LU87188A1 - COMBINATION OF PYRIMIDINE DERIVATIVES AND DURA AND / OR ALLANTOIN DERIVATIVES FOR INDUCING AND STIMULATING HAIR GROWTH AND REDUCING FALLING - Google Patents

Abstract

The combination comprises: a) a component (A) containing a pyrimidine derivative of formula: <IMAGE> in which R1 denotes <IMAGE> in which R3 and R4 denote hydrogen, alkyl, alkenyl, alkylaryl, cycloalkyl, R3 and R4 can also form a heterocycle with the nitrogen atom to which they are linked, and the group R2 is chosen from hydrogen, alkyl, alkenyl, alkoxyalkyl, cycloalkyl, aryl, alkylaryl, arylalkyl, alkylarylalkyl, alkoxyarylalkyl or haloarylalkyl, and b) a component (B) containing at least one urea derivative, the components (A) and (B) forming part of one and the same composition or being intended for use separately, either simultaneously or successively or separated by an interval of time, on the hair and the scalp.

Description

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Association of pyrimidine derivatives and urea derivatives and / or allantoin to induce and stimulate hair growth and reduce hair loss.

The invention relates to the combination of pyrimidine derivatives and urea and / or allantoin derivatives with a view to inducing and stimulating hair growth and reducing hair loss, as well as to compositions and methods implemented.

10 The activity of the hair follicles is cyclical.

The active anagen phase which lasts several years and during which the hair lengthens, is followed by a rest phase (telogen) of some 15 months. At the end of this rest period, the hair falls out and another cycle begins again. The hair is therefore constantly renewed; out of the 100,000 to 150,000 hairs in hair, at any given moment, around 10% are at rest and will therefore be replaced in a few months.

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In almost all cases, hair loss occurs on genetically predisposed subjects and it affects men in particular. More particularly, it is androgenetic or androgenic alopecia.

This alopecia is a disturbance of capillary renewal which leads, firstly, to an acceleration of the frequency of the cycles at the expense of the quality of the hair, 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 preferentially affected: in particular the temporal or frontal gulfs in men and in women there is a diffuse alopecia of the vertex.

It has already been proposed to use compounds such as 6-amino-1,2-dihydro-1 hydroxy-2-imino-4 piperidino-pyrimidine or "Minoxidil" in compositions making it possible to reduce or suppress the effect of 20 l alopecia and induce and stimulate hair growth and decrease hair loss.

The Applicant has now discovered that by combining pyrimidine derivatives with urea or its derivatives, in particular allantoin, it was possible to induce and stimulate hair growth in an improved manner and to have an action on the braking of their fall.

It also found that the compositions thus prepared exhibited better cutaneous bioavailability, as well as an increase in efficiency.

This effectiveness is characterized in particular by a higher activity compared to the pyrimidine derivatives used alone, the compounds associated with these derivatives having in themselves no action at level 3 of hair growth or of slowing down hair loss. .

The compositions are also characterized by a faster action and allow the pyrimidine derivatives to be used in much lower amounts.

In order to determine the effectiveness or the speed of action of the compositions for treating alopecia, the trichogram or the phototrichogram is generally used which makes it possible to determine, among other things, the percentage of hair in the anagen phase relative to the hair. in telogen phase.

An object of the invention therefore consists of the association of urea or 'urea derivatives such as allantoin with pyrimidine derivatives in order to induce or stimulate hair growth and reduce hair loss. .

Another object is constituted by cosmetic and / or pharmaceutical compositions containing such a combination.

The invention also relates to a cosmetic treatment process.

An object of the invention is also constituted by devices with several compartments 25 containing the association defined above.

Other objects of the invention will appear on reading the description and the examples which follow.

The combination according to the invention is essentially characterized in that it comprises: a) a component (A) containing, in a physiologically acceptable medium, at least one pyrimidine derivative corresponding to the formula: (I) ί .

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P

Η2Ν JSL NH

* 1 R3 d, in which Rj denotes the group -N ^ 10 Tl4 R3, R4, independently of one another, denote hydrogen, an alkyl, alkenyl, alkylaryl, cycloalkyl, R3 and R4 group which can also form a heterocycle with the nitrogen atom to which they are linked chosen from the aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, hexahydroazepinyl, heptamethyleneimine, octamethyleneimine, morpholine, alkyl (lower) -4 piperazidinyl groups, heterocyclic groups which may be substituted on the atoms Carbon through one to three lower alkyl, hydroxy or alkoxy groups; the group R2 is chosen from a hydrogen atom, an alkyl, alkenyl, alkylalkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, alkylarylalkyl, alkoxyarylalkyl or haloarylalkyl group, as well as the physiologically acceptable acid addition salts; and b) a component (B) containing in a physiologically acceptable medium, at least one compound corresponding to the formula: î NH2 - C - NH - R (II) in which R denotes hydrogen or the group of formula:

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Λ 5 Η Ν (III) Γ ~ \ as well as the salts and complexes of these compounds; components (A) and (B) forming part of a same composition or being intended to be used separately, either simultaneously, or successively or staggered in time in order to induce and stimulate hair growth and decrease their fall.

For the compounds of formula (I), the alkyl or alkoxy groups preferably denote a group having 1 to 4 carbon atoms; the alkenyl group preferably denotes a group having 2 to 5 carbon atoms; the aryl group preferably denotes phenyl and the cycloalkyl group preferably denotes a group having 4 to 6 carbon atoms.

The preferred compounds of formula (I) are more particularly chosen from the compounds in which R2 denotes hydrogen and R ·] denotes a group: R3 "\ ^ R4 in which R3 and R4 denote, independently of one another, hydrogen or a C1 to C4 alkyl group or R3 and R4 form a piperidinyl ring or alternatively ethyl groups and their salts, such as for example sulfate.

Mention may more particularly be made of the compound consisting of 6-amino-1,2-dihydro-1-hydroxy-2-imino-35 diethylamino-pyrimidine and the compound consisting of I-6-6-amino dihydro-1,2 hydroxy- 1 imino-2 piperidino-4 pyrimidine, also called "Minoxidil", as well as their salts such as for example sulfate.

The compounds of formula (II) or their particularly preferred salts or complexes are chosen from urea, allantoin or allantoin complexes such as allantoin-p-aminobenzoic acid, allantoin-galacturonic acid, allantoin-polygalacturonic acid, allantoin-glycyrrhetinic acid, allantoin-ascorbic acid, allantoin-biotin, allantoin-pantothenic acid, allantoin-succinic acid, allantoin-acetylmethionine, allantoin sodium ribonucleinate, allantoin-sodium succinate, allantoin-zinc undecÿlenate, allantoin-calcium pantothenate; aluminum complexes such as magnesium aluminum hydroxide allantoinate, aluminum hydroxychloride allantoinate, allantoin aluminum hydroxychloride p-aminobenzoate, and hydroxide complexes aluminum or aluminum hydroxychloride of biotin and allantoin, those of galacturonic or polygalacturonic acid and allantoin, and those of pantothenic acid and allantoin.

The pyrimidine derivatives of formula (I) are preferably used in component (A) in proportions of between 0.05 and 10% by weight and in particular between 0.05 and 5% by weight and preferably between 0, 5 and 4% by weight.

The derivatives of formula (II), their salts and their complexes are preferably used in proportions of between 0.1 and 30% by weight and preferably between 0.1 and 20% by weight and in particular between 0.1 and 10% by weight.

The pyrimidine derivatives of formula (I) when the components (A) and (B) are in the same t-composition, are used in proportions of between 0.05 and 6% by weight relative to the total weight of the composition and preferably between 0.1 and 5% by weight and in particular between 0.5 and 2% by weight.

The derivatives of formula (II) as well as their salts and their complexes are used in this case in the single composition in çjes proportions of between 0.05 and 30% by weight relative to the total weight of the composition and preferably between 0 , 05 and 10% by weight and in particular between 0.05 and 5% by weight.

The physiologically acceptable medium for components (A) and (B) is a medium which can be used in pharmacy and in cosmetics and can be constituted by water, a mixture of water and one or more organic solvents or by a mixture of physiologically acceptable organic solvents.

These compositions can be pressurized in aerosol devices in the presence of a propellant.

The solvents more particularly usable are chosen from alcohols, lower in C1-C4, such as ethyl alcohol, isopropyl alcohol, tert-butyl alcohol, alkylene glycols such as propylene glycol, alkyl ethers of mono- and dialkylene glycol such as more particularly ethylene glycol monoethyl ether, propylene glycol monomethyl ether and diethylene glycol monoethyl ether.

Physiologically acceptable media can be thickened or not. To thicken them, thickening or gelling agents that are well known in the art can be used, such as more particularly heterobiopolysaccharides such as xanthan gum. and scleroglucans, η ι 8 derivatives of cellulose, acrylic polymers crosslinked or not.

The solvents, when used in the aqueous medium, are preferably present in proportions of between 1 and 80% by weight relative to the total weight of the composition or of each of the components (A) and (B).

The thickeners, when used, are preferably present in proportions of between 0.1 and 5% by weight and in particular between 0.4 and 3% by weight relative to the total weight of each of the components (A ) and (B) when these components are used separately or relative to the total weight of the composition containing the components (A) and (B).

The compositions consisting either of one and / or the other of components (A) and (B) or of the composition containing the two components (A) and (B), can also contain any other adjuvants usually used in compositions intended for topical application for cosmetic or pharmaceutical use and more particularly preservatives, complexing agents, dyes, basifying or acidifying agents, surface-active, anionic, cationic, non-ionic, amphoteric agents or their mixtures, anionic, cationic, nonionic or amphoteric polymers as well as their mixtures. The pH of these compositions can vary between 4 and 9.

In component (A), the pyrimidine derivatives of formula (I) can be present, either in dissolved form in the physiologically acceptable medium or else in whole or in part in suspension in this medium, in particular in micronized form. In this case, the pyrimidine derivatives of formula (I) 9 may be present in the form of particles having a particle size less than 80 microns and preferably less than 20 microns and in particular less than 5 microns.

One embodiment of the invention consists in using the combination in accordance with the invention in the form of a composition containing the components (A) and (B).

Another preferred form of the invention consists in preserving in separate devices the components (A) and (B) and in preparing the composition containing the pyrimidine derivatives of formula (I) and the derivatives of formula (II) or their complex, extemporaneously just before use.

The invention may also consist in applying the components (A) and (B) separately, either successively or over time.

The combination according to the invention can be conditioned in this case in a device with several compartments also called a "kit" or necessary, a first compartment of which contains the component (A) containing the pyrimidine derivatives of formula (I) in a physiologically acceptable medium and the second compartment containing the component (B), containing in a physiologically acceptable medium the derivatives of formula (II) or their salts or complexes.

The combination in accordance with the invention makes it possible to treat hair loss therapeutically by acting more particularly on the dysfunction of the biological mechanisms at the origin of hair growth.

The treatment may consist in carrying out a daily application of the composition containing the components (A) and (B) defined above, either prepared · "10" in advance, or prepared at the time of use for a period of a few months and this at the rate of one application per day.

The combination according to the invention also has the advantage of being non-irritating, hydrating, bacteriostatic and keratinizing.

The combination in accordance with the invention also makes it possible to cosmetically treat the hair with a view to giving it greater vigor and a better appearance.

A subject of the invention is also the use of the combination as defined above for the preparation of a medicament optionally applied in two stages, intended for the treatment of alopecia and acting in particular on the dysfunction of the cycle hair.

The following examples are intended to illustrate the invention without, however, being limiting in nature.

* * s 11 EXAMPLE 1

A lotion with the following composition is prepared: 5 - Urea 3.0 g - Minoxidil 1.5 g - Ethanol / propylene glycol (95/5) qs 100.0 g »10 This composition is applied at a rate of 2 grams at the frequency of 'once a day.

15 EXAMPLE 2

A lotion with the following composition is prepared: 20 - Allantoin 0.23 g - Minoxidil 2.0 g - Propylene glycol 20.0 g - Ethyl alcohol 50.0 g - Preservative qs 25 - Water qs 100.0 g

This composition is applied in an identical manner to Example 1.

*% EXAMPLE 3 12

Two compositions (A) and (B) are respectively packaged containing: 5 Composition (A): - Minoxidil 2.0 g - Propylene glycol 20.0 g - Ethyl alcohol 50.0 g 10 - Water qs 100.0 g

Composition (B): 15 - Urea 6.0 g - Propylene glycol 20.0 g - Ethyl alcohol 50.0 g - Water qs 100.0 g 20 The extemporaneous mixture of compositions (A) and (B) is applied once per day at a rate of 2 g of each of the compositions.

Two compositions (A) and (B) are respectively packaged containing: 13 EXAMPLE 4 5 Composition (A): - Minoxidil with an average particle diameter of less than 2 microns 3.0 g - Crosslinked polyacrylic acid 10 PM = 3 million, sold under the name CAR30P0L 934 by the

GOODRICH '1.0g - Propylene glycol 4.5 g - 2-Amino-2-methyl-propanol-1 qs pH 7 15 - Preservative qs - Water qs 100.0 g

Composition (B): - Allantoin 0.60 g 20 - Preservative qs - Water qs 100.0 g

The extemporaneous mixture of compositions (A) and (B) is applied at the rate of 1 gram of mixture once a day.

s EXAMPLE 5

Two compositions (A) and (B) containing respectively:

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14 5 Composition (A): - Minoxidil with a particle diameter, average less than 2 microns 4.0 g - Crosslinked polyacrylic acid 10 PM = 3 million, sold under the name CARBOPOL 934 by the

GOODRICH 1.0 g - Propylene glycol 4.5 g - 2-amino-2-methyl-propanol-1 qs pH 7 15 - Preservative qs - Water qs 100.0 g

Composition (B): 20 - Urea 16.0 g - Ethyl alcohol 42.0 g - Water qs 100.0 g

Each day, the compositions are applied in succession staggered in time, in the morning 1 g of the composition (A), in the evening 1 g of the composition (B) or vice versa.

EXAMPLE 6 15 "

Two compositions (A) and (B) containing, respectively, are packaged: 5 Composition (A): -, Minoxidil 2.5 g - Ethanol / propylene glycol (95/5) qs 100.0 g 10 Composition (B): - Allantoin 0.3 g - Xanthan gum sold under the name KELTROL T 15 by the company KELCO 1.0 g - Preservative qs - Water qs 100.0 g 20 The compositions are applied in succession staggered in time, each day, 1 g of (A) in the morning, then 1 g of (B) in the evening or vice versa.

EXAMPLE 7 "

Two compositions (A) and (B) containing, respectively, are packaged; * 16 5 Composition (A): - Amino-6 dihydro-1,2 hydroxy-1. 2-imino-4-diethylamino pyrimidine 2.0 g - Propylene glycol 20.0 g 10 - Ethyl alcohol 50.0 g - Water qs 100.0 g

Composition (B): 15 - Allantoin 0.3 g - Propylene glycol 20.0 g - Ethyl alcohol 50.0 g - Preservative qs - Water qs 100.0 g 20

Each day, the compositions are applied in succession staggered in time, in the morning 1 g of the composition (A), in the evening 1 g of the composition (B) or vice versa, on the alopecic areas of the scalp.

Claims (14)

1. Combination intended to induce and stimulate hair growth and reduce hair loss, characterized in that it comprises: a) a component (A) containing in a physiologically acceptable medium, at least one pyrimidine derivative corresponding to the formula: (j) H 2. Association according to claim 1, characterized in that the compound of formula (I) consists of amino-6 dihydro-1,2-hydroxy-1 imino-2 piperidino-4 pyrimidine or "Minoxidil". 3. Association according to claim 1, characterized in that the compound of formula (I) consists of 6-amino-1,2-dihydro-1,2-hydroxy-2-imino-4-diethylamino-pyrimidine. 4. Association according to claim 1, characterized in that the compounds of formula 30 (II) are chosen from urea, allantoin, allantoin-p-aminobenzoic acid, allantoin-galacturonic acid, allantoin-polygalacturonic acid, allantoin-glycyrrhetinic acid, allantoin-ascorbic acid, allantoin-biotin, allantoin-pantothenic acid, allantoin-succinic acid, v 1 19> 11allantoin-acetylmethionine, 1 ' allantoin-sodium ribonucleinate, allantoin-sodium succinate, allantoin-zinc undecylenate, allantoin-calcium pantothenate; Allantoin-magnesium aluminum hydroxide, allantoinate aluminum hydroxychloride, alloinoin aluminum hydroxychloride p-aminobenzoate and complexes of aluminum hydroxide or aluminum hydroxychloride of biotin and allantoin, complexes of galacturonic or polygalacturonic acid and allantoin, complexes of pantothenic acid and allantoin. 5. Combination according to any one of claims 1 to 4, characterized in that the pyrimidine derivative of formula (I) is used in component (A) in proportions of between 0.05 and 10% by weight , and preferably between 0.05 and 5% by weight, and that the derivative of formula (II), its salts or its complexes is (are) present (s) in component (B) in proportions of between 0, 1 and 30% by weight 20 and preferably between 0.1 and 20% by weight. 5 NH2 - C - NH - R (II) in which R denotes hydrogen or a group of formula:? 10 ^> = 0 (III) / I OH H as well as the physiologically acceptable salts and complexes of these compounds; The components (A) and (B) forming part of the same composition or being intended to be used separately, either simultaneously, or successively or staggered in time on the hair and the scalp. 6. Association according to any one of claims 1 to 4, characterized in that the components (A) and (B) are present in the same composition and comprise the pyrimidine derivative of formula (I) in proportions included between 0.05 and 6% by weight relative to the total weight of the composition and preferably between 0.1 and 5% by weight and that the derivative of formula (II), its salts or its complexes is (are) present ( s) in proportions: between 30 0.05 and 30% by weight relative to the total weight of the composition and preferably between 0.05 and 10% by weight relative to the total weight of the composition. 7. Association according to any one of claims 1 to 6, characterized in that the physiologically acceptable medium consists of “4? > 20 water, a mixture of water and one or more organic solvents or with a mixture of pharmaceutically or cosmetically acceptable organic solvents. 8. Association according to claim 7, 5 characterized in that the solvents are chosen from lower C1-C4 alcohols, alkylene glycols, alkyl ethers of mono- and dialkylene glycol. . 9. Association according to any one of claims 10 to 8, characterized in that at least one of the physiologically acceptable media of the components (A) and (B) is thickened by means of thickening agents and / or gelling agents . 10. Association according to any one of claims 1 to 9, characterized in that at least one of the components (A) and / or (B) also contains at least one cosmetically or pharmaceutically acceptable adjuvant chosen from the agents preservatives, complexing agents, dyes, alkalizing or acidifying agents, anionic, cationic, nonionic or amphoteric surfactants and their mixtures, anionic, cationic, nonionic or amphoteric polymers as well as their mixtures . 10 H2N N NH 111 15 R1. in which R 1 denotes the group —is T 4 4 in which R 3 and R 4, independently of each other, denote hydrogen, an alkyl, alkenyl, alkylaryl, cycloalkyl group, R 3 and R 4 can also form a heterocycle with the nitrogen atom to which they are linked, chosen from the aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, hexahydroazepinyl, heptamethyleneimine, octamethyleneimine, morpholine, and (lower) -4 piperazidinyl groups, the heterocyclic groups being able to be substituted on the atoms carbon through one to three lower alkyl, hydroxy or alkoxy groups; the group R2 is chosen from a hydrogen atom, an alkyl, alkenyl, alkylalkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, alkylarylalkyl, alkoxyarylalkyl or haloarylalkyl group, as well as the physiologically acceptable acid addition salts; and * t 18 b) a component (B) containing in a physiologically acceptable medium, at least one derivative corresponding to the formula: jj> 11. Multi-compartment device or "kit" or necessary, characterized in that it comprises, in a first compartment, component (A) containing at least in a physiologically acceptable medium a pyrimidine derivative corresponding to the formula ( I) and in a second compartment, component (B) containing in a physiologically acceptable medium, at least one derivative of formula (II), its salts or its complexes. 12. Combination according to any one of claims 1 to 10 for its application as "21" medicament in the treatment of alopecia. 13. Use of the combination according to any one of claims 1 to 10 for the preparation of a medicament intended to treat alopecia. 14. A method of cosmetic treatment of hair or scalp comprising the application of the association defined in any one of claims 1 to 10.> Drawings: ........... boards _____pages including. ...... J ....... of guard ....... pages of description ....... JL. 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