LU87304A1 - NOVEL DERIVATIVES OF UREYLENE TRIAMINO-2,4,6 PYRIMIDINE OXIDE-3, THEIR PREPARATION AND THEIR USE IN COSMETICS AND DERMOPHARMACY - Google Patents

Abstract

Compound corresponding to the formula: <IMAGE> in which: R3 and R4 which are identical or different, denote hydrogen, alkyl, alkenyl, cycloalkyl, aryl or aralkyl or a heterocyclic ring; R1 and/or R2, independently of each other, denote hydrogen, a carbamoyl group, of formula: <IMAGE> provided, however, that R1 and R2 do not simultaneously denote a hydrogen atom; R7 and/or R8, independently of each other, denote hydrogen, alkyl, cycloalkyl, aryl or aralkyl which are substituted by a hydroxyl, amino and/or carboxylic group, a sugar residue or a heterocyclic ring.

Description

New derivatives of ureylene-2,4,6-triamino pyrimidine oxide-3, their preparation and their use in cosmetics and dermopharmacy.

The present invention relates to new pyrimidine oxide-3 derivatives, their preparation and to cosmetic or pharmaceutical compositions intended in particular for use in topical application.

In the prior art, piperidino-6 diamino-2,4 pyrimidine oxide-3 or "Minoxidil" is already known for its antihypertensive agent properties, but also for its use in the treatment of hair loss. , alopecia areata, scaling dermatitis, alopecia, etc.

The Applicant had discovered new pyrimidine oxide-3 derivatives which are mono- or diureas in positions 2 and / or 4 of 2,4,6-triamino pyrimidine oxide-3.

These compounds have been the subject of a patent application in Luxembourg No. 86 959.

The monoured compounds were synthesized by addition of an isocyanate or by reaction of a carbamoyl chloride on one of the two amine functions of the 2,4,6-triamino pyrimidine oxide-3.

The diurea compounds were synthesized using an excess of isocyanate.

In the two aforementioned cases / from isocyanates or carbamoyl chlorides, the ureas obtained could not contain hydrophilic groups such as hydroxyl or amine radicals; these radicals being incompatible with an isocyanate or carbamoyl chloride function. In addition, the number of commercial carbamoyl chloride is very limited. Thus, the carbamoyl chlorides in which the nitrogen atom is part of a cycle are not sold.

The Applicant has just discovered new products derived from pyrimidine oxide-3 which are mono- or di-ureas in positions 2 and / or 4 of triamino-2,4,6 pyrimidine oxide-3 whose atom d nitrogen of the urea function which is not linked to the pyrimidine nucleus is substituted or disubstituted by a radical comprising one or more hydroxyl or amine function (s) or forms when it is disubstituted a heterocycle comprising one or more heteroome (s) .

She discovered that these new ureas were particularly effective in regrowing hair and could be used in particular in the treatment of diseases of the scalp, such as alopecia areata, hair loss, flaky dermatitis, alopecia.

The subject of the invention is therefore new derivatives of 2,4,6-triamino pyrimidine oxide-3.

Another object of the invention is constituted by their preparation process.

The invention also relates to the cosmetic and / or pharmaceutical compositions using these compounds.

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

The compounds in accordance with the invention are essentially characterized by the fact that they correspond to the formula:

in which: R3 and R4, identical or different, denote a hydrogen atom, an alkyl radical, linear or branched in Cy-Cyg, alkenyl having 2 to 18 carbon atoms, cycloalkyl having 5 to 8 carbon atoms, optionally substituted by one or more lower alkyl group (s), a cycloalkene group, the alkyl, alkenyl or cycloalkyl groups possibly being themselves substituted by one or more hydroxyl group (s), R3 and / or R4 also denote an aryl group or aralkyl, corresponding to the formula:

in which: n can take the values from 0 to 4 and where R5 and / or Rg, independently of one another, denote hydrogen, a lower C 1 -C 6 alkyl group, a nitro, hydroxyl, alkoxy group or a halogen atom, or a carboxylic group, as well as the salified forms, esters and amides thereof, R3 and R4, taken together with the nitrogen atom to which they are linked, can form a heterocycle of 3 to 7 carbon atoms,

R1 and / or R2, independently of one another, denote a hydrogen atom or a carbamoyl group, of formula:

provided however that Ri and R2 do not simultaneously denote a hydrogen atom, and in which: R7 and / or Rß denote, independently of one another, a hydrogen atom, an alkyl group, linear or branched in Ci-Cig, substituted by one or more hydroxyl and / or amino group (s), this alkyl chain possibly being able to be interrupted by one or more heteroatom (s) such as a sulfur, nitrogen or oxygen, a cycloalkyl, aryl or aralkyl group, substituted by a hydroxyl, amino and / or carboxylic group; R7 and / or Rg can also denote a sugar residue; R7 and Rg can form, with the nitrogen atom to which they are attached, a heterocycle comprising one or more heteroome (s).

The compounds in accordance with the invention can also exist in the tautomeric form corresponding to the following formulas (IA) and (IB):

It is understood that these tautomeric forms (I), (IA) and (IB) can be presented in the mixture in variable proportions and one can be preponderant compared to the others depending on the nature of the substituents R3, R4, Rlr r2 or depending on the nature of the solvent.

In accordance with the invention, the alkyl radicals having from 1 to 18 carbon atoms, substituted by one or more hydroxyl or amino group (s) are preferably chosen from the 2-hydroxy, 2-dihydroxy radicals, 3 propyl, 2-hydroxy propyl, 2-hydroxy ethoxyethyl, 2-hydroxyethylaminoethyl, 2-amino ethyl.

Cycloalkyl radicals, substituted by one or more hydroxyl or amino group (s) are preferably Cg-Cg cycloalkyl groups. When R7 and Rg form with the nitrogen atom to which they are attached a heterocycle comprising one or more heteroatorae (s), the groups morpholino, piperidino, pyrrolidino, piperazino, N-alkyl 4'-piperazino are preferably understood, in which the alkyl group in position 4 'preferably contains 1 to 6 carbon atoms, one of which is optionally substituted by a hydroxyl group or corresponds to a thiazolidine.

The preferred compounds, in accordance with the invention, are those in which one of the groups R 1 or R 2 denotes a hydrogen atom, the other group R 2 or R 1 being other than hydrogen and correspond to the following formula (la):

in which R3, R4, R7 and Rg have the meanings defined in formula (i) above.

The particularly preferred compounds in accordance with the invention are the compounds of formula (Ib) and their isomers of formula (Ic):

in which R7 and Rg have the meanings indicated above.

The compounds according to the invention and in particular the compounds of formula (Ia) defined above are prepared according to a first variant, according to a process essentially consisting in treating 11 amino-7-chloro-5-oxadiazolo-1,2,4 / 2,3c / pyrimidinone-2 of formula (iVa) or its isomer of formula (IVb):

with an amine of formula:

in which R7 and Rg have the meanings indicated above, then in treating the resulting derivative with an amine of formula:

in which R3 and R4 have the meanings defined above.

The process according to the invention can be illustrated by the following reaction scheme A.

REACTIONAL SCHENiA A

The first stage of this process consists in treating the 7-amino-chloro-5-2H-oxadiazolo-1,2,4 [2,2c] pyrimidinone-2 with an amine of formula:

in which R7 and Rg have the meanings defined in formula (I) and corresponds to the opening of the oxadiazolone cycle. Cn obtains the monourea derivative of formula (V) whose amino function in position 4 is transformed into urea.

The second step consists in reacting the urea of formula (V) on an amine of formula:

to obtain the compounds according to the invention and more particularly the monoured compounds of formula (Ia).

Depending on the basicity and the number of equivalents of the amine used, it is possible to directly obtain the compounds of formula (la) for which the amino groups

are the same using an excess of amine.

Depending on the nature of the group

desired, it is preferable to proceed in two stages and to react the urea corresponding to the formula (V) with the corresponding amine.

This process is particularly advantageous in the case where the amino group

is very polar and the amino group

denotes a morpholino, pipêrazino, N-alkyl-4 'pipêrazino, Ν, Ν-diethylamino, pipêridino or pyrrolidino group.

According to a second variant, the compounds according to the invention are synthesized, corresponding to formula (Ib), as illustrated in the following scheme B, with a quantitative yield, by treating the 7-amino piperidino-5-2H-oxadiazolo -1,4.4 [2,3c / pyrimidinone-2 of formula (Via):

with an amine equivalent of formula

in which R7 and Rß have the meanings indicated above, as illustrated in the following reaction scheme B:

REACTIONAL DIAGRAM B

The isomeric compounds corresponding to the formula (Ie) in accordance with the invention can be obtained by treating the 7-amino piperidino-5-2H-oxadiazolo-1,2,4 [2., 3a7 pyrimidinone-2 of formula ( VIb) with the amine of formula

as illustrated in the following reaction scheme C:

REACTIONAL DIAGRAM C

This synthesis is more particularly suitable when using a primary amine (R7 or R5 denoting a hydrogen atom).

Indeed, when a secondary amine such as piperidine is used, urea (le) is obtained, but the latter, unstable, evolves towards its isomer (Ib).

The present invention also relates to new derivatives of oxadiazolo-1,2,4 / 2,3ç7 pyrimi-dinone-2 and their isomers, characterized in that they correspond to the following formulas (IVa) and (IVb) :

These derivatives constitute intermediate compounds used for the preparation of the compounds of formula (I) in accordance with the invention.

The intermediate compounds of formulas (IVa) and (IVb), in accordance with the invention, are prepared according to a process consisting in treating in a first step, 2,4-chloro-6-chloro-3-pyrimidine pyrimidine of formula (VII) :

with a carbamoyl chloride of formula:

in which R denotes an alkyl group, in a polar aprotic solvent to obtain the mixture of isomeric monourea derivatives, of formulas (IXa) and (iXb):

In a second step, the mixture of monourea derivatives (IXa) and (iXb) is treated with an excess of carbamoyl chloride of formula (VIII) to obtain the amino-7 chloro-5-2H-oxadiazolo-1,2, 4 [2,3c / pyrimidinone-2 of formula (IVa) and its isomer of formula (IVb).

This process can be represented according to the following reaction scheme D:

AT

REACTIONAL DIAGRAM D

During the first step, chlorure, Ν-dimethylcarbamoyl chloride is preferably used. The reaction is carried out in a polar aprotic solvent such as dimethylsulfoxide, tetrahydro-furan or dioxane.

The mixture of the monourées compounds of formulas (IXa) and (IXb) is obtained in proportions varying according to the solvent used.

Thus, by using dioxane as solvent, the compound of formula (IXb) is in the majority.

It is not necessary to purify this mixture to carry out the second step of this process.

When the latter is treated in an excess of carbamoyl chloride of formula (VIII), the mixture consisting of oxadiazolo-1,2,4 / 2,3çj pyrimidinone-2 and oxadiazolo-1,2,4 / 2,3a / pyrimidinone-2 is rich in oxadiazolo-1,2,4 / 2,3cƒ pyrimidinone-2.

It is therefore possible to obtain, by this process with good yield, the pure amino-chloro-5-2K-oxadiazolo-1,2,4 / 2,3c / pyrimidinone-2 of formula (IVa).

The compounds according to the invention can be used in the cosmetic or pharmaceutical field, in particular in topical applications.

The Applicant has surprisingly found that the compounds in accordance with the invention have a cardiovascular effect which is clearly lower than that of the compounds whose amino functions in position 2 and / or 4 are free. They also exhibit good stability.

Cosmetic or pharmaceutical compositions which constitute another object of the invention are used, in particular for treating the scalp and more particularly alopecia areata, hair loss, alopecia, flaky dermatitis, etc.

These compositions are essentially characterized by the fact that they contain, in a pharmaceutically or cosmetically suitable support for topical application, at least one compound corresponding to formula (I) or to the tautomeric forms thereof and / or one of its salts , esters or amides.

The compositions in accordance with the invention may comprise any support suitable for topical application and compatible with the active substance, the compounds possibly being in this support, either in the dissolved state or in the dispersed state.

The compositions intended for use in pharmacy are in the form of ointments, tinctures, creams, ointments, powders, patches, soaked pads, solutions, emulsions, lotions, gels, sprays or suspensions. They can be either anhydrous or aqueous, depending on the clinical indication.

The compounds are present in these compositions in concentrations of between 0.1 and 10% by weight and in particular of between 0.2 and 5% by weight.

The cosmetic compositions are in particular intended to be used in the form of lotions, gels, soaps or shampoos and contain, in a physiologically acceptable carrier, at least one compound of formula (I) or one of its salts, esters or amides .

The concentration of the compounds of formula (I) is preferably in these cases between 0.01 and 5% by weight, in particular between 0.05 and 3% by weight.

The compositions in accordance with the invention may contain various additives usually used in cosmetics or in pharmacy and which are inert with respect to the active substance. Mention may be made for this purpose of moisturizing agents such as thiamorpho-linone and its derivatives or urea; antiseborrhoeic agents such as S-carboxymethylcysteine, S-benzylcysteamine and their derivatives, tioxolcne; agents promoting hair regrowth such as phenytoin (diphenyl-5,5 imidazolinedione-2,4) or oxypropanium iodide, retinoic acid and its derivatives, the compounds described in patent applications EP-A-0220118 , EP-A-0232199, FR-A-2600064, FR-A-2601002, FR-A-2599031, EP-A-0260162, GB-A-2197316, anthralin and its derivatives; steroidal or nonsteroidal anti-inflammatory agents; carotenoids and, more particularly, ß-carotene, eicosatetraynoic-5,8,11,14 and eicosa-triynoic-5,8,11 acids and their esters and amides.

The compositions can also contain preserving agents, stabilizing agents, pH regulating agents, agents modifying osmotic pressure, emulsifying agents, UV-A and UV-B filters, antioxidants such as 11σ (-tocopherol, butylhydroxyanisole or butylhydroxytoluene.

The subject of the invention is also a method of cosmetic treatment of the hair consisting in applying to the scalp at least one composition as defined above.

Another object of the invention is finally constituted by the use of the compounds of formula (I) in the preparation of a medicament for the treatment of alopecia areata, hair loss, flaky dermatitis.

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

EXAMPLE 1

Preparation of N- (4-amino-3-chloro-3-oxide pyrimidinyl-2) N ', N1-dimethylurea and its N- isomer (2-amino-chloro-6-3-oxide 3-pyrimidinyl-4) Ν', Ν1- dimethylurea.

To a suspension of 50 g of 2,4-diamino-6-chloro-3-oxide pyrimidine in 500 cm 3 of anhydrous dioxane, stirred at ordinary temperature, 1.2 equivalent of N, N-dimethyl-carbamoyl chloride is quickly added. The mixture is then brought to a temperature of 70 ° C for · 2 hours. The starting material is completely transformed. The mixture is cooled by an ice bath. The crystallized product is drained, washed with ethyl ether, then dried under reduced pressure.

70 g of N- (4-amino-chloro-3-oxide 3-pyrimidinyl-2) N1, N'-dimethylurea, containing about 10% of its isomer, are obtained in the form of beige crystals with a melting point of 192 ° vs.

The NMR spectrum corresponds to the expected structures.

EXAMPLE 2

Preparation of amino-7 chloro-5-2H-oxadiazolo-1,2,4 / 2,3c7 pyrimidinone-2.

To a suspension of 50 g of N- (4-amino-6-chloro-3-oxide-2-pyrimidinyl) N 1, N'-dimethylurea in 500 cm3 of dioxane stirred at ordinary temperature, 2 equivalents of Ν, chlorure chloride are added -dimethylcarbamoyl. The mixture obtained is left overnight at room temperature, then brought for 24 hours to a temperature between 70 ° and 80 ° C. At the end of the reaction, the medium becomes practically homogeneous. It is then poured directly into 800 cm3 of isopropyl ether stirred at 0 ° C.

The expected product crystallizes. It is drained, washed several times with isopropyl ether, then dried under reduced pressure.

33.3 g of amino-7 chloro-5-2H-oxadiazolo-1,2,4 / 2,3c / pyrimidinone-2 are obtained in the form of beige crystals with a melting point of 247eC.

The NMR spectrum corresponds to the expected structure.

Elementary analysis: C5H3CI N4O2 CH N 0 Cl

Calculated 32.19 1.62 30.03 17.15 19.01

Found 32.38 1.60 30.19 16.97 18.88

EXAMPLE 3

Preparation of N- (2-amino-6-chloro-3-oxide pyrimi-dinyl-4) N 11- (pentanediyl) urea.

To a suspension of 300 mg of amino-7 chloro-5-2H-oxadiazolo-1,2,4 [2,3c] pyrimidinone-2 in 20 cm3 of ethanol, stirred at ordinary temperature under an inert atmosphere, 2 piperidine equivalents. The reaction is carried out in a heterogeneous phase and after three hours, the starting product is completely transformed. The solid is drained, washed with ethanol and dried.

320 mg of N- (2-amino-6-chloro-3-oxide-pyrimidinyl-4) N ', N' - (pentanediylJurea are obtained in the form of pale yellow crystals, with a melting point of 226 ° C.

Elementary analysis: Cioh14c1 N5 ° 2 C H Cl N 0

Calculated 44.20 5.13 13.05 25.78 11.78

Found 44.27 5.20 13.13 25.98 12.05

EXAMPLE 4

Preparation of N- (piperidino-6 amino-2-oxide 3-pyrimidinyl-4) N ', N' - (pentanediyl) urea.

To a suspension of 200 rag of amino-7 chloro-5-2H-oxadiazolo-1,2,4 j2,3cj pyrimidinone-2 in 15 cm3 of n-butanol, 2 equivalents of piperidine are added. The stirred mixture is brought to a temperature of 80 ° C. A quarter of an hour later, the reaction medium is homogeneous. After two hours, the starting material is completely transformed. The reaction mixture is then poured into water. The organic phase is decanted, washed with a solution of IN hydrochloric acid, then with water and finally dried over sodium sulfate.

The butanol solution is concentrated until the product begins to crystallize, then this solution is frozen. The solid is drained and washed with acetone, then dried.

250 mg of N- (piperidino-6 amino-2-oxide-3 pyrimidinyl-4) N ', N' - (pentanediyl Jurea are obtained in the form of beige crystals with a melting point of 225 ° C.

This product is analyzed in hydrated form.

Elementary analysis: C-15H24N6 ° 2/1/2 H20 C H N 0

Calculated 54.86 7.37 25.59 12.18

Found 54.77 7.33 25.63 11.50

This urea is also synthesized by treating N- (2-amino-chloro-6-3-oxide-pyrimidinyl-4) N ', N' - (pentanediyl Jurea from Example 3, with 2 equivalents of piperidine in butanol, brought to 80 ° C. The N- (piperidino-6 amino-2-3-oxide-pyrimidinyl-4) N ', N1- (pentanediyl) urea is quantitatively obtained.

This N- (piperidino-6 amino-2-3-oxide pyrimidinyl-4) Ν ', Ν' - (pentanediyl) urea is also prepared from amino-7 (pipêridino) -5-2H-oxadiazolo-1, 2,4 / 2,3c / pyrimidinone-2.

A suspension of 1 g of this product is carried in 20 cm 3 of ethanol with 2 equivalents of piperidine at 80 ° C for two hours. The reaction medium very quickly becomes homogeneous.

The solution is then concentrated until the first crystals appear, then ethyl ether is added so that the rest of the product crystallizes. The solid is drained, washed with ether and dried.

1.25 g of N- (piperidino-6 amino-2-oxide-3 pyrimidinyl-4) N ', N' - (pentanediyl) urea are obtained in the form of pearly needles with a melting point of 225 ° C.

Elemental analysis: C15H24N6O2

C H N O

Calculated 56.43 7.55 26.23 9.99

Found 56.35 7.56 26.28 10.23

EXAMPLE 5

Preparation of N- (2-amino-6-chloro-3-oxide pyrimi-dinyl-4) N '- (hydroxyethyl) urea.

To a suspension of 1 g of amino-7 chloro-5-2H-oxadiazolo-1,2,4 / 2,3çj pyrimidinone-2 in 50 cm3 of anhydrous ethanol, 4 equivalents of ethanol amine are added. The stirred mixture is brought to a temperature between 70 ° and 80 ° C for six hours. By cooling, the expected product crystallizes. It is drained, washed with ethyl ether, then dried.

0.9 g of N- (2-amino-chloro-3-oxide 3-pyrimidinyl-4) N '- (hydroxyethyl) urea is obtained in the form of a white powder with a melting point of 254 ° C.

Elemental analysis: CyH ^ oCl N5O3 C H Cl N 0

Calculated 33.95 4.07 14.32 28.28 19.38

Found 34.20 4.11 14.51 28.20 19.40

EXAMPLE 6

Preparation of N- (piperidino-6 amino-2-3-oxide pyrimidinyl-4) K1- (2-hydroxyethyl) urea.

A suspension of 0.5 g of N- (2-amino-6-chloro-3-oxide-pyrimidinyl-4) N '- (hydroxyethyl) urea in 20 cm3 of butanol-1 and 0.4 cm3 of piperidine, is brought to 80 ° C for four hours. Time after which the starting material is completely transformed.

By cooling the solution, the expected product crystallizes. It is drained, washed with ethyl ether and dried.

0.350 g of N- (piperidino-6 amino-2-oxide-3 pyrimidinyl-4) N '- (2-hydroxyethyl) urea is obtained in the form of a white powder with a melting point of 248 ° C.

Elementary analysis: Ci2K20N603 C H N 0

Calculated 48.63 6.80 28.36 16.20

Found 48.61 6.81 28.39 16.23

EXAMPLE 7

Preparation of N- (pyrrolidino-6 amino-2-oxide 3-pyrimidinyl-4) N ', N' - (butanediyl) urea.

To a suspension of 2 g of amino-7 chloro-5-2H-oxadiazolo-1,2,4 / 2,3c / pyrimidinone-2 in 50 cm3 of ethanol, 4 equivalents of pyrrolidine are added. This stirred mixture is brought to 80 ° C for 2 hours. The medium quickly becomes homogeneous.

By cooling, the expected product crystallizes, it is drained, washed with ethyl ether and dried.

1.9 g of N- (pyrrolidino-6 amino-2-oxide-3 pyrimidinyl-4) H ', N' - (butanediyl) urea are obtained in the form of white pearly flakes, the melting point of which is 240 ° C.

Elementary analysis: Ci3H20N6 ° 2 C H N 0

Calculated 53.41 6.90 28.75 10.94

Found 53.31 6.96 28.23 11.22

EXAMPLE 8

Preparation of N- (2-amino-6-chloro-3-oxide pyrimidiny1-4) N '- (2,3-dihydroxy propyl) urea.

To a suspension of 2 g of aniino-7 chloro-5-2H-oxadiazolo-1,2,4 [2,3c] pyrimidinone-2 in 50 cm3 of ethanol, 1.1 equivalent of 2-dihydroxy is added, 3 propylamine. With stirring, this mixture is brought to reflux for three hours. At this stage, the starting product is transformed.

By cooling, the expected product crystallizes. It is drained, washed with ethyl ether and dried.

1.4 g of N- (2-amino-6-chloro-3-oxide pyrimidinyl-4) N '- (2,3-dihydroxy-propyl) urea are obtained in the form of white crystals with a melting point of 219 ° C. .

Elemental analysis: CgH ^ Cl N5O4 C H Cl N 0

Calculated 34.61 4.36 12.77 25.22 23.05

Found 34.73 4.08 12.69 25.17 23.23

EXAMPLE 9

Preparation of N- (piperidino-6 amino-2-3-oxide pyrimi-dinyl-4) N1- (2,3-dihydroxy propyl) urea.

A mixture of 1 g of N- (2-amino-6-chloro-3-oxide 3-pyrimidinyl-4) N '- (2,3-dihydroxy propyl Juré and 0,7 cm3 of piperidine in 50 cm3 of ethanol, is brought under reflux for 30 hours, after which time the majority of the starting material is transformed.

By cooling, the expected product crystallizes. It is drained, washed with ethyl ether and dried.

1 g of N- (piperidino-6 amino-2-3-oxide pyrimidinyl-4) N '- (2,3-dihydroxy-propyl) urea is obtained in the form of white crystals with a melting point of 224 ° C. which are analyzed in the form hydrated.

Elementary analysis: 0ι3Η22Ν604 / 1/2 H2O

C H N 0

Calculated 46.70 6.63 25.14 21.53

Found 46.72 6.54 24.89 21.66

EXAMPLE 10

Preparation of N- (morpholino-6 amino-2-3-oxide pyrimi-dinyl-4) N ', N' - (oxa-3 pentanediyle) urea.

A mixture of 2 g of amino-7 chloro-5-2H-oxa-diazolo-1,2,4 [_2,3ç / pyrimidinone-2 and 3.7 cm3 of morpholine in 50 cm3 of ethanol, is brought at a temperature of about 70 ° C for two hours.

By cooling the mixture to 0 ° C, the expected product crystallizes. It is drained, washed several times with ethyl ether and dried.

2.6 g of N- (6-morpholino-2-amino-3-pyrimidinyl-4) N ', N' - (3-oxa-pentanediyl) urea are partially obtained in the form of the hydrochloride.

This product is stirred in 100 cm3 of water. By adding sodium bicarbonate, the pH of the solution is brought to about 8. The expected product is then extracted three times with methylene chloride. These organic phases are combined, washed with water and dried over sodium sulfate, then concentrated.

The solid is recrystallized from ethanol.

1.5 g of N- (6-morpholino-2-amino-3-pyrimidinyl-4) N ', N' - (oxa-3 pentanediyl) urea are obtained in the form of white pearly flakes whose melting point is greater than 260 ° C.

This product is analyzed in hydrated form.

Elementary analysis: Ci3H2 () N604 '1/4 H2O

C H N O

Calculated 47.48 6.28 25.56 20.68

Found 47.41 6.28 25.47 21.30

g EXAMPLE 11

Preparation of N- (piperidino-6 amino-4 oxide-3 pyrimidinyl-2) N 1- (hydroxyethylurea).

To a suspension of 0.5 g of amino-7 piper-dino-5-2H-oxadiazolo-1,2,4 / 2,3a7 pyrimidinone-2 in 20 cm3 of butanol-1, 0.5 cm3 d1 is added ethanolamine. The mixture thus obtained is placed under stirring at a temperature of approximately 90 ° C.

The medium gradually becomes homogeneous. After four hours, the starting material is transformed. The butanol is removed by evaporation under vacuum and the product obtained is stirred in acetone. The solid is drained, washed with acetone and then dried.

0.5 g of N- (piperidino-6 amino-4-oxide-3 pyrimidinyl-2) N '- (hydroxyethylethylurea) is obtained in the form of white crystals, the melting point of which is 174 ° C.

Elemental analysis: C12H20N6O3, x / 4 H2 °

C H N O

Calculated 47, SI 6.87 27.94 17.28

Found 47.66 6.41 27.43 17.55

EXAMPLE 12

Preparation of N- (piperidino-6 amino-2-oxide-3 pyrimi-dinyl-4) N * - (methylglucamirie) urea.

To a suspension of 11 g of amino-7 (piperi-dino) -5-2H-oxadiazolo-1,2,4 / 2,3 çj pyrimidinone-2 in 300 cm3 of ethanol, stirred at room temperature, is added 3.1 g of N-methylglucamine. The mixture is then brought to 80 ° C for four hours. The reaction medium gradually becomes homogeneous. The starting material being completely transformed, the solution is cooled to 0 ° C. The expected product crystallizes. It is wrung and dried.

14.5 g of N- (piperidino-6 amino-2-oxide 3-pyrimidinyl-4) N '- (methylglucamine) urea are obtained in the form of white crystals with a melting point of 186 ° C.

Elementary analysis: C17H30N5O7 C H N 0

Calculated 47.43 7.02 19.52 26.02

Found 46.90 7.06 19.27 27.05

EXAMPLES OF COMPOSITIONS

1) A lotion with the following composition is prepared: - N- (piperidino-6 amino-2-3-oxide pyrimidinyl-4) N '- (2-hydroxyethyl) urea 2 g - Propylene glycol 20 g - Ethyl alcohol 50 g - Water qs 100 g 2) The lotion intended to stimulate hair regrowth is prepared with the following composition: - ÎT- (pipêridino-6 amlno-2-oxide-3 pyrimidinyl-4) ir- (methylglucamine) urea 5 g - Propylene glycol 20 g - Ethanol 50 g - Water qs loo g 1 to 2 ml of these lotions are applied to the alopecic areas of the scalp; these applications, possibly accompanied by a massage to promote penetration, being carried out once or twice a day.

3) The following composition is prepared in the form of a gel: - N- (piperidino-6 amino-2-3-oxide pyrimidinyl-4) H '- (methylglucamine) urea 2 g - Hydroxypropylcellulose sold by the

HERCULES under the trade name "KLUCEL G" 3 g - Propylene glycol 20 g - Ethanol 50 g - Preservative qs - Water qs 100 g 4) The following composition is prepared in the form of a gel: - N- (piperidino-6 amino-2 3-oxide-pyrimidinyl-4) N1- (2,3-dihydroxypropyl) urea 3 g - Kethylhydroxypropylcellulose sold by the company DOW CHEMICAL under the trade name "METHOCEL F" 1 g - Ethanol 40 g - Water qs 100 g

Claims (17)

1. Compound characterized by the fact that it corresponds to the formula:

in which: R3 and R4, identical or different, denote a hydrogen atom, an alkyl radical, linear or branched in C ^ -C ^ g, alkenyl having 2 to 18 carbon atoms, cycloalkyl having 5 to 8 atoms carbon, optionally substituted by one or more lower alkyl group (s), a cycloalkene group, the alkyl, alkenyl or cycloalkyl groups which can themselves be substituted by one or more hydroxyl group (s), R3 and / or R4 also denote a aryl or aralkyl group, corresponding to the formula:

in which: n can take the values from 0 to 4 and where R5 and / or R6, independently of one another, denote hydrogen, a lower alkyl group in C ^ -Cg, a group nitro, hydroxyl, alkoxy or a halogen atom, or a carboxylic group, as well as the salified forms, esters and amides thereof, R 3 and R4, taken together with the nitrogen atom to which they are linked, can form a heterocycle of 3 with 7 carbon atoms, Rl and / or R2, independently of one another, denote a hydrogen atom or a carbamoyl group, of formula:

provided however that Ri and R2 do not simultaneously denote a hydrogen atom, R7 and / or R8 denote, independently of each other, a hydrogen atom, an alkyl radical, linear or branched in Cy-CyS 'substituted by one or more hydroxyl and / or amino group (s), this alkyl chain possibly being interrupted by one or more heteroatom (s) chosen from sulfur, nitrogen or oxygen, R7 and R3 also denote a cycloalkyl, aryl or aralkyl group, substituted by a hydroxyl, amino and / or carboxylic group, R7 and / or R8 also denote a sugar residue, R7 and Rs can form with the nitrogen atom to which they are attached , a heterocycle comprising one or more heteroatoms, as well as their tautomeric form corresponding to the formulas:

2. Compound according to Claim 1, characterized in that in the formula (I), the C 1 -C 4 alkyl radical substituted by one or more hydroxyl or amino group (s) is chosen from the 2-hydroxy radicals ethyl, 2,3-dihydroxypropyl, 2-hydroxypropyl, 2-hydroxyethoxyethyl, 2-hydroxyethylaminoethyl, 2-aminoethyl, as the heterocyclic group formed by the groups R7 and R8 with the nitrogen atom to which they are attached, is chosen from morpholino, pipêridino, pyrrolidino, pipêrazino, N-alkyl 4'-piperazino groups, in which the alkyl group in position 4 'preferably contains from 1 to 6 carbon atoms, one of which may be substituted by a hydroxyl or thiazolidine group. 3. Compound according to any one of claims 1 to 2, characterized in that it corresponds to the following formula (la):

wherein R3, R4, R7 and Rg have the meaning indicated in claim 1. 4. Compound according to claim 1 or 2, characterized in that it corresponds to formulas (Ib) and (le):

in which R7 and Rg have the meanings indicated in claim 1. 5. Intermediate compound used for the preparation of the compounds according to any one of claims 1 to 4, characterized in that it corresponds to the formulas:

6. Process for the preparation of the compounds according to any one of claims 1 to 4, in particular of the compounds corresponding to formula (la) or their isomers, characterized in that the compound according to claim 5 is treated with a amine of formula:

in which R7 and Rg have the meanings indicated in claim 1, that the resulting monourea derivative is treated with an amine of formula:

wherein R3 and R4 have the meanings defined in claim 1. 7. Process for the preparation of the compounds according to claim 4 corresponding to formula (Ib):

characterized in that the amino-7 piperidino-5-2H-oxadiazolo-1,2,4 / 2,3c7 pyrimidinone-2 of formula (Via) is treated:

by the amine of formula:

wherein R7 and Rg have the meanings defined in claim 1. 8. Process for preparing the compound according to claim 4, corresponding to formula (Ie):

in which R7 or Rg denotes a hydrogen, characterized in that the amino-7 piperidino-5 ~ 2H-oxadiazolo-1,2,4 / 2,3a7 pyriraidinone-2 of formula (VIb) is treated:

with a primary amine of formula:

in which R7 and Rg have the meanings indicated above. 9. Process for the preparation of the intermediate compounds of formulas (IVa) and (IVb) according to claim 5, characterized in that the 2,4-chloro-6-chloro-3-pyrimidine pyrimidine is treated in a first step formula (VII):

with a carbamoyl chloride of formula (VIII):

in which R denotes an alkyl group, in a polar aprotic solvent, chosen from dimethyl sulfoxide, tetrahydrofuran or dicxane, to obtain the mixture of isomeric monourea derivatives of formulas (IXa) and (IXb):

that said mixture is treated with an excess of carbamoyl chloride (formula VIII) to obtain the amino-7 chloro-5-2H-oxadiazolo-1,2,4 [2,3c / pyrimidinone-2 of formula (IVa ) and its isomer of formula (IVb). 10. Cosmetic or pharmaceutical composition, characterized in that it contains, in a support suitable for topical application, at least one compound corresponding to any one of claims 1 to 4. 11. Pharmaceutical composition according to claim 10, characterized in that it is in the form of ointments, tinctures, creams, ointments, powders, patches, soaked pads, solutions, emulsions, lotions, gels, sprays or anhydrous or aqueous suspensions, containing at least one compound as defined in any one of claims 1 to 4. 12. Composition according to Claim 11, characterized in that the compounds of formula (I) are present in concentrations of between 0.1 and 10% by weight relative to the total weight of the composition, in particular between 0.2 and 5% by weight. 13. Cosmetic composition. according to claim 10, in the form of lotions, gels, soaps, shampoos, characterized in that it contains in a physiologically acceptable carrier, at least one of the compounds as defined in any one of the claims 1 to 4, at a concentration of between 0.01 and 5% by weight. 14. Composition according to claim 13, characterized in that it contains in addition hydrating agents, antiseborrhoeic agents, agents promoting hair regrowth, anti-inflammatory agents, steroidal or non-steroidal, carotenoids, acids eicosatetraynoic-5,8,11,14 and eicosatriynoic-5,8,11 and their esters and amides. 15. Composition according to any one of claims 10 to 14, characterized in that it also contains preservatives, stabilizing agents, pH regulating agents, agents modifying osmotic pressure, emulsifying agents, filters UV-A and UV-B, antioxidant agents. 16. Cosmetic hair treatment method, characterized in that at least one composition as defined in any one of claims 10 to 15 is applied to the scalp. 17. Use of the compounds according to any one of claims 1 to 4, for the preparation of a medicament for the treatment of alopecia areata, hair loss, desquamating dermatitis.