E: Preparation of 4'-phenyl-4-phenyl-4-oxo-2-methyl butyrate
calcium
A suspension of one mole of 4-phenyl-4'-phenyl-4-oxo-2-methyl butyric acid is neutralized with sodium hydroxide (N) and then this solution is treated with a stoichiometric amount of calcium chloride hydrate in solution. The calcium salt precipitates and the product of formula is quantitatively recovered by filtration.

Example 2 E: Preparation of 4'-phenyl-4-phenyl-4-oxo-2-methyl butyrate
zinc
In a manner similar to that described in Example 1E, but using zinc sulphate, the product of formula

EXPERIMENTS
I) Properties
a) Skin tolerance
Tolerance was sought for each compound in five adult albino guinea pigs. The application of undiluted product three times a week for two weeks on the previously mown flank of the animal causes no appreciable skin reaction.

b) Cutaneous ear tolerance
Epicutaneous tests were conducted on New Zealand rabbits. After mowing the flanks of the animal, the stratum corneum is scratched. The results evaluated according to the DRAYZE scale showed that for most products the irritation index is very low.

c) Inhibition of the functioning of the sebaceous glands
A 14C glucose solution is incubated with sebaceous glands of rat foreskin; the metabolism of 14C glucose then leads to the formation of labeled 14C lipids and thus radioactive sebum.

The presence of an inhibitor of the functioning of the sebaceous glands causes a decrease in the formation of lipids, this inhibitory power for a given time (4 hours in the experiment), is defined by the counting of the radioactivity of the lipids for the control rats compared to lipid radioactivity for treated rats.

This inhibitory power is expressed in the table below as a percentage of decrease in radioactivity under standard conditions between controls and rats treated with 3 mol and 1 mol 2 solutions of product.

<Tb>

Product <SEP> used <SEP> Z <SEP> inhibition <SEP> Z <SEP> inhibition
<tb><SEP> 10-3 <SEP> mole <SEP> 10-2 <SEP> mole
<tb><SEP> F <SEP> 1594 <SEP> 45 <SEP> Z <SEP> 99.2
<tb><SEP> F <SEP> 1439 <SE> 40 <SE> Z <SEP> 85
<tb><SEP> F <SEP> F <SEP> 1495 <SEP><SEP><SEP> 25 <SEP> Z <SEP> 60 <SEP>
<tb><SEP> F <SEP> 1594 <SEP> 40 <SEP>% <SEP> 85
<tb> Salt <SEP> cysteamine
<tb><SEP> F <SEP> 1594 <SEP> salt <SEP> Zn <SEP> - <SEP> 45 <SEP>% <SEP> 92
<tb><SEP> F <SEP> 1594 <SEP> salt <SEP> 50 <SEP>% <SEP> 99 <SEP>% <SEP>
<tb><SEP> Pyridoxine
<Tb>
d) Action on experimental seborrhea in rats
The seborrheic state in animals is caused by a diet deficient in biotin.

Only male Wistar rats are used which are more deficient and more regular than females.

The experiment involves a batch of 10 animals under diet deficient for 7 weeks.

After four weeks of deficient diet the rat has symptoms that result in
- a disorder of weight growth
- seborrheic eczema
- a more or less pronounced fall of the hairs
- dermatosis around the mouth and eyes
a secretion of sebum in the sebaceous glands.

The activity of the products tested is quantified by the decrease in the surface of the sebaceous glands and the increase in the number of hair follicles. The most interesting results are obtained with F 1594 and its salts.

II) Applications
The increased secretion of the sebaceous glands is responsible for seborrhea and various dermatoses.

In addition, this hyperfunction can be involved in various forms of acne vulgaris.

Some minor forms of these disturbances, while not strictly speaking pathological, are unsightly or uncomfortable and can be treated with cosmetological or dermopharmaceutical preparations.

The compounds according to the present invention and more particularly F 1594 and its salts can be used in preparations intended to treat seborrhea and acne-prone skin; these preparations are solid, liquid or pasty. They comprise within suitable excipients at least one compound according to the general formula or a salt thereof.

By way of nonlimiting example, some compositions or preparations obtained with the derivatives which are the subject of the invention are cited.

a) Anti-seborrheic shampoo
F 1594 0.5 to 5%
Pantothenate of Ca 1%
excipient
b) Shampoo
F 1439 0.2 to 2%
Alkoyl sodium ethoxy sulfosuccinate
Hypoallergenic fragrance
Excipient pH = 7 + 0.5
c) Dry shampoo
F 1594 Ca salt 0.1 to 5%.

Excipient and anionic surfactant
d) Cream for oily skin
F 1594 zinc salt (0.1 to 5%)
Vitamin A glycerol ester Polyoxyethylene glycol
Glycerin
e) Lotion for acne-prone skin
Vitamin A
F 1594 (0.1 to 5%)
Sweet almond oil
Hydroalcoholic excipient.

Claims (2)

 i) Use in cosmetology of derivatives of general formula (I)

A represents a linear or branched, saturated or unsaturated alkyl of 2 to 4 carbon atoms.

R1 and R2 may also form with the aromatic ring a bicyclic system of formula:  alkyl, alkoxy.

R1 and R2 are the same or different; they represent a hydrogen, a halogen, an alkoxy, an alkyl, a cycloalkyl, a phenoxy, a substituted phenyl of formula: in which R3 represents a hydrogen, a As well as the salts of the acids obtained with cosmetologically applicable mineral or organic bases.  3) Use in cosmetology salts of derivatives according to claim 2 and more particularly the following inorganic salts: sodium, potassium, calcium, zinc, aluminum, manganese.  -CH2 - CH2

 2) Use in cosmetology of the products of general formula (I) and more particularly the derivatives or (A) represents the following groups  4) Use in cosmetology salts of derivatives according to claim 2 and more particularly the following organic salts: triethanolamine, dimethylamino ethanol, pyridoxine, guanidine, imidazole.  6) Use in cosmetology of the compounds according to claims 1 to 5 and more particularly in the care of acne-prone and seborrheic skin taking into account the regulating properties of the sebaceous glands.  - Phenyl-4 'phenyl-4-oxo-4-methyl-2-butyrate of zinc  - Phenyl-4 'phenyl-4 oxo-4-methyl-2 calcium butyrate  - Phenyl-4 'phenyl-4-oxo-4-methyl-2 sodium butyrate  4-phenyl-4'-phenyl-4-oxo-2-methyl-butyric acid  4-O-chlorophenyl-4'-phenyl-4-oxo-2-methyl butyric acid  - 4-phenyl-4'-phenyl-4-oxo-2-methyl-2-butenic acid  - 4-O-chlorophenyl-phenyl-4-oxo-2-methyl-2-butenic acid  - (4-phenyl-3-methoxy-3-phenyl) -4-oxo-4-methylene-2-butyric acid  - Acid (1'-2'-3'-4'-tetrahydronaphthalene) -4-oxo-4-methylene-2-butyric  - naphthalene-4-oxo-4-methylene-2-butanic acid  - (4-p-phenylphenyl) 4-oxo-butyric acid  4- (4-Chlorophenyl-4-phenyl) -4-oxo-2-methylene-butyric acid  4- (4-p-Phenoxyphenyl) -4-oxo-2-butyric butyric acid  - (p-chlorophenyl) -4-methylene-2-oxo-butyric acid  - 4-phenyl-2-methylene-4-oxo-butyric acid  - (p-cyclohexyl) phenyl-4-methylene-2-oxo-4-butyric acid  4- (4-p-phenyl phenyl) -4-oxo-2-butyric butyric acid  5) Use in cosmetology of the derivatives according to claims 1 to 4 and more particularly the following derivatives  7) The cosmetological compositions containing as active ingredients the compounds according to claims 1 to 5.  8) Cosmetological forms such as creams, lotions or shampoos containing an active ingredient according to claims 1 to 5, alone or in combination with other active ingredients.