FR2747039A1 - Use of N-aryl 2-hydroxy alkylamide(s) - Google Patents

Abstract

The use in cosmetic and pharmaceutical compositions of N-aryl-2-hydroxy alkyl-amides of formula (I), their isomers, acyl derivatives, or salts, is new. R1 = CN, halo or 1-4C halo-substituted alkyl; R2 = CN or halo; R3 = 1-2C alkyl, optionally substituted by halo; and R4 = H, 1-4C halo-substituted alkyl, or aryl optionally substituted by one or more of halo, OH, COOH, NO2, CN, 1-4C alkyl, 1-4C alkoxy, 1-4C alkanoyl or perfluoroalkyl.

Description

The present invention relates to the use as active ingredient, in a physiologically acceptable medium, in a cosmetic composition or for the preparation of a pharmaceutical composition, of an effective amount of N- (3,4 dicyano-phenyl) - 3, 3, 3-trifluoro-2-hyd roxy-2-methylpropionamide, intended to induce and / or stimulate hair growth and / or curb hair loss.

In humans, hair growth and hair renewal are mainly determined by the activity of the hair follicles. Their activity is cyclical and essentially comprises three phases, namely the anagen phase, the catagen phase and the telogen phase.

The active anagen phase or growth phase, which lasts several years and during which the hair lengthens, is followed by a very short and transient catagen phase which lasts a few weeks, then a rest phase, called the telogen phase, which lasts some months.

At the end of the rest period, the hair falls out and another cycle begins again. The hair is therefore constantly renewed, and of the approximately 150,000 hairs in hair, at each instant, around 10% of them are at rest and will therefore be replaced in a few months.

However, different causes can cause significant, temporary or permanent loss of hair. Alopecia is essentially due to a disturbance in capillary renewal which leads, firstly, to the acceleration of the frequency of the cycles at the expense of the quality of the hair and then of their quantity. There is a gradual depletion of the hair by regression of the so-called "terminal" hair at the down stage. Areas are affected preferentially, in particular the temporal or frontal gulfs in men, and in women, there is a diffuse alopecia of the vertex.

The term alopecia covers a whole family of damage to the hair follicle, the final consequence of which is the partial or general permanent loss of hair.

In a significant number of cases, early hair loss occurs in genetically predisposed subjects and it affects men in particular. More particularly, it is androgenetic or androgenic or androgenogenetic alopecia.

For many years, research has been carried out in the cosmetic or pharmaceutical industry on substances which make it possible to suppress or reduce alopecia, and in particular to induce or stimulate hair growth or to reduce hair loss.

With this in mind, a large number of very diverse active compounds have certainly already been proposed, such as, for example, 2,4-diamino 6-piperidinopyrimidine 3oxide or "Minoxidil" described in US Pat. Nos. 4,139,619 and US 4,596,812 or else its numerous derivatives such as those described for example in patent applications EP 0353123, EP 0356271, EP 0408442, EP 0522964, EP 0420707, EP 0459890, EP 0519819.

 It remains, in general, that it would be interesting and useful to be able to have active compounds other than those already known, potentially more active and / or less toxic.

This object and others are achieved by the present invention which relates to the use as active principle, in a physiologically acceptable medium, in a cosmetic composition or for the preparation of a pharmaceutical composition, of an effective amount of N - (3,4-dicyano-phenyi) -3,3,3-trifluoro- 2-hydroxy-2-methylpropionamide or of at least one of its isomers, of at least one of its acylated forms or still at least one of its salts, this compound or the pharmaceutical composition being intended to induce and / or stimulate hair growth and / or slow down their fall.

This compound has remarkable activities which justify its use as an active ingredient to induce and / or stimulate hair growth and / or slow down hair loss.

He is indeed an excellent opener of potassium channels, main property of
Minoxidil, the only compound recognized to date as effective in the treatment of hair loss.

 It is also a good receptor antagonist of androgens, androgens being responsible for a particularly widespread form of alopecia, androgen-dependent alopecia.

To the knowledge of the Applicant, it has never been proposed in the prior art the use of this compound with mixed activity, opener of potassium channels I anti-androgen, to fight against hair loss.

The effective amount of compound to be used obviously corresponds to the amount necessary to obtain the desired result. Those skilled in the art are therefore able to assess this effective amount which depends on the nature of the compound used and the person thus treated.

To give an order of magnitude, according to the invention, in a cosmetic composition, the compound may be present at a concentration of between 104% and 5%, by weight relative to the total weight of the composition and preferably between 10- 3% and 1%. In the preparation of a pharmaceutical composition, the compound can be used at a concentration between 10-5% and 10% by weight relative to the total weight of the composition and preferably between 1 on2% and 2%.

The pharmaceutical composition according to the invention can be administered parenterally, enterally or even topically. Preferably, the pharmaceutical composition is administered topically.

The physiologically acceptable medium in which the active agent is used according to the invention can be anhydrous or aqueous. The term “anhydrous medium” means a solvent medium containing less than 1% of water. This medium may consist of a solvent or a mixture of solvents chosen more particularly from lower C2-C4 alcohols such as ethyl alcohol, alkylene glycols such as propylene glycol, and alkyl ether alkylene glycols or dialkylene glycols, including the alkyl or alkylene radicals contain from 1 to 4 carbon atoms. The term “aqueous medium” means a medium consisting of water or a mixture of water and another physiologically acceptable solvent, chosen in particular from the organic solvents mentioned above. In the latter case, these other solvents, when they are present, represent approximately 5 to 95% by weight of the composition.

 It is possible that the physiologically acceptable medium may contain other adjuvants usually used in the cosmetic or pharmaceutical field, such as surfactants, thickening or gelling agents, cosmetic agents, preservatives, alkalizing or acidifying agents well known. in the prior art, and in sufficient quantities to obtain the desired form of presentation, in particular more or less thickened lotion, gel, emulsion, or cream. The use can optionally be done in a pressurized aerosol form or sprayed from a pump bottle.

 It is also possible to use, in combination with the active ingredient, compounds which further improve the activity on regrowth and / or on the braking of hair loss, and which have already been described for this activity.

Among these latter compounds, there may be more particularly mentioned without limitation
- nicotinic acid esters, including in particular tocopherol nicotinate, benzyl nicotinate and C1-C6 alkyl nicotinates such as methyl or hexyl nicotinates;
- pyrimidine derivatives, such as 2,4-diamino 6-piperidinopyrimidine 3oxide or "Minoxidil" described in patents US 4 139619 and US 4596812;
- agents promoting hair regrowth such as those described by the applicant in the European patent application published under the number 0648488;
- antibacterial agents such as macrolides, pyranosides and tetracyclines, and in particular Erythromycin;
- calcium antagonists, such as Cinnarizine, Diltiazem,
Nimodipine and Nifedipine;
- hormones, such as Estriol or analogues, or Thyroxine and its salts;
- steroidal anti-inflammatory agents, such as corticosteroids (for example: 'Hydrocortisone)
- antiandrogenic agents, such as Oxendolone, Spironolactone,
Diethylstilbestrol and Flutamide
- steroidal or non-steroidal 5-a-reductase inhibitors such as Finasteride
- potassium agonists such as Cromakalim and Nicorandil.

To the above list, other compounds can also be added, namely for example Diazoxide, Spiroxazone, phospholipids such as lecithin, linoleic and linolenic acids, salicylic acid and its derivatives described in the French patent. FR 2 581 542, like the derivatives of salicylic acid carrying an alkanoyl group having from 2 to 12 carbon atoms in position 5 of the benzene ring, hydroxycarboxylic or ketocarboxylic acids and their esters, lactones and their corresponding salts,
Anthralin, carotenoids, eicosatetrayenoic and eicosatriyenoic acids or their esters and amides, vitamin D and its derivatives, extracts of plant or bacterial origin.

It is also conceivable that the composition comprising at least one compound as defined above is in liposomal form, as notably described in patent application WO 94/22468 filed on October 13, 1994 by the company Anti Cancer Inc. Thus, the compound encapsulated in liposomes can be delivered selectively to the hair follicle.

The cosmetic composition according to the invention is to be applied to the alopecic areas of the scalp and hair of an individual, and is optionally left in contact for several hours and is optionally to be rinsed off. It is possible, for example, to apply the composition containing an effective amount of at least one compound as defined above, in the evening, to keep it in contact overnight and, if necessary, to shampoo in the morning. These applications can be renewed daily for one or more months depending on the individual.

Thus, the subject of the present invention is also a method of cosmetic treatment of the hair and / or scalp, characterized in that it consists in applying to the hair and / or the scalp, a composition comprising an effective amount of N- (3,4-dicyano-phenyl) -3,3,3-trifluoro-2-hydroxy-2methylpropionamide, to leave it in contact with the hair and / or scalp, and optionally to rinse.

The treatment process has the characteristics of a cosmetic process insofar as it makes it possible to improve the aesthetics of the hair by giving it greater vigor and an improved appearance.

We will now give by way of illustration examples which cannot in any way limit the scope of the invention.

Example 1. IC50 of N- (3,4-dicyano-phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropionamide determined for its effect on potassium channels and on androgen receptors
The IC50 corresponds to the concentration which reduces by 50% either an induced pharmacological mechanism, such as muscle contraction, or the attachment of a molecule to its membrane receptor.

To determine the IC50 of the compounds for their effect on the potassium channels, these were tested according to the methods of Newgreen et al. (Br. J; Pharmacol., 1990, 100, 605-613), Bray et al. (Arch. Pharmacol., 1991, 344, 351-359), and Wickerden et al. (Br. J; Pharmacol., 1991, 103, 1148-1152):
To determine the IC50 of the compounds for their effect on the androgen receptors, these were tested according to the method of Schilling and Liao ('7hue
Prostate ", 1984, 5, 581-588):
Values are given in zM.

A: N- (3,4-dicyano-phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropionamide.

B: N- (4-nitro-3-trifluoromethyl-phenyl) - 3,3,3-trifluoro-2-hyd roxy
2-methylpropionamide;
C: N- (4-cyano-phenyl) - 3, 3, 3-trifluoro-2-hydroxy-2-methylpropionamide.

Compounds B and C with structures close to those of the compound of the invention were tested by way of comparison.

Compound K channels + Androgen receptors
A 1 10
B>10> 10
C 10> 10
N- (3, 4-d icyano-phenyl) -3, 3, 3-trifluoro-2-hyd roxy-2-methylpropionamide (compound A) has a good affinity for the androgen receptor and an excellent channel-opening effect potassium, whereas in comparison the compounds B and C, close by their structure have a bad affinity for the androgen receptor and a bad opening effect of potassium channels.

Example 2:
Examples of compositions containing N- (3, 4-d icyano-phenyl) -3, 3 '3-trifluoro-2-hydroxy-2-methylpropionamide.

These compositions are obtained by the usual techniques commonly used in cosmetics or in pharmacy.

Anti-hair loss lotion - N- (3,4-dicyano-phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropionamide 0.1 g - Propylene glycol 10.0 g - Isopropyl alcohol qs 100.0 g
1 ml of this lotion is applied to the scalp, once or twice a day.

Niosome gel.

Chimexane NSO 1.8 g
Monosodium stearoylglutamate 0.2 g N- (3,4-d icyano-phenyl) -3, 3, 3-trifluoro-2-hyd roxy-2-methylpropionamide 1.0 g
Carbomer 0.2 g
Triethanolamine qs pH = 7
Preservatives qs
Perfumes qs
Demineralized water qs 100.0 g
Apply this gel to the scalp once or twice a day.

Anti-hair loss lotion: - N- (3,4-dicyano-phenyl) -3, 3,3-trifluoro-2-hyd roxy-2-methylpropionamide 0.5 g - Propylene glycol 30.0 g - Ethyl alcohol 40.5 g -Water qs 100.09
This lotion is applied to the scalp, once or twice a day, at the rate of 1 ml per application.

Thickened hair loss lotion - N- (3,4-dicyano-phenyl) -3, 3, 3-trifluoro-2-hydroxy-2-methylpropionamide 1.0 g - Kawaïne 2.0 g - Hydroxypropylcellulose sold by the company
Hercules under the name Klucel G 3.5 g - Ethyl alcohol qs 100.0 g
This thickened lotion is applied to the scalp, once or twice a day, at the rate of 1 ml per application.

Niosome lotion:
Chimexane NLO 0.475 g
Cholesterol 0.475 g
Monosodium stearoylglutamate 0.05 g
N- (3,4-d icyano-phenyl) -3, 3,3-trifluoro-2-hydroxy-2-methylpropionamide 1.0 g
Preservatives qs
Dyes qs
Perfume qs
Demineralized water qs 100.0 g
This lotion is applied to the scalp, once or twice a day, at the rate of 1 ml per application.

fall protection lotion.

- N- (3,4-dicyano-phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropionamide 1.5 g - Propylene glycol monomethyl ether sold under the
name Dowanol PM by the company Dow Chemical 20.0 g - Hydroxypropylcellulose sold by the company Hercules
under the name Klucel G 3.0 g - Ethyl alcohol 40.0 g - Water qs 100.0 g
This thickened lotion is applied to the scalp, once or twice a day, at the rate of 1 ml per application.

With each of the compositions described in the above examples, it has been found, after several months of treatment and depending on the subjects treated, a slowing down of hair loss and / or a regrowth effect.

Claims (4)

1. Use, in a cosmetic composition or for the preparation of a pharmaceutical composition, of an effective amount of N- (3,4-dicyano-phenyl) 3,3,3-trifluoro-2-hydroxy-2-methylpropionamide or at least one of its isomers, or at least one of its acylated forms or also at least one of its salts, this compound or the pharmaceutical composition being intended to induce and / or stimulate hair growth and / or slow hair loss. 2. Use in a cosmetic composition according to the preceding claim, characterized in that the compound present is used at a concentration between 104% and 5%, by weight relative to the total weight of the composition and preferably between 10- 3% and 1%. 3. Use for the preparation of a pharmaceutical composition according to claim 1, characterized in that the compound is used at a concentration of between 10-5% and 10% by weight relative to the total weight of the composition and preferably between 1 on2% and 2%. 4. Cosmetic treatment process for the hair and / or scalp, characterized in that it consists in applying to the hair and / or the scalp, a cosmetic composition as defined in any one of claims 1 and 2 to leave it in contact with the hair and / or scalp, and optionally to rinse.