WO2006067327A2 - Benzodiazepine peripheral receptor antagonists for treating dry skin - Google Patents

Abstract

The invention relates to the use of a composition containing at least one benzodiazepine peripheral receptor antagonist (PBR) for treating dry skin or dry scalps. Said composition can be used for cosmetic purposes, for treating the drying of the skin, especially after the menopause, or for dermatological purposes, for treating disorders related to oligoseborrheic dry skin, especially dermatitis.

Description

The present invention relates to the use of a composition containing at least one peripheral benzodiazepine receptor (PBR) antagonist for the cosmetic or dermatological treatment of dry skin or dry scalp, in particular of igoleborrhoeic dry skin or leather dry hair oligoseborrhoeic.

Many women over the age of thirty-five, and especially after menopause, frequently complain of dry skin, and the resulting discomfort or unsightly symptoms (desquamation, dullness, cutaneous atony). Now, this desiccation is due, as we know now, to a decrease in the production of sebum with age.

In addition, children whose sebaceous function is not yet active often show signs of dry skin.

Sebum is the natural product of the sebaceous gland (annex of the pilosebaceous unit) which, together with the sweat produced by the eccrine or apocrine glands, is a natural moisturizer of the epidermis. It consists essentially of a more or less complex mixture of lipids. Typically, the sebaceous gland produces squalene, triglycerides, aliphatic waxes, cholesterol waxes and optionally free cholesterol (Stewart, M.E., Semin Dermatol 11, 100-105 (1992)). The action of bacterial lipases converts a variable part of triglycerides into free fatty acids.

The sebocyte constitutes the competent cell of the sebaceous gland. Sebum production is associated with the terminal differentiation program of this cell. During this differentiation, the metabolic activity of the sebocyte is essentially focused on lipid biosynthesis (lipogenesis) and more specifically on the neosynthesis of fatty acids and squalene.

Oligoseborrhoeic dry skin is characterized by secretion and insufficient excretion of sebum. Classically, a sebum rate of less than 100 μg / cm ² measured at the forehead is considered to be characteristic of such dry skin. Dry skin is often associated with a lack of desquamation, a dull complexion, a sluggish skin texture. A dry scalp is often associated with dull, sluggish hair.

These aesthetic disorders and discomforts evolve with age, the chronological aging being accompanied by a loss of functionality of the sebaceous appendages. A compound which makes it possible to stimulate the production of the lipids constituting sebum by the cells of the sebaceous gland (the sebocytes) would therefore be of definite interest for the treatment of disorders associated with dry skin and / or a dry scalp, preferably oligoseborrhoeic.

The pharmacological effects of benzodiazepines (anxiolytics, anticonvulsants, muscle relaxants, and sedatives) result from their binding to the central benzodiazepine receptors (CBRs) present at the receptor complex GABA-A (gamma-aminobutyric acid). The term GABA-A receptor denotes a macromolecular complex which, in addition to the GABA site, comprises sites for the attachment of benzodiazepines, barbiturates, alcohol and certain steroids. It is a receptor associated with a channel, preferably permeable to chlorine ions (Cl ^" ) incidentally to bromine ions (Br ^" ). The opening of this channel after binding ligands described above resulting in the penetration of CI ions ^"and hyperpolarization.

CBR is present exclusively in the central nervous system (CNS) and is localized on neurons.

Benzodiazepines are also known to bind to peripheral receptors. These peripheral receptors are called benzodiazepine receptors (PBRs) or mitochondrial benzodiazepine receptors (MBRs).

DBI (Diazepam Binding Inhibitor), an 11kDa polypeptide of 86 amino acids, is described as an endogenous ligand for PBRs. DBI is so named because it is capable of inhibiting the binding of tritiated diazepam to brain membranes and the opening of GABA-activated chlorine channel _A (Beurdeley-Thomas et al., "The peripheral benzodiazepine receptors: a Journal of Neuro-Oncology, 46: 45-56, 2000. Zisterer et al., "Peripheral-type benzodiazepine receptors", Gen. Pharmac., Vol.29, No. 3, pp. 305-314, 1997).

J. Invest. Dermatol. 1993, 101 (6), p.800-803 already describes the presence of PBR at the level of the sebaceous gland, and the ability of DBI to regulate the synthesis of cholesterol and lipid in the sebaceous gland. The authors describe that DBI, the endogenous ligand of PBR, could, via its binding to acyl-CoA, stimulate the synthesis of cholesterol and lipid.

According to well-established pharmacological definitions, a molecule capable of triggering, by its binding to specific receptors, a biological action similar to the activity of the endogenous ligand, is by definition an agonist. In contrast, a molecule whose nature of interaction with the same receptors is different and which is therefore unable to triggering the action-effect sequence (thus devoid of intrinsic activity) is by definition an antagonist (Schorderet et al., "Pharmacology", Frison-Roche and Slatkine Editions, 1992). As described in J. Invest. Dermatol. 1993, 101 (6), p.800-803, DBI, is therefore a PBR agonist whose biological action leads to the synthesis of cholesterol and lipid.

The Applicant has now surprisingly and unexpectedly discovered that peripheral benzodiazepine receptor antagonist (PBR) derivatives make it possible to stimulate the synthesis of sebum by the sebocytes.

The documents The Fur. G. et al., Life. Science, 1983, 33, 449-457 and WO00 / 44384, WO02 / 07727, FR2811990, WO00 / 44751, WO03 / 082874, WO03 / 068753 and WO03 / 030937 already describe PBR antagonists and their use for preventing or treating of diseases related to dysfunction of peripheral benzodiazepine receptors.

US 6,767,533 discloses the use of PBR ligands to protect the skin from the effects of deleterious stresses, such as U.V.

FR 2 811897 also describes the use of derivatives capable of binding peripheral benzodiazepine receptors, for the preparation of medicaments for the treatment of dysfunction of these receptors, in particular inflammatory diseases.

However, it has not yet been suggested to use a PBR antagonist for the treatment of dry skin and / or dry scalp.

The present invention therefore relates to the cosmetic use, for the treatment of dry skin or dry scalp, preferably oligoseborrheic, a composition containing at least one peripheral benzodiazepine receptor antagonist (PBR).

The Applicant defines a peripheral benzodiazepine receptor antagonist (PBR) as any molecule of organic or inorganic origin having an affinity for peripheral receptor binding sites for benzodiazepines, and (i) capable of decreasing the production of pregnenolone induced by a PBR agonist (MBR) and / or,

(ii) whose affinity for peripheral benzodiazepine receptors is defined by entropy-dependent thermodynamic character and / or, (iii) promote the regeneration of nerve cells and / or promote cardiac recovery after ischemia and / or oppose the growth of breast cancer cell lines.

The measurement of the affinity for peripheral receptor binding sites for benzodiazepines can be carried out according to one of the binding studies described in WO00 / 44384, WO02 / 07727, FR2811990, WO00 / 44751, WO03 / 082874, WO03 / 068753 or WO03 / 030937.

Measurement of the ability to decrease the PBR agonist-induced production of pregnenolone (MBR) can be performed according to the method described in WO03 / 068753 and WO03 / 030937.

The measurement of the entropy-dependent character of the affinity for peripheral benzodiazepine receptors can be carried out according to the method described in the document Le Fur. G. et al., Life. Science, 1983, 33, 449-457

Preferably, the PBR antagonists according to the invention are:

(A) PK11195 (or 1- (2-chlorophenyl) -N- (1-methyl-propyl) -3-isoquinoline carboxamide) as described in Le Fur. G. et al., Life. Science, 1983, 33, 449-457.

(B) the compounds of the following general formula (I) as described in WO03 / 030937:

in which: - A and C each represent, independently of one another, a 5- to 10-membered carbon ring or heterocyclic ring; - B represents

ou dans lequel R³ représente un atome d'hydrogène; un alkyl en C₁-C₈ éventuellement substitué par un groupe phényl; un groupe acyle en C₂-C₈ éventuellement substitué par un groupe phényl; un alkoxylcarbonyl en C₁-C₈; ou un alkylène en C₁-C₄, - X et Y représentent chacun, indépendamment l'un de l'autre, -CH₂-, -O-, ou -CHR⁴- dans lequel R⁴ représente un alkyl en C₁-C₄, ou un alkylène en C₂-C₅, p et q représentent chacun, indépendamment l'un de l'autre, un nombre entier égal à 0 ou variant de 2 à 4, étant entendu que p et q ne sont pas simultanément égal à 0, - R¹ et R² représentent chacun, indépendamment l'un de l'autre: 1 ) un atome d'halogène,

or wherein R ³ represents a hydrogen atom; a C ₁ -C ₈ alkyl optionally substituted with a phenyl group; a C ₂ -C ₈ acyl group optionally substituted with a phenyl group; a C ₁ -C ₈ alkoxylcarbonyl; or C ₁ -C ₄ alkylene; X and Y are each independently of each other -CH ₂ -, -O-, or -CHR ⁴ - wherein R ⁴ is C ₁ alkyl; -C ₄ , or a C ₂ -C ₅ alkylene, p and q each represent, independently of one another, an integer equal to 0 or ranging from 2 to 4, it being understood that p and q are not not simultaneously equal to 0, - R ¹ and R ² each represent, independently of each other: 1) a halogen atom,

2) OR ⁵ ,

3) SR ⁵ ,

4) NR ⁶ R ⁷ ,

5) a nitro, 6) a cyano,

7) COR ⁸ ,

8) a ring or a 3- to 10-membered carbon heterocycle, optionally substituted with 1 to 5 groups chosen from a C ₁ -C ₈ alkyl, the said alkyl being optionally substituted with 1 to 5 groups chosen from a halogen atom; OR ⁵ , SR ⁵ , NR ⁶ R ⁷ , nitro group, cyano group, COR ⁸ and phenyl; a halogen atom; OR ⁵ ; SR ⁵ ; NR ⁶ R ⁷ ; a nitro; a cyano; COR ⁸ and a ring or a carbon-containing heterocycle of 5 to 10 members, the said ring or heterocycle being optionally substituted with 1 to 5 groups chosen from a halogen atom, OR ⁵ , SR ⁵ , NR ⁶ R ⁷ , a nitro group a cyano group, COR ⁸ and a phenyl and a C ₁ -C ₈ alkyl, or

9) a C ₁ -C ₈ alkyl, optionally substituted with 1 to 5 groups chosen from a halogen atom, OR ⁵ , SR ⁵ , NR ⁶ R ⁷ , a nitro, a cyano, COR ⁸ and a ring or a ring; carbon-containing heterocycle of 5 to 10 members, the said ring or heterocycle being optionally substituted with 1 to 5 groups chosen from a halogen atom, OR ⁵ , SR ⁵ , NR ⁶ R ⁷ , a nitro, a cyano, COR ⁸ and a phenyl and a C ₁ -C ₈ alkyl, said alkyl being optionally substituted with 1 to 5 groups selected from a halogen atom, OR ⁵ , SR ⁵ , NR ⁶ R ⁷ , a nitro, a cyano, COR ⁸ and a phenyl; wherein:

- R ⁵ represents: 1) a hydrogen atom;

2) a C ₁ -C ₈ alkyl, optionally substituted with 1 to 5 groups chosen from a halogen atom, OR ⁹ , SR ⁹ , NR ¹⁰ R ¹¹ , a nitro, a cyano, COR ¹² and a ring or a 3- to 10-membered carbon heterocyclic ring, said ring or heterocycle being optionally substituted with 1 to 5 groups selected from a halogen atom, OR ⁹ , SR ⁹ , NR ¹⁰ R ¹¹ , a nitro, a cyano COR ¹² , a phenyl and a C ₁ -C ₈ alkyl, said alkyl being optionally substituted with 1 to 5 groups selected from a halogen atom, OR ⁹ , SR ⁹ ,

NR ¹⁰ R ¹¹ , nitro, cyano, COR ¹² and phenyl;

3) a ring or a carbon-containing heterocycle of 3 to 10 members, optionally substituted with 1 to 5 groups chosen from a C ₁ -C ₈ alkyl, the said alkyl being optionally substituted with 1 to 5 groups chosen from a halogen atom; OR ⁹ , SR ⁹ , NR ¹⁰ R ¹¹ , nitro, cyano, COR ¹² and phenyl; a halogen atom; OR ⁹ ; SR ⁹ ; NR ¹⁰ R ¹¹ ; a nitro; a cyano; COR ¹² ; a phenyl and a ring or a 3- to 10-membered carbon heterocyclic ring, said ring or heterocycle being optionally substituted with 1 to 5 groups selected from a halogen atom, OR ⁹ , SR ⁹ , NR ¹⁰ R ¹¹ , a nitro, a cyano, COR ¹² , phenyl and C ₁ -C ₈ alkyl;

4) COR ¹³ , in which R ¹³ represents a C ₁ -C ₈ alkyl, the said alkyl being optionally substituted with 1 to 5 groups chosen from a halogen atom, OR ⁹ , SR ⁹ , NR ¹⁰ R ¹¹ , a nitro, cyano, COR ¹² and phenyl; or a ring or a 3- to 10-membered carbon heterocyclic ring, said ring or heterocycle being optionally substituted with 1 to 5 groups chosen from a halogen atom, OR ⁹ , SR ⁹ , NR ¹⁰ R ¹¹ , a nitro, a cyano, COR ¹² , phenyl and C ₁ -C ₈ alkyl, and C ₁ -C ₈ alkyl; - R ⁶ and R ⁷ are each independently of one another: 1) a hydrogen atom; 2) a C ₂ -C ₈ acyl, optionally substituted with 1 to 5 groups chosen from a halogen atom, OR ⁹ , SR ⁹ , NR ¹⁰ R ¹¹ , a nitro, a cyano, COR ¹² and a ring or a ring; 3 to 10-membered carbon heterocycle, said ring or heterocycle being optionally substituted with 1 to 5 groups chosen from a halogen atom, OR ⁹ , SR ⁹ , NR ¹⁰ R ¹¹ , a nitro, a cyano, COR ¹² , and a ring or a 3- to 10-membered carbon heterocycle, the said ring or heterocycle being optionally substituted with 1 to 5 groups chosen from a halogen atom, OR ⁹ , SR ⁹ , NR ¹⁰ R ¹¹ , a nitro, a cyano, COR ¹² , and a C ₁ -C ₈ alkyl, the said alkyl being optionally substituted with 1 to 5 groups chosen from a halogen atom, OR ⁹ , SR ⁹ , NR ¹⁰ R ¹¹ , a nitro, a cyano, COR ¹² and phenyl;

3) COOR ¹² ;

4) CONR ¹⁰ R ¹¹ ; 5) a ring or carbonaceous heterocycle of 3 to 10 members, optionally substituted with 1 to 5 groups selected from a C ₁ -C ₈ alkyl, said alkyl being optionally substituted with 1 to 5 groups selected from a halogen atom; OR ⁹ , SR ⁹ , NR ¹⁰ R ¹¹ , nitro, cyano, COR ¹² and phenyl; a halogen atom; OR ⁹ ; SR ⁹ ; NR ¹⁰ R ¹¹ ; a nitro; a cyano; COR ¹² ; a phenyl and a ring or a 3- to 10-membered carbon heterocyclic ring, said ring or heterocycle being optionally substituted with 1 to 5 groups selected from a halogen atom, OR ⁹ , SR ⁹ , NR ¹⁰ R ¹¹ , a nitro, a cyano, COR ¹² , and a C ₁ -C ₈ alkyl, the said alkyl being optionally substituted with 1 to 5 groups chosen from a halogen atom, OR ⁹ , SR ⁹ , NR ¹⁰ R ¹¹ , a nitro, a cyano , COR ¹² ; or

6) a C ₁ -C ₈ alkyl, optionally substituted with 1 to 5 groups chosen from a halogen atom, OR ⁹ , SR ⁹ , NR ¹⁰ R ¹¹ , a nitro, a cyano, COR ¹² and a ring or a ring; 3 to 10-membered carbon heterocycle, said ring or heterocycle being optionally substituted with 1 to 5 groups chosen from a halogen atom, OR ⁹ , SR ⁹ , NR ¹⁰ R ¹¹ , a nitro, a cyano, COR ¹² , and a C ₁ -C ₈ alkyl, said alkyl being optionally substituted with 1 to 5 groups selected from a halogen atom, OR ⁹ , SR ⁹ , NR ¹⁰ R ¹¹ , a nitro, a cyano, COR ¹² ; - R ⁸ represents

1) a hydrogen atom;

2) OR ⁹ ;

3) NR ¹⁰ R ¹¹ ;

4) a ring or carbonaceous heterocycle of 3 to 10 members, optionally substituted with 1 to 5 groups selected from a halogen atom; OR ⁹ ; SR ⁹ ;

NR ¹⁰ R ¹¹ ; a nitro; a cyano; COR ¹² ; a phenyl; a C ₁ -C ₈ alkyl, the said alkyl being optionally substituted with 1 to 5 groups chosen from a halogen atom, OR ⁹ , SR ⁹ , NR ¹⁰ R ¹¹ , a nitro, a cyano, a COR ¹² and a phenyl ; and a ring or a 3- to 10-membered carbon heterocycle, optionally substituted with 1 to 5 groups selected from halogen, OR ⁹ , SR ⁹ , NR ¹⁰ R ¹¹ , nitro, cyano, COR ¹² , an alkyl C ₁ -C ₈ and phenyl; or

5) a C ₁ -C ₈ alkyl, optionally substituted with 1 to 5 groups chosen from a halogen atom, OR ⁹ , SR ⁹ , NR ¹⁰ R ¹¹ , a nitro, a cyano, COR ¹² and a ring or a ring; 3 to 10-membered carbon heterocycle, the said ring or heterocycle being optionally substituted with 1 to 5 groups chosen from a halogen atom, OR ⁹ , SR ⁹ , NR ¹⁰ R ¹¹ , a nitro, a cyano, COR ¹² , and a C ₁ -C ₈ alkyl, said alkyl being optionally substituted with 1 to 5 groups selected from a halogen atom, OR ⁹ , SR ⁹ , NR ¹⁰ R ¹¹ , a nitro, a cyano, COR ¹² , and a phenyl; in which: R ⁹ represents a hydrogen atom, a C ₁ -C ₈ alkyl, an acyl

C ₂ -C ₈ alkyl, said alkyl or acyl optionally substituted with alkoxy C ₁ -C ₈ alkylthio, C ₁ -C _8, or a carbon ring or a heterocycle with 3 to 10 members,

Each of R ¹⁰ and R ¹¹ represents, independently of one another, a hydrogen atom, a C ₁ -C ₈ alkyl or a phenyl, and

R ¹² represents a hydrogen atom, a phenyl, a C ₁ -C ₈ alkyl optionally substituted with a phenyl, and a C ₁ -C ₈ alkoxy optionally substituted with a phenyl, and

m and n each represent, independently of one another, an integer equal to

0 or ranging from 1 to 5.

(C) the compounds of the following general formula (II) as described in the document WO03 / 030937:

in which:

R ^YA represents a hydrogen atom or a hydroxyl group, - R ^1YA represents a hydrogen atom or a methyl,

R ^2YA represents a pyridyl or a phenyl substituted with 1 to 3 groups, which may be identical or different, chosen from: a halogen atom, a trifluoromethyl, a nitro, an acetyl, a linear or branched C-alkyl; ₁ -C ₄ , a linear or branched C ₁ -C ₄ alkyloxy, a linear or branched C ₁ -C ₇ alkylmercapto, substituted alkylmercapto of general formula -S- (CH ₂ ) _n γ _A -CH (R ^3YA ) (R ^4YA ), in which:

• n ^YA represents an integer ranging from 1 to 2,

R ^3YA represents a hydrogen atom or a methyl, and R ^4YA represents a hydroxyl group; an amine of general formula

-NR ^8YA R ^9YA , wherein:

R ^8YA represents a hydrogen atom or a methyl,

R ^9YA represents a methyl, a benzyl or a substituted benzyl, or R ^8YA and R ^9YA , taken together with the nitrogen atom carrying them, form a substituted pyrolidine ring, a sulphonyl of general formula -SO ₂ R ^5YA , wherein R ^5YA , represents an amine or a C ₁ -C ₃ alkyl, and o an aminoethoxycarbonyl of the general formula -COO (CH ₂ ) ₂ -NR ^6YA R ^7YA , wherein R ^6YA and R ^7YA represent, each , independently of one another, a hydrogen atom, a methyl or an ethyl.

(D) the compounds of the following general formula (III) as described in WO03 / 030937:

dans laquelle:

in which:

- R ^{1YB and} R ^1YB each represent, independently of one another, a linear or branched C ₁ -C ₆ alkyl; a C ₃ -C ₇ cycloalkyl; a C ₁ -C ₃ alkyl substituted with a phenylalkyl or a cycloalkyl; an alkenyl or a C ₃ -C ₆ alkynyl, it being understood that the double bond of said alkenyl or the triple bond of said alkynyl is not in position 1 or

2 with respect to the nitrogen atom;

^YB and ^YB are each, independently of one another, a nitrogen atom or a CH group;

X ^1YB and X ^2YB each represent, independently of one another, a halogen atom, a linear or branched C ₁ -C ₃ alkyl, a linear or branched alkoxy,

C ₁ -C ₃ , nitro or trifluoromethyl and;

Ar ^YB represents a phenyl, a pyridyl, a thienyl or a phenyl substituted with one or two groups, each independently of one another, chosen from an atom halogen, linear or branched alkyl C ₁ -C ₄ alkyl, linear alkoxy or branched C ₁ -C ₄ alkyl, a linear or branched alkylthio, C ₁ -C ₄ alkyl, trifluoromethyl and nitro.

(E) the compounds of the following general formula (IV) as described in WO03 / 030937:

dans laquelle:

in which:

R ^1YC represents an unsubstituted phenyl, a phenyl substituted with one or two groups, each independently of one another, selected from a halogen atom, a linear or branched C ₁ -C ₆ alkyl, a linear alkoxy or branched in C ₁ -

C ₆ ; or thienyl;

R ^2YC represents a hydrogen atom, a linear or branched alkyl comprising a number of carbon atoms ranging from 1 to 6 and optionally a nitrogen atom and / or a substituent chosen from an amino, an alkylamino or a dialkylamino; R ^3YC represents a group of general formula (R ^4YC ) (R ^5YC ) N-CO-Q ^YC , in which: Q ^γc represents a linear or branched C ₁ -C ₆ alkyl, where R ^4YC and R ^5YC represent each, independently of one another, a linear or branched C ₁ -C ₆ alkyl, phenyl, or phenyl substituted with one or two groups, each independently of one another, selected from an atom halogen, linear or branched alkyl C ₁ -C ₆ alkoxy linear or branched C ₁ -C ₆ alkyl;

- X ^γc represents a hydrogen atom or a halogen atom;

- Y ^γc represents an oxygen atom or a sulfur atom.

(F) the compounds of the following general formula (V) as described in WO03 / 030937:

in which:

^YD and ^YD are each independently of one another a nitrogen atom or a CH group;

^YD and ^YD are each, independently of each other, a hydrogen atom, a halogen atom, a C ₁ -C ₃ alkyl, a C ₁ -C ₃ alkoxy, a nitro or trifluoromethyl; Z ^YD represents a phenyl, a thienyl or a pyridyl, said phenyl being unsubstituted or substituted by one or two groups, each independently of one another, chosen from a C ₁ -C ₄ alkyl, a lower alkoxy C ₁ -C ₄ , trifluoromethyl or nitro R ^YD represents a hydrogen atom or a C ₁ -C ₃ alkyl;

- R ^1YD and R ^2YD each represent, independently of one another, a C ₁ -C ₆ alkyl; a C ₃ -C ₆ cycloalkyl, a phenyl, a C ₁ -C ₃ phenylalkyl, a C ₃ -C ₆ cycloalkyl-C ₁ -C ₃ alkyl group or a C ₃ -C ₆ alkenyl, it being understood that the double bond of alkenyl is not in position 1 or 2 with respect to the nitrogen atom; or NR ^1YD R ^2YD represents a pryrrolidine, a piperidine, a mopholine or a thiomorpholinoe;

X ^YD represents CHR ^3YD , NR ^4YD , SO, SO ₂ , O or S; - R ^3YD represents a hydrogen atom or a C ₁ -C ₃ alkyl;

R ^4YD represents a C ₁ -C ₃ alkyl; m ^YD represents an integer equal to 0 or 1;

n ^YD represents an integer equal to 0 or ranging from 1 to 2; with the proviso that: (1) if X ^YD is SO, SO ₂ or, NR ^4YD , then m ^YD + n ^YD is at least 1,

(2) if A ^YD and B ^YD each represent a nitrogen atom, Z ^YD is para to B ^YD , then X ^YD does not represent CHR ^3YD ,

(3) if Z ^YD represents a CH group, B ^YD represents a nitrogen atom, Z ^YD is an ortho position relative to B ^YD , X ^YD represents an oxygen atom, and R ^YD represents a hydrogen atom , then m ^YD + n ^YD is not equal to 1, and

(4) 2-phenylquinolin-4-yl-N, N'-dimethylcarbamate is excluded. The compounds of formula (I) to (V) may be prepared following the synthetic methods described in WO03 / 030937

(G) the compounds of the following general formula (VI) or a pharmacologically acceptable salt thereof as described in WO03 / 068753:

dans laquelle: le cycle A représente un monocycle carboné en C₅-C₈ ou un monocycle hétérocyclique de 5 à 8 chaînons comprenant 1 à 2 atomes d'azote, 1 à 2 atomes d'oxygène et/ou un atome soufre,

in which: ring A represents a C ₅ -C ₈ carbon monocycle or a 5- to 8-membered heterocyclic monocycle comprising 1 to 2 nitrogen atoms, 1 to 2 oxygen atoms and / or a sulfur atom,

X represents (1) -CH ₂ -, (2) -O-, (3) -S-, (4) -S (O) - or (5) -SO ₂ -,

L ¹ and L ² each independently of one another is a C ₁ -C ₄ saturated alkylene group, an alkylene group or a C ₂ -C ₄ alkenylene group, wherein the total number of carbon atoms in L ¹ and L ² are 3 or 4, - R ¹ and R ² are each independently of one another:

(1) an alkyl group C ₁ -C ₈ alkenyl group, C ₂ -C ₈ alkynyl group, C ₂ - C _8, optionally substituted with 1 to 5 groups selected from ring B, OR ^5, NR ⁶ R ^7, COR ^8, -OCOR ^8, OCONR ⁶ R ^7, COOR ^8, SR ^9, SOR ^8, SO ₂ R ^8, SO ₂ NR ⁶ R ^7, a halogen atom, a carboxyl group, a cyano group and nitro group, (2) ring B, (3) OR ⁵ , (4) NR ⁶ R ⁷ , (5) COR ⁸ , (6) OCOR ⁸ , (7) OCONR ⁶ R ⁷ , (8) COOR ⁸ ,

(10) SR ⁹ , (11) SOR ⁸ , (12) SO ₂ R ⁸ , (13) SO ₂ NR ⁶ R ⁷ , (14) a halogen atom, (15) a carboxyl group, (16) a cyano group, (17) a nitro group, (18) an oxo group, or (19)

dans lesquels:

wherein:

ring B represents (i) a C ₃ -C ₁₀ mono-cyclic or bicyclic carbon ring, or (ii) a 5 to 10-membered monocyclic or bicyclic heterocycle comprising 1 to 2 nitrogen atoms, 1 to 2 carbon atoms, oxygen and / or a sulfur atom, said ring B is optionally substituted with 1 to 5 groups selected from (i) a C ₁ -C ₈ alkyl group, a C ₂ -C ₈ alkenyl group, a C ₂ -C ₈ alkynyl group, optionally substituted with 1 to 5 groups selected from ring B, OR ⁵ , NR ⁶ R ⁷ , COR ⁸ , OCOR ⁸ , OCONR ⁶ R ⁷ , COOR ⁸ , SR ⁹ , SOR ⁸ , SO ₂ R ⁸ , SO ₂ NR ⁶ R ⁷ , a halogen atom, a carboxyl group, a cyano group and a nitro group, (ii) OR ⁵ , (iii) NR ⁶ R ⁷ , (iv) COR ⁸ , (v) OCOR ⁸ , (vi) OCONR ⁶ R ⁷ (vii) COOR ⁸ , (viii) CONR ⁶ R ⁷ , (ix) SR ⁹ , (x) OR ⁸ , (xi) SO ₂ R ⁸ , (xii) SO ₂ NR ⁶ R ⁷ , (xiii) an atom halogen, (xiv) a carboxyl group, (xv) a cyano group, (xvi) a nitro group, (xvii) an oxo group, - R ⁵ represents (i) a hydrogen atom, (ii) a group C ₁ -C ₈ alkenyl group, C ₂ -C ₈ alkynyl group, C ₂ -C _8, optionally substituted with 1 to 5 groups selected from ring B, OR ^15, NR ¹⁶ R ^17, COR ¹⁸ , OCOR ¹⁸ , OCONR ¹⁶ R ¹⁷ , COOR ¹⁸ , SR ¹⁹ , SOR ⁸ , SO ₂ R ⁸ , SO ₂ NR ⁶ R ⁷ , ring C, a halogen atom, a carboxyl group, a cyano group and a nitro group, (iii) -Si (R ¹⁰ ) ₃ or (iv) cycle C,

R ⁶ and R ⁷ each independently of one another represent (i) a hydrogen atom, or (ii) a group -D ¹ -D ² , wherein:

• D ¹ represents (a) a single bond, (b) -C (O) -, (c) -C (O) O or (d) - SO ₂ -; D ² represents (a) a C ₁ -C ₈ alkyl group, an alkenyl group

C ₂ -C ₈ alkynyl group, C ₂ -C _8, optionally substituted by ring C, or (b) ring C, said ring C represents (a) a carbon mono- or bicyclic ring, C ₃ -C ₁₀ or (b) a mono- or bicyclic heterocycle 5 to 10 members containing 1 to 2 nitrogen atoms, 1-2 oxygen atoms and / or sulfur atom, said ring C is optionally substituted with 1 to 5 groups selected from C ₁ -C ₈ alkyl, OR ¹⁵ , NR ¹⁶ R ¹⁷ , COR ¹⁸ , OCOR ¹⁸ , OCONR ¹⁶ R ¹⁷ , COOR ¹⁸ , SR ¹⁹ , SOR ⁸ , SO ₂ R ⁸ , SO ₂ NR ⁶ R ⁷ , ring C, a halogen atom, a carboxyl group, a cyano group and a nitro group, an oxo group,

R ⁸ represents (i) a C ₁ -C ₈ alkyl group, a C ₂ -C ₈ alkenyl group, a C ₂ -C ₈ alkynyl group, optionally substituted by the C 2 ring, or (ii) the ring VS,

R ⁹ represents (i) a hydrogen atom, (ii) a C ₁ -C ₈ alkyl group, a C ₂ -C ₈ alkenyl group or a C ₂ -C ₈ alkynyl group, optionally substituted with at least one group selected from OR ¹⁵ , NR ¹⁶ R ¹⁷ , COR ¹⁸ , OCOR ¹⁸ , OCONR ¹⁶ R ¹⁷ , COOR ¹⁸ , SR ¹⁹ , SOR ⁸ , SO ₂ R ⁸ , SO ₂ NR ⁶ R ⁷ , a halogen atom, or (Ni) ring B,

the plurality of R ¹⁰ represents, independently of one another, a C ₁ -C ₈ alkyl group or a phenyl group; R ¹⁵ and R ¹⁹ each represent, independently of one another, a alkyl group of C ₁ -C ₈ alkenyl group, C ₂ -C ₈ alkynyl group, C ₂ -C ₈ acyl group, C ₂ -C _8,

- R ¹⁶ and R ¹⁷ are each independently of one another, (ii) an alkyl group C ₁ -C ₈ alkenyl group, C ₂ -C ₈ alkynyl group, C ₂ - C ₈ (ii) a phenyl group, optionally substituted by an alkyl group

C ₁ -C ₈ alkenyl group, C ₂ -C ₈ alkynyl group, C ₂ -C ₈ alkyl, a halogen atom, an alkoxy group, C ₂ -C ₈ alkenyloxy group or a C ₂ -C ₈ ,

R ¹⁸ represents a C ₁ -C ₈ alkyl group, a C ₂ -C ₈ alkenyl group, a C ₂ -C ₈ alkynyl group and r represents an integer ranging from 2 to 4, m and n; each represents, independently of each other, an integer equal to 0 or ranging from 2 to 4,

R ³ represents a (i) a hydrogen atom, (ii) a B-ring, or (iii) a C ₁ -C ₈ alkyl group, a C ₂ -C ₈ alkenyl group or a C ₂ alkynyl group. -C ₈ , optionally substituted with 1 to 5 groups selected from ring B, OR ⁵ , NR ⁶ R ⁷ , COR ⁸ , OCOR ⁸ ,

OCONR ⁶ R ⁷ , COOR ⁸ , CONR ⁶ R ⁷ , SR ⁹ , SOR ⁸ , SO ₂ R ⁸ , SO ₂ NR ⁶ R ⁷ , a halogen atom, a carboxyl group, a cyano group and a nitro group, R ⁴ represents a hydrogen atom, a C ₁ -C ₈ alkyl group, a C ₂ -C ₈ alkenyl group, a C ₂ -C ₈ alkynyl group, - R ³ and R ^{4 which} can optionally form together with the nitrogen atom carrying them, a 5- to 10-membered mono- or bicyclic heterocycle containing a nitrogen atom, and optionally from 1 to 3 other nitrogen atoms, an oxygen atom and / or an atom of wherein said heterocycle is optionally substituted with 1 to 5 groups selected from C ₁ -C ₈ alkyl, OR ¹⁵ , NR ¹⁶ R ¹⁷ , COR ¹⁸ , OCOR ¹⁸ , OCONR ¹⁶ R ¹⁷ , COOR ¹⁸ , SR ¹⁹ , SOR ⁸ , SO ₂ R ⁸ , SO ₂ NR ⁶ R ⁷ , a halogen atom, a carboxyl group, a cyano group and a nitro group, an oxo group.

The compounds of formula (VI) may be prepared according to the synthetic methods described in WO03 / 068753.

(H) pyridazino [4,5-b] indole-1-acetamide derivatives of general formula (VII) as described in WO00 / 44384 ,:

in which:

X represents a halogen atom,

Y represents one or more atoms or groups chosen from hydrogen, halogens and hydroxyl, methyl, methoxy and nitro groups,

R 1 represents a (C ₁ -C ₄ ) alkyl group,

R ₂ and R 3, independently of one another, represent a hydrogen atom or a (C ₁ -C ₄ ) alkyl group, or R ₂ and R ₃ together with the nitrogen atom which carries them, a pyrrolidinyl, piperidinyl or morpholinyl group,

The compounds of formula (VII) can be prepared according to the synthetic methods described in WO00 / 44384.

Advantageously, the compounds of formula (VII) are chosen from compounds 1 to 34 of Table 1 below.

table 1

"Me" and "Et" denote, respectively, a methyl and ethyl group. "Pyrrolid", "Piperid" and "Morph" denote, respectively, a pyrrolidinyl, piperidinyl and morpholinyl group.

dans laquelle:(I) derivatives of 1- (4-oxo-3,5-dihydro-4H-pyridazino [4,5-b] indole-1-carbonyl) piperazine, of formula (VIII) as described in document FR2811990:

in which:

X ¹ represents a hydrogen or halogen atom,

Y ¹ represents one or more atoms or groups chosen from hydrogen, halogens and methyl, hydroxy and methoxy groups,

R ₄ represents a hydrogen atom or a (C ₁ -C ₄ ) alkyl group, R ₅ represents a hydrogen atom, a linear, branched or cyclic (C ₁ -C ₆ ) alkyl group, a (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₆ ) alkyl, a phenyl group, a pyridinyl group or a phenylmethyl group.

The compounds of general formula (VIII) may exist in the form of bases or addition salts with acids.

The compounds of formula (VIII) can be prepared according to the synthetic methods described in document FR2811990.

Advantageously, the compounds of formula (VIII) are chosen from compounds 35 to 52 of Table 2 below.

table 2

In the "R ₅ " column, "C ₆ H ₅ " denotes a phenyl group, "CC ₆ H ₁₁ " denotes a cyclohexyl group and "C ₅ H ₄ N" denotes a pyridin-2-yl group. In the "Salt" column, "-" denotes a compound in the base state and "HCl" denotes a hydrochloride; The molar ratio acid: base is indicated opposite.

(J) pyridazino (4,5) indole-1-acetamide derivatives of formula (IX) as described in WO02 / 07727:

dans laquelle:

in which:

- X "represents a halogen atom, - Y" represents one or more atoms or groups chosen from hydrogen, halogens and hydroxyl, methyl and methoxy groups,

R ₆ represents a hydrogen atom or a (C ₁ -C ₄ ) alkyl group,

R ₇ represents a hydrogen atom, a linear or branched (C ₁ -C ₄ ) alkyl group, a (C ₁ -C ₄ ) hydroxyalkyl group, a (C ₃ -C ₇ ) cycloalkyl group or a (C ₁ -C ₄ ) group; ₁ -C ₆ ) alkyl, phenyl group, pyridinyl group or phenyl (C ₁ -C ₄ ) alkyl group.

The compounds of general formula (IX) may exist in the form of bases or addition salts with acids. The compounds of formula (IX) may be prepared according to the synthetic methods described in WO02 / 07727.

Advantageously, the compounds of formula (IX) are chosen from compounds 53 to 66 of Table 3 below.

table 3

In the "R ₇ " column, "CC ₃ H ₅ " refers to a cyclopropyl group, wherein C ₆ H _{1 1} denotes a cyclohexyl group, C ₆ H ₅ denotes a phenyl group and 2-C ₅ H ₄ N denotes a pyridine group. 2-yl. In the "Salt" column, "-" denotes a compound in the base state and "HCl" denotes a hydrochloride; the molar ratio acid: base is indicated opposite.

(K) 3-heteroaryl-3,5-dihydro-4-oxo-4H-pyridazino [4,5-b] indole-1-acetamide derivatives of formula (X) as described in WO03 / 082874.

in which:

X '"represents a halogen atom,

R ₈ represents a hydrogen atom or a (C ₁ -C ₄ ) alkyl group,

- R ₉ and Rio represent, independently of each other, a hydrogen atom, a linear (C ₁ -C ₄ ) alkyl group or else R ₈ and R ₁₀ form, with the nitrogen atom which gate, a pyrrolidinyl, piperidinyl or morpholinyl or 4- (C ₁ -C ₄ ) alkylpiperazinyl group, and

Het represents a heteroaromatic group of pyridinyl, quinolinyl, isoquinolyl, pyrimidinyl, pyrazinyl or pyridazinyl type, the heteroaromatic group possibly bearing one or more halogen atoms and / or one or more (C ₁ -C ₄ ) alkyl or (C _{1) groups;} -C ₄ ) alkoxyl.

The compounds of general formula (X) may exist in the form of bases or addition salts with acids, as well as with the hydrate or solvate state.

The compounds of formula (X) may be prepared according to the synthetic methods described in WO03 / 082874.

Advantageously, the compounds of formula (X) are chosen from compounds 67 to 78 of Table 4 below.

table 4

The compounds of formulas (I), (II), (III), (IV) and (V) which are preferred according to the invention are chosen from compounds of formulas (la-1) to (la-32) and (Ib -1) to (lb-32) following:

Très préférentiellement, les composés de formules (I)-(V) sont les suivants :

Very preferably, the compounds of formulas (I) - (V) are as follows:

Les composés de formule (Vl) préférés selon l'invention sont choisis parmi les composés de formule (VNa), (Vl-b), (Vl-c), (Vl-d), (Vl-e), (Vl-f), (Vl-g), (Vl-h), (Vl-i), (Vl-J)₁ (Vl-k), (Vl-m) suivantes, dans lesquelles les symboles ont les significations données précédemment:

The compounds of formula (VI) which are preferred according to the invention are chosen from compounds of formula (VNa), (VI-b), (VI-c), (VI-d), (VI-e), f), (VI-g), (VI-h), (VI-i), (VI-J) ₁ (VI-k), (VI-m), in which the symbols have the meanings given above:

Advantageously, the compounds of formula (VI) are chosen from compounds of formulas (VI-a-1), (VI-a-2), (VI-a-3), (VI-a-4), (VI -a-5), (VI-a-6), (VI-a-7), (VI-a-8), (VI-a-9), (VI-a-10), (VI-a-6) -11), (VI-a-12), (VI-a-13), as follows:

Très préférentiellement, les composés de formule (Vl) sont choisis parmi les composés suivants: :

Very preferably, the compounds of formula (VI) are chosen from the following compounds:

8-fluoro-1-phenylcarbamoyl-2,3,4,5-tetrahydro-1H-1-benzazepine; - 1- (2 _I 6-dichlorophenylcarbamoyl) -2,3,4,5-tetrahydro-1H-1-benzazepine; 1- (4-hydroxyphenylcarbamoyl) -2,3,4,5-tetrahydro-1H-1-benzazepine.

The present invention also relates to the cosmetic use of at least one PBR antagonist as defined above, as an agent for the treatment of dry skin or dry scalp.

In particular, the PBR antagonists will be useful according to the invention for preventing or reducing the physiological oligoseborrhoeic states and / or linked to intrinsic mechanisms, that is to say states of dryness of the skin and / or scalp which are not primarily induced by interactions with external factors or stress.

The composition according to the invention is particularly well suited to the treatment of oligoseborrheic dry skin, that is to say skin having a sebum level of less than 100 μg / cm ² at the forehead. This type of skin is frequently found in women around the menopause, so that the composition used according to the invention is preferably applied to women over the age of forty, especially about 50 years or more.

The invention also relates to a cosmetic method for combating the signs of dry skin and / or dry scalps, and in particular to improve the radiance of the complexion, to fight against dull or sluggish hair or the appearance of signs of desquamation, or regulate the production of sebum, wherein is applied to the skin and / or the scalp at least one PBR antagonist or a composition containing it as defined in the foregoing. The PBR antagonists will thus have a function of improving the production of sebum, to maintain it at a physiological level.

Another subject of the present invention is the use of at least one antagonist of the

PBR as defined above, for the preparation of a composition, in particular a pharmaceutical or dermatological composition, intended to treat disorders related to oligoseborrhoeic dry skin, especially dermatitis. According to an advantageous embodiment, the composition is not intended to fight against skin inflammation.

The amount of peripheral benzodiazepine receptor antagonist (PBR) that can be used according to the invention is of course dependent on the desired effect and can therefore vary to a large extent. In general, the PBR antagonist will be present in an amount sufficient to significantly increase sebum production and advantageously to increase sebum production by sebocyte culture by at least 10%, as described in Example 1. 1 below.

To give an order of magnitude, the peripheral benzodiazepine receptor antagonist (PBR) may be used in an amount representing from 0.001% to 10% of the total weight of the composition, preferably in an amount representing from 0.01% to 5% by weight. %, and even more preferably from 0.05 to 1% of the total weight of the composition.

The composition according to the invention is generally suitable for topical application to the skin (including the scalp), preferably the skin of the face, and therefore contains a physiologically acceptable medium, that is to say compatible with the skin and / or its integuments (eyelashes, nails, hair).

This composition may be in any galenical form normally used in the cosmetic and dermatological fields, and it may especially be in the form of an oily solution, optionally gelled, of an emulsion obtained by dispersion of a fatty phase in an aqueous phase. [HIE] or vice versa (W / O), or a triple emulsion (W / O / W or H / E / H) or a vesicular dispersion of ionic and / or nonionic type. These compositions are prepared according to the usual methods. It is preferred to use according to this invention a composition in the form of an oil-in-water emulsion. Indeed, by these components (in quantity and quality) the fatty phase of the oil-in-water emulsion makes it possible to mimic the composition of the sebum, in order to allow a better availability of the peripheral benzodiazepine receptor antagonist (PBR ) at the differentiating sebocytes that constitute the target. In particular, the PBR antagonist (s) can be formulated in a composition mimicking the composition of sebum as described in WO 02/26207, WO 02/11693 or WO03 / 037288. Such cosmetic compositions mimicking sebum, comprise at least one lipophilic fraction comprising itself at least: from 5% to 20% of squalene, from 50% to 70% of a mixture of linear fatty acid triglycerides having a chain from 12 to 22 carbon atoms and linear fatty acids having a chain of 12 to 22 carbon atoms, from 15 to 25% of linear fatty acid esters and linear fatty alcohols having chains of 12 to 22 carbon atoms, from 0.5% to 3% of cholesterol esters whose acidic fraction comprises a chain of

12 to 22 carbon atoms, and 0% to 5% cholesterol. the ratio of unsaturated fatty chains to saturated fatty chains being between 10 and 0, 1.

This composition may be more or less fluid and have the appearance of a white or colored cream, an ointment, a milk, a lotion, a serum, a paste, a mousse . It can optionally be applied in the form of an aerosol. It can also be in solid form, in particular in the form of a stick. It can be used as a care product and / or as a make-up product for the skin. It can also be used as a shampoo or conditioner.

In a known manner, the composition used according to the invention may also contain the usual adjuvants in the cosmetic field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, preservatives, antioxidants, solvents, perfumes, fillers. , filters, pigments, odor absorbers and dyestuffs. The amounts of these various adjuvants are those conventionally used in the field under consideration, and for example from 0.01 to 20% of the total weight of the composition. These adjuvants, depending on their nature, can be introduced into the fatty phase, into the aqueous phase or into the lipid vesicles. In any case, these adjuvants, as well as their proportions, will be chosen so as not to interfere with the desired properties of the peripheral benzodiazepine receptor (PBR) antagonists according to the invention. When the composition used according to the invention is an emulsion, the proportion of the fatty phase can range from 5 to 80% by weight, and preferably from 5 to 50% by weight relative to the total weight of the composition. The oils, emulsifiers and coemulsifiers used in the composition in emulsion form are chosen from those conventionally used in the field under consideration. The emulsifier and the coemulsifier are present in the composition in a proportion ranging from 0.3 to 30% by weight, and preferably from 0.5 to 20% by weight relative to the total weight of the composition.

As oils which can be used in the invention, mention may be made of mineral oils (vaseline oil), vegetable oils (avocado oil, soya oil), animal oils (lanolin), vegetable oils and the like. synthesis (perhydrosqualene), silicone oils (cyclomethicone) and fluorinated oils (perfluoropolyethers). Fatty alcohols (cetyl alcohol), fatty acids, waxes (carnauba wax, ozokerite) can also be used as fats.

As emulsifiers and coemulsifiers that can be used in the invention, mention may be made, for example, of fatty acid and polyethylene glycol esters such as PEG-100 stearate, and fatty acid and glycerine esters such as glyceryl stearate. .

As hydrophilic gelling agents, mention may in particular be made of carboxyvinyl polymers (carbomer), acrylic copolymers such as copolymers of acrylates / alkylacrylates, polyacrylamides, polysaccharides, natural gums and clays, and, as lipophilic gelling agents, it is possible to mention mention modified clays such as bentones, metal salts of fatty acids, hydrophobic silica and polyethylenes.

As active agents, it will be advantageous to introduce into the composition used according to the invention at least one compound chosen from: desquamating agents; moisturizing agents; soothing agents; agents stimulating proliferation and / or differentiation of keratinocytes and anti-bacterial agents.

The addition of desquamating agents or regulating the proliferation or differentiation of keratinocytes to the composition according to the invention make it possible to avoid any possible effects. adverse events related to stimulation of seborrhea. Similarly, antibacterial or bacteriostatic agents would, by moderating the proliferation of the resident microflora, achieve the same effect.

In addition, the moisturizing agents can complement the effect obtained using the benzodiazepine peripheral receptor antagonists (PBR) according to the invention, and the soothing agents are useful for improving the comfort of oligoseborrheic dry skin.

Examples of such additional assets are given below.

Desquamating agents

By "desquamating agent" is meant any compound capable of acting:

or directly on desquamation by promoting exfoliation, such as β-hydroxy acids, in particular salicylic acid and its derivatives (including n-octanoyl-5-salicylic acid); α-hydroxy acids, such as glycolic, citric, lactic, tartaric, malic or mandelic acids; urea; gentisic acid; oligofucoses; cinnamic acid; Saphora japonica extract; resveratrol;

or on the enzymes involved in the desquamation or the degradation of the coméodesmosomes, the glycosidases, the stratum corneum chymotryptic enzym (SCCE) or even other proteases (trypsin, chymotrypsin-like). Mention may be made of the chelating agents for mineral salts: EDTA; N-acyl-N, N ', N', ethylene diaminetriacetic acid; aminosulfonic compounds and in particular (N-2-hydroxyethylpiperazine-N-2-ethane) sulfonic acid (HEPES); 2-oxothiazolidine-4-carboxylic acid (procysteine) and its derivatives; glycine-type alpha amino acid derivatives (as described in EP-0 852 949, as well as sodium methyl glycine diacetate marketed by BASF under the trade name TRILON M); honey ; sugar derivatives such as O-octanoyl-6-D-maltose and N-acetyl glucosamine.

Moisturizing agent By "moisturizing agent" is meant:

or a compound acting on the barrier function, with a view to maintaining the hydration of the stratum corneum, or an occlusive compound. There may be mentioned ceramides, sphingoid-based compounds, lecithins, glycosphingolipids, phospholipids, cholesterol and its derivatives, phytosterols (stigmasterol, β-sitosterol, campesterol), essential fatty acids, 1-2 diacylglycerol, 4-chromanone, pentacyclic triterpenes such as ursolic acid, petrolatum and lanolin;

or a compound directly increasing the water content of the stratum corneum, such as thralose and its derivatives, hyaluronic acid and its derivatives, glycerol, pentanediol, sodium pidolate, serine, xylitol, lactate sodium, glycerol polyacrylate, ectoin and its derivatives, chitosan, oligo- and polysaccharides, cyclic carbonates, N-lauroyl pyrrolidone carboxylic acid, and N-α-benzoyl-L-arginine;

or a compound activating the sebaceous glands such as sapogenins, and vitamin D and its derivatives.

Agents stimulating proliferation and / or differentiation of keratinocytes

Agents stimulating the proliferation of keratinocytes, usable in the composition according to the invention, include retinoids such as retinol and its esters, including retinyl palmitate; phloroglucinol; nut cake extracts sold by the company GATTEFOSSE; and extracts of Solanum tuberosum marketed by SEDERMA.

Retinoids are preferred for use in this invention, particularly retinol and its esters, which can range from 0.00001 to 5% and most preferably from 0.1 to 2% of the total weight of the composition.

Agents stimulating the differentiation of keratinocytes include, for example, minerals such as calcium; lupine extract marketed by Silab under the trade name Photopreventine® ^®; sodium beta-sitosteryl sulphate marketed by Seporga under the trade name Phytocohesin ^® ; and corn extract marketed by Solabia under the trade name Phytovityl ^®.

Soothing agents

Among the raw materials that are effective as soothing agents, the following active agents may be mentioned in a non-limiting manner: pentacyclic triterpenes, such as β-glycyrrhetinic acid and its salts and / or derivatives (glycyrrhetic acid monoglucuronide, stearyl glycyrrhetinate, acid 3- stearoyloxy glycyrrhetique), ursolic acid and its salts, oleanolic acid and its salts, betulinic acid and its salts; extracts of Paeonia suffruticosa and / or lactiflora, Rosmarinus officinalis, willowherb, Pygeum, Boswellia serrata, Centipeda cunnighami, Helianthus annuus, Cola nitida, clove and Bacopa moniera; salts of salicylic acid and in particular zinc salicylate; algae extracts, in particular Laminaria saccharina; Canola oil, Tamanu oil, Calophillum oil, unsaturated omega 3 oils such as rose hip, blackcurrant, ecchium, fish oil; α-bisabolol and chamomile extracts; allantoin; diesterphosphoric vitamin E and C; capryloyl glycine; tocotrienols; the piperonal; the aloe vera ; phytosterols; cortisone, hydrocortisone, indometacin beta methasone; strontium salts; substance P antagonists; CGRP antagonists; and bradykinin antagonists.

Among the substance P antagonists, there are the thermal waters and in particular the thermal water of the Vichy basin and the thermal water of La Roche Posay; bacterial extracts and in particular the extract of non-photosynthetic filamentous bacteria described in the patent application EP-0 761 204, preferably prepared from bacteria belonging to the order of Beggiatoales, more particularly to the genus Vitreoscilla and better still from a strain of Vitreoscilla filiformis.

A non-limiting example of a CGRP antagonist that can be used in the present invention consists of an extract of (preferably undifferentiated) cells from at least one plant of the Iridaceae family, obtained by in vitro culture. Iridacea belongs preferably to the genus Iris. In particular, it is preferred to use an aqueous extract of Iris pallida as described in EP-0 765 668. A nonlimiting example of a bradykinin antagonist that can be used in the present invention consists of an extract of at least one plant of the family Rosaceae, preferably cultivated in vivo. Preferably, according to the invention, a plant belonging to the genus Rosa is used, advantageously of the Rosa gallica species, more preferably a glyclycolic extract of Rosa gallica petals, as described in the patent application EP-O 909 556.

Anti-bacterial agents

The antibacterial agents that may be used in the present invention may especially be chosen from 2,4,4'-trichloro-2'-hydroxy diphenyl ether (or triclosan), 3,4,4'-trichlorobanilide and phenoxyethanol. , phenoxypropanol, phenoxyisopropanol, hexamidine isethionate, metronidazole and its salts, miconazole and its salts, itraconazole, terconazole, econazole, ketoconazole, saperconazole, fluconazole, clotrimazole, butoconazole, oxiconazole, sulfaconazole, sulconazole, terbinafine, ciclopirox, ciclopiroxolamine, undecylenic acid and its salts, benzoyl peroxide, 3-hydroxy benzoic acid, 4-hydroxy benzoic acid, phytic acid, N-acetyl-L-cysteine acid, lipoic acid, azelaic acid and its salts, arachidonic acid, resorcinol, 2,4,4'-trichloro-2'-hydroxy diphenyl ether, 3,4,4'-trichlorocarbanalide, octopirox, octoxyglycerine, octanoylglycine, aprylyl glycol, 10-hydroxy-2-decanoic acid, dichlorophenyl imidazol dioxolan and its derivatives described in patent WO9318743, famesol, phytosphingosines and mixtures thereof.

The preferred bacterial agents are triclosan, phenoxyethanol, octoxyglycerine, octanoylglycine, 10-hydroxy-2-decanoic acid, caprylyl glycol, famesol and azelaic acid.

The invention will now be illustrated by the following nonlimiting examples. In these examples, the amounts are indicated in weight percent. EXAMPLES

EXAMPLE 1 Demonstration of the Activity of Benzodiazepine Peripheral Antagonist Receptor Derivatives on Lipogenesis

PK11195 (1- (2-chlorophenyl) -N- (1-methyl-propyl) -3-isoquinoline carboxamide)) was tested on a model of immortalized human sebocytes in culture, from the SZ95 line described in Zouboulis, CC , Seltmann, H., Neitzel, H. & Orfanos, CE., Establishment and Characterization of an Immortalized Human Sebaceous Gland CeII A, J. Invest Dermatol., 113, 1011-1020 (1999).

This test consisted in measuring the amount of lipids produced by the sebocytes of the (confluent) line, in the presence or absence of active agents diluted in DMSO, so that the final amount of DMSO in the culture medium is 0.1%. After 2 days of treatment, the adherent cells are treated with NiIe Red (1 μg / ml). The lipid content is then quantified by measuring the fluorescence of the dye (excitation / emission pairs: 485-540 nm for neutral lipids, constitutive of sebum).

The tests are done in sixplicate (dosed and control products) and the experiment is repeated four times.

The table below shows the results obtained for PK11195.

* (0%, variation compared to control sebocytes without active ingredient)

A 102% increase in the amount of lipids characteristic of sebum was observed for the sebocytes treated with 100 μM of PK11195, compared to the control and a 78% increase in the quantity of lipids characteristic of sebum for the sebocytes treated with 10 μM PK11195. Example 2 Cosmetic and Dermatological Compositions

These compositions are prepared in a conventional manner for those skilled in the art. The amounts given in these examples are indicated in percentages by weight.

A. Lotion PK11195 1% Salicylic acid 1% Propylene glycol 5% Alcohol 87% Water qs 100%

This lotion can be used in the evening to revitalize the sebaceous function.

B. Cream

Compound No. 50 of formula (VIII) 1.0%

N-octanoyl-5-salicylic acid 1.0%

Methylparaben 0.1%

Propylparaben 0.1%

Lanoline 5.0%

Vaseline oil 4.0%

Sesame oil 4.0%

Cetyl alcohol 5.0%

Glycerol monostearate 2.0%

Triethanolamine 1.0%

Propylene glycol 5.0%

Carbomer 940 0.1%

Water qs 100%

This cream, used in bi-daily applications, helps to revive the radiance of dry skin. C. Ointment

Compound No. 36 of Formula (VIII) 1.0%

Salicylic acid 1.0%

Glycerol monostearate 3.0%

Propylene glycol 12.0%

Petrolatum 82.9%

Water qs 100%

D. Gel

Compound 2 (14) 1.0%

Salicylic acid 1.0%

Hydroxy propyl cellulose 1.0%

PPG-12-Buteth-16 2.0%

Triethanolamine 0.2%

Propylene glycol 5.0%

Alcohol 45.0%

Carbomer 940 0.2%

Water qs 100%

E. Emulsion oil in water

Compound 1 (16) 0.30%

Lyophilized extract of rosemary 0.20%

Glycerol stearate 2.00%

Polysorbate 60 1.00%

Stearic acid 1.40%

Triethanolamine 0.70%

Carbomer 0.40%

Olive oil 12.00%

Liquid fraction of shea butter 12.00%

Octyldodecanol 6.00%

Isononyl isononanoate 10.00%

Antioxidant 0.05%

Perfume 0.50%

Conservative 0.30%

Water qs 100% F. Cream

Compound 2 (105) 0.50%

Retinol 0.10%

Glycerin 3.00%

0.10% Xanthan gum

Oxyethylenated sorbitan stearate 0.90%

PEG-100 stearate and glyceryl stearate 2.10%

Cetyl alcohol 2.60%

Isononyl isononanoate 11.00%

Octydodecanol 15.00%

Butylhydroxytoluene 0.10%

Octocrylene 2.00%

Triethanolamine 0.30%

Tocopherol acetate 1.00%

Preservatives 0.60%

Water qs 100%

G. Cream

Compound 25 of formula (I-b5) 0.3%

O-octanoyl-6'-D-maltose * 2.0%

Triethanolamine 0.3%

PEG-100 stearate and glyceryl stearate 2.5%

PEG-50 stearate 2.5%

Cetyl alcohol 1.0%

Stearyl alcohol 3.0%

Isononyl isononaate 20.0%

Propylparaben 0.1%

Carbopol 0.3%

Water qs 100%

obtained as described in application EP-0 566438

Claims

1. Cosmetic use, for the treatment of dry skin or dry scalp, of a composition containing at least one peripheral benzodiazepine receptor antagonist. 2. Cosmetic use of at least one peripheral benzodiazepine receptor antagonist as defined in claim 1, as an agent for the treatment of dry skin or dry scalp. 3. Use of at least one peripheral benzodiazepine receptor antagonist as defined in claim 1, for the preparation of a composition intended to treat disorders related to dry skin or oligo-seborrheic dry scalp. 4. Use according to claim 3, characterized in that said disorders are dermatitis. 5. Use according to any one of claims 1 to 4, characterized in that said composition is applied to women over forty years. 6. Use according to any one of the preceding claims, characterized in that said peripheral benzodiazepine receptor antagonist represents 0.001 to 10% of the total weight of the composition. 7. Use according to any one of the preceding claims, characterized in that the composition is suitable for topical application to the skin. 8. Use according to any one of the preceding claims, characterized in that said composition also contains at least one desquamating agent. 9. Use according to claim 8, characterized in that said desquamating agent is chosen from: salicylic acid and its derivatives (including n-octanoyl 5-salicylic acid); α-hydroxy acids, such as glycolic acid, citric acid, lactic acid, tartaric acid, malic or mandelic; urea; gentisic acid; oligofucoses; cinnamic acid; Saphora japonica extract; resveratrol; IΕDTA; N-acyl-N, N ', N', ethylene diaminetriacetic acid; aminosulfonic compounds and in particular (N-2-hydroxyethylpiperazine-N-2-ethane) sulfonic acid (HEPES); 2-oxothiazolidine-4-carboxylic acid (procysteine) and its derivatives; derivatives of alpha amino acids of the glycine type (such as sodium methyl glycine diacetate); honey ; and sugar derivatives such as PO-octanoyl-6-D-maltose and N-acetyl glucosamine. 10. Use according to any one of the preceding claims, characterized in that said composition also contains a moisturizing agent. 11. Use according to claim 10, characterized in that said moisturizing agent is chosen from: ceramides, sphingoid-based compounds, lecithins, glycosphingolipids, phospholipids, cholesterol and its derivatives, phytosterols (stigmasterol, β- sitosterol, campesterol), essential fatty acids, 1-2 diacylglycerol, 4-chromanone, pentacyclic triterpenes such as ursolic acid, petrolatum and lanolin; thralose and its derivatives, hyaluronic acid and its derivatives, glycerol, pentanediol, sodium pidolate, serine, xylitol, sodium lactate, glycerol polyacrylate, ectoin and its derivatives, chitosan oligo- and polysaccharides, cyclic carbonates, N-lauroyl pyrrolidone carboxylic acid, N-α-benzoyl-L-arginine; sapogenins; and vitamin D and its derivatives. 12. Use according to any one of the preceding claims, characterized in that said composition also contains at least one soothing agent. 13. Use according to claim 12, characterized in that said soothing agent is selected from: pentacyclic triterpenes, such as β-glycyrrhetinic acid and its salts and / or derivatives, ursolic acid and its salts, the acid oleanolic acid and its salts, betulinic acid and its salts; extracts of Paeonia suffruticosa and / or lactiflora, Rosmarinus officinalis, willowherb, Pygeum, Boswellia serrata, Centipeda cunnighami, Helianthus annuus, Cola nitida, clove and Bacopa moniera; salts of salicylic acid and in particular zinc salicylate; algae extracts, in particular Laminaria saccharina; canola oil, Tamanu oil, calophillum oil, unsaturated omega 3 oils such as muscat rose, cassis, ecchium, fish; α-bisabolol and chamomile extracts; allantoin; diesterphosphoric vitamin E and C; capryloyl glycine; tocotrienols; the piperonal; the aloe vera ; phytosterols; cortisone, hydrocortisone, indometacin beta methasone; a strain of Vitreoscilla filiformis, an aqueous extract of Iris pallida and a hydroglycolic extract of Rosa gallica petals. 14. Use according to any one of the preceding claims, characterized in that said composition also contains at least one agent promoting proliferation and / or differentiation of keratinocytes. 15. Use according to claim 14, characterized in that said agent promoting the proliferation of keratinocytes is a retinoid, such as retinol and its esters. 16. Use according to any one of the preceding claims, characterized in that the composition also contains at least one antibacterial agent. 17. Use according to claim 16, characterized in that said antibacterial agent is chosen from: triclosan, phenoxyethanol, octoxyglycerine, octanoylglycine, 10-hydroxy-2-decanoic acid, caprylyl glycol, farnesol and azelaic acid. 18. Use according to any one of the preceding claims, characterized in that the composition is in the form of an oil-in-water emulsion.