FR2677247A1 - COMPOSITION FOR BRAKING THE FALL OF HAIR AND FOR INDUCING AND STIMULATING THEIR GROWTH, BASED ON PYRIDINE-1 OXIDE DERIVATIVES. - Google Patents

Abstract

Composition for combatting hair loss and inducing and stimulating hair growth, containing a compound of formula (I) in which: R1 and R2 are hydrogen; an alkyl; -NHR6 where R6 is hydrogen; an alkyl; (a), (b) or (c), where R7 and R8 are an alkyl; R4 is hydrogen; or -OR9, -SR9, where R9 is an alkyl, an alkenyl, a phenylalkyl; R4 is -NR10R11, where R10 and R11 are an alkyl, an alkenyl, a phenylalkyl, or form a heterocycle; R3 and R5 are hydrogen, methyl, nitro, amino, chlorine or bromine; Y is O or OSO3. The invention also concerns cosmetically or pharmaceutically acceptable acid addition salts of the composition.

Description

Composition for curbing hair loss and for inducing and stimulating their growth, based on pyridine 1-oxide derivatives.

 The invention relates to compositions for use, in particular topical application, for curbing hair loss and for inducing and stimulating their growth, containing pyridine 1-oxide derivatives.

Pyridine derivatives 1-oxide are known from the state of the art, in particular those described in US Pat.
US-A-4,021,562, for their properties of anti-hypertensive agents.

On the other hand, certain pyridine 1-oxide 3-carboxylic acids and their esters are known as hair growth agents, used alone or in the presence of 2,4-diamino-6-piperidino pyrimidine 3-oxide or "Minoxidil". They are described in particular in Japanese Patent JP 01261321, JP 02088515, the patent
U.S. 4,866,067, JP 01301612.

 The Applicant has discovered novel compositions for the treatment and prevention of hair loss, used in particular for topical application, which are particularly effective for treating the scalp, by means of other types of compounds derived from pyridine l-oxide. use for the treatment of hair loss was until now unknown.

 The compounds retained by the Applicant, in addition to the fact that they are effective for regrowth of hair, and in particular to slow down their fall, induce and stimulate their growth, are also useful for the treatment of alopecia areata and desquamating dermatitis.

 The subject of the invention is therefore new compositions for the treatment and prevention of hair loss, based on particular compounds derived from pyridine 1-oxide, defined below.

 Another object relates to the use of these compounds for the preparation of a medicament for the therapeutic treatment of hair loss.

 Yet another object is the use of these compounds for the preparation of cosmetic and pharmaceutical compositions.

 The invention also relates to a cosmetic treatment method.

 Other objects will appear on reading the description and examples.

dans laquelle R1 et R2, indépendamment l'un de l'autre, désignent un atome d'hydrogène, un radical alkyle en C1-C4, un groupement -NHR6, dans lequel R6 désigne un atome d'hydrogène, un radical alkyle en C1-C4, un groupe choisi parmi ceux de formule:

où R7 et Rg, identiques ou différents, désignent un alkyle en C1-C4;
R4 désigne un atome d'hydrogène; un groupe -ORg ou un groupe -SR9, dans lesquels Rg désigne un radical alkyle en Cl-Cg, alcényle en C3 C8, phénylalkyle en Cl-C4;
R4 peut désigner un groupement de formule -NRloRll où Rlo et Roll, identiques ou différents, désignent un radical alkyle en C1-Cs, alcényle en C3-C8, phénylalkyle en C1-C4 ou bien forment avec l'atome d'azote auquel ils sont reliés, un hétérocycle choisi parmi pyrrolidino, pipéridino, morpholino, 4-alkylpipéridino, heptaméthylimino, ces hétérocycles pouvant contenir des radicaux alkyle en
C1-C3;;
R3 et R5, identiques ou différents, désignent un atome d'hydrogène, un radical méthyle, un groupement nitro, un groupement amino, un atome de chlore ou de brome;
Y désigne O ou OSO3.The compositions according to the invention are essentially characterized in that they contain, in a physiologically acceptable medium, at least one compound of the following formula:

in which R1 and R2, independently of each other, denote a hydrogen atom, a C1-C4 alkyl radical, a group -NHR6, in which R6 denotes a hydrogen atom, a C1-alkyl radical; -C4, a group chosen from those of formula:

where R7 and Rg, identical or different, denote a C1-C4 alkyl;
R4 denotes a hydrogen atom; an -ORg group or a -SR9 group, wherein Rg is a C1-C8 alkyl, C3-C8 alkenyl, C1-C4 phenylalkyl;
R4 may denote a group of formula -NRloRll wherein Rlo and Roll, which may be identical or different, denote a C1-Cs alkyl, C3-C8 alkenyl or phenylC1-C4 alkyl radical or form with the nitrogen atom to which they are connected, a heterocycle selected from pyrrolidino, piperidino, morpholino, 4-alkylpiperidino, heptamethylimino, these heterocycles may contain alkyl radicals
C1-C3 alkyl ;;
R3 and R5, which may be identical or different, denote a hydrogen atom, a methyl radical, a nitro group, an amino group, a chlorine or bromine atom;
Y is O or OSO3.

 The compounds of formula (I), according to the present invention, can be converted into their cosmetically or pharmaceutically acceptable acid addition salts such as the salts of sulfuric, hydrochloric, hydrobromic, phosphoric, acetic, benzoic and salicylic acids, glycolic, succinic, nicotinic, tartaric, malic, pamoic, methanesulfonic, picric, lactic, etc.

 Homologous compounds are known per se and have been described in patent applications DE 2.112.832, EP 067.511, FR 2.472.201, WO 86.026.46, EP 068.833, EP 184.322, EP 103.553, CN 85.103.357, EP 042,669, DE 2,235,746, DE 3,514,073, DE 2,165,752, US Patent 3,826,643, US 4,021,562; in J. Org., Chem., 37 (23), 3584-7 (1972).

 They are used in particular for their hypolytic and antilipolytic properties, as herbicides, as nutritional supplements for animal nutrition, as ulcer inhibitors or as agents for treating vascular and degenerative diseases of the brain.

où R1 et R2 désignent un groupement -NHR6 avec R6 ayant la désignation indiquée ci-dessus; où R4 désigne -NR1OR11 , où R10 et R11 ont la même signification indiquée ci-dessus, peuvent être obtenus selon le procédé décrit dans
US 4.021.562.The compounds of formula:

where R1 and R2 denote a group -NHR6 with R6 having the designation indicated above; where R4 is -NR1OR11, where R10 and R11 have the same meaning given above, can be obtained according to the method described in
US 4,021,562.

 The compounds according to the invention of formula (I), in which Y denotes an oxygen atom, can be converted into their 0-sulphate homologues by chemical sulphation according to the conventional methods described in the literature (J. Med Chem 1983 , 26, p.

1791-1793).

 The sulfur trioxide-pyridine, sulfur trioxide-trimethylamine or sulfur trioxide-ethyldiisopropylamine complexes are used as sulphating reagents.

 The solvents used are preferably dimethylformamide, acetonitrile, chloroform or their binary mixtures. The temperature is of the order of 0 to 250C and the reaction time varies between 1 hour and 24 hours.

dans laquelle:
R1 et R2 désignent simultanément NH2;
R4 désigne hydrogène ou le groupe -NR1OR11 où R10 et R11 ont la même signification indiquée ci-dessus.The preferred compounds according to the present invention are chosen from those of formula (Ib) below

in which:
R1 and R2 simultaneously denote NH2;
R4 denotes hydrogen or the group -NR1OR11 where R10 and R11 have the same meaning indicated above.

 More particularly preferred compounds are 2,6-diaminopyridine 1-oxide-2,6-diamino-4-piperidinopyridine oxide.

 The compositions according to the present invention, containing in a physiologically acceptable medium, at least one compound corresponding to formula (I) or one of its physiologically acceptable acid addition salts, may be applied in the cosmetic or pharmaceutical field, especially in topical application. They are intended for the treatment and prevention of hair loss including alopecia, alopecia as well as desquamating dermatitis.

 These compositions may comprise, as a physiologically acceptable medium, any medium suitable for topical application, either in cosmetics or in pharmacy, and which is compatible with the active substance.

 The compounds in accordance with the invention may be in this medium, either in the dissolved state or in the dispersed state, in particular in micronized form.

 The compositions intended for use in pharmacy are in the form of ointment, tincture, cream, ointment, powder, patch, impregnated buffer, solution, emulsion or vesicular dispersion, lotion, gel, spray or suspension.

They can be either anhydrous or aqueous, depending on the clinical indication
The compounds according to the invention are present in these pharmaceutical compositions at concentrations of between 0.1 and 10% by weight and in particular between 0.2 and 5% by weight.

 The cosmetic compositions are especially intended to be used in the form of a lotion, a gel, a soap, a shampoo, an aerosol or a mousse and contain, in a cosmetically acceptable support, at least one compound of formula (I) or one of its acid addition salts.

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

The compositions according to the invention may contain various additives usually used in cosmetics or pharmaceuticals and in particular active substances, such as moisturizing agents such as thiamorpholinone and its derivatives or urea; antiseborrhoeic agents, such as S-carboxymethylcysteine,
S-benzylcysteamine, and their derivatives; thioxolone.

The compounds in accordance with the invention may be combined with compounds which further improve their activity on regrowth and / or on the braking of hair loss, such as, more particularly, the following compounds
nicotinic acid esters, especially C1-C6 alkyl nicotinates and in particular methyl or hexyl nicotinate, benzyl nicotinate or tocopherol nicotinate;
the steroidal and non-steroidal anti-inflammatory agents well known in the state of the art and in particular hydrocortisone, its salts and its derivatives, niflumic acid;
retinoids and more particularly t-trans retinoic acid, also called tretinoin, isotretinoin, retinol or vitamin A and its derivatives, such as acetate, palmitate or propionate, motretinide, etretinate, zinc t-trans retinoate;
antibacterial agents chosen more particularly from macrolides, pyranosides and tetracyclines and especially erythromycin;
calcium antagonists, such as Cinnarizine and
diltiazem;
hormones, such as estriol or analogues, or thyroxine and its salts;
antiandrogenic agents, such as oxendolone, spironolactone, diethylstilbestrol;
OH radical scavengers, such as dimethylsulfoxide.

It is also possible to associate with the compounds of the invention, optionally in a mixture with the others, compounds such as
Diazoxide corresponding to 3-methyl-7-chloro [2H] benzothiadiazine-1,2,4-dioxide-1; Spiroxasone or 7- (acetylthio) -4 ', 5'-dihydrospiro [androst 4-ene-17,2' - (3'H) furan] -3 one; phospholipids, such as lecithin; linoleic and linolenic acids; salicylic acid and its derivatives described more particularly in French Patent 2,581,542, and more particularly the salicylic acid derivatives bearing an alkanoyl group having 2 to 12 carbon atoms at the 5-position of the benzene ring; hydroxycarboxylic or ketocarboxylic acids and their esters, lactones and their corresponding salts; anthralin, carotenoids, eicosatetraynoic-5,8,11,14 or eicosatriynoic-5,8,11 acids, their esters and amides.

 The compounds in accordance with the invention may also be combined with surfactants including those chosen from nonionic and amphoteric surfactants.

Among the nonionic surfactants, mention may be made of the polyhydroxypropyl ethers described in particular in French Patent Nos. 1,477,048; 2,091,516; 2,169,787; 2,328,763; 2,574,786; oxyethylenated (C 8 -C 9) alkyl phenols having 1 to 100 moles of ethylene oxide and preferably 5 to 35 moles of ethylene oxide; aikylpolyglycosides of formula
CI, H2n + 1 (C6H1O5) xH (A) wherein n ranges from 8 to 15 inclusive and x from 1 to 10 inclusive.

 Among the amphoteric surfactants, mention will be made amphocarboxyglycinates and amphocarboxypropionates defined in the CTFA dictionary, 3rd edition, 1982, and sold, in particular, under the name MIRANOLe by MIRANOL Company.

 The compounds according to the invention can be introduced into carriers which further improve the activity at the regrowth, by having both cosmetically advantageous properties, such as ternary volatile alkyl ether mixtures. alkylene glycol, in particular C 1 -C 4 alkyl, C 1 -C 4 alkylene glycol or dialkylene glycol, preferably C 1 -C 4 dialkylene glycol, ethyl alcohol and water, the glycolic solvent denoting the monoethylethers of ethylene glycol, monomethyl ether of propylene glycol, monomethyl ether of diethylene glycol.

The compounds in accordance with the invention may also be introduced into gelled or thickened physiologically acceptable carriers, such as essentially aqueous supports gelled with heterobiopolysaccharides, such as xanthan gum, scleroglucans or cellulose derivatives such as cellulose ethers. , hydroalcoholic supports gelled with polyhydroxyethylacrylates or methacrylates or thickened essentially aqueous supports, in particular polyacrylic acids crosslinked with a polyfunctional agent, such as the
Carbopol sold by the GOODRICH Company.

 The thickeners 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 the composition.

 These compositions may also contain preserving agents, stabilizing agents, pH-regulating agents, osmotic pressure-modifying agents, emulsifying agents, UVA and UVB filters, antioxidant agents, such as VO: -tocopherol, butylhydroxyanisole, butylhydroxytoluene.

 The physiologically acceptable medium may consist of water or a mixture of water and a solvent or a mixture of solvents, the solvents being chosen from cosmetically or pharmaceutically acceptable organic solvents and chosen from lower alcohols. C1-C4, alkylene glycols, alkylene glycol and diacylene glycol aikyl ethers. The solvents, when present, are in proportions of between 1 and 80% by weight relative to the total weight of the composition.

 The subject of the invention is also a process for cosmetic treatment of the hair or scalp, comprising applying to them at least one composition as defined above, in order to improve the aesthetics of the hair.

 Another subject of the invention is the use of the composition containing the compounds of formula (I) defined above, for the preparation of a medicament having the effect of inducing or stimulating hair growth and to slow down their fall.

 The treatment consists mainly in applying to the alopecic areas of the scalp of an individual, the composition as defined above.

 The preferred mode of application is to apply 1 to 2 g of the composition on the alopecic zone, at a frequency of one to two applications per day, for 1 to 7 days per week and this for a period of 1 to 6 months.

 The compositions may especially be used in the treatment of alopecia areata, hair loss, desquamating dermatitis or alopecia.

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

EXAMPLES OF PREPARATION
EXAMPLE 1 2,6-Diamino-4-piperidino pyridin 1-oxide

This product is obtained in several stages according to the following diagram

<tb><SEP> 0 <SEP> 0
<tb> EtOOCHNNgNHCOOEt <SEP> H2N <SEP> N <SEP> NH2
<tb> EtOOCHN <SEP> 0: - <SEP> H2N1 <SEP> cn
<tb><SEP> IEtOH
<tb><SEP> Ass <SEP> (11)
<Tb>
The preparation of the compound (III) was carried out according to the already known method (JACS 1956, 78, 4130).

2,6-diethoxvcarbonylamino 4-chloronvridine 1-oxide (II)
To a mixture of 40 g of 2,6-diethoxycarbonylamino 4-chloropyridine (IT) in 400 ml of acetic acid, 40 ml of 30% hydrogen peroxide are added. It is stirred for 5 hours at 700C. The solution is poured into 4.5 liters of ice water. The product obtained is filtered and washed with water.

 Recrystallization from 1.4 l of acetone gives 32 g of product.

Yield = 76%
PF = 1500C.

Elemental analysis for CllH14N305Cl; M = 303.5
CHNO C1
Calculated 43.49 4.61 13.84 26.36 11.7
Found 43.46 4.65 13.77 26.25 11.65
The 13C NMR and mass spectra are in agreement with the structure.

2-diamino 4-piperidino pyridine 1-oxide (I!
A mixture of 30 g of 2,6-diethoxycarbonylamino-4-chloropyridine-1-oxide (I) and 250 ml of piperidine is refluxed for 30 hours under an argon atmosphere. The reaction mixture is dried and the residue is taken up in 600 ml of absolute ethanol and 72 g of potassium hydroxide.

 The mixture is stirred for 30 hours under reflux.

 Drying of the basic mixture gives a residue which, stirred with 150 ml of water, gives a precipitate which is filtered and washed with water.

 This product is taken up in 50 ml of acetone, the filter and then recrystallized from a mixture of water and ethanol 1/1.

 2.5 g of product are obtained.

Yield = 12%
PF = 2600C decomposition.

Elemental analysis for C10H16N4O; M = 208
CHNO
Calculated 57.69 7.69 26.92 7.69
Found 57.68 7.77 27.03 7.80
The 1 H NMR and mass spectra are consistent with the structure.

EXAMPLE 2 2-6 diamino pyridine 1-oxide

<tb> H <SEP> 2 <SEP> CH3CONH <SEP> NHCoeH3
<tb><SEP> v <SEP> (CH3C0) 20 <SEP> W
<tb><SEP> l25
<tb><SEP> 2, <SEP> 6-diaminopyridine <SEP> 2,6-diacetamidopyridine
<tb><SEP> (I)
<tb><SEP> 0
<tb><SEP> Monoperoxyphthalate <SEP> of <SEP> Mg <SEP> CH <SEP> 3CONH <SEP> 9 \ NHCOCH3
<tb><SEP> CH3COOH <SEP> e <SEP> l <SEP> lX
<tb><SEP> 45qC
<tb><SEP> 2,6-diacetamidopyridine <SEP> l-oxide
<tb><SEP> (He)
<tb><SEP> NaOMI20 /
<tb><SEP> 0
<tb><SEP> t
<tb><SEP> H2N <SEP> ToYNH2
<tb><SEP> IX
<tb><SEP> 2,6-diarninopyridine <SEP> oxide
<tb><SEP> (HI)
<tb> 2,6-Diacetamido pyridine (D
50 g of 2,6-diamino pyridine are added to 100 ml of acetic anhydride.

 The solution is heated at 1250C for 3 hours.

 The solution is poured into 1 liter of ice water.

 The precipitate obtained is filtered and washed with water.

 Recrystallization from 1.5 l of water and 0.1 l of ethanol gives 67 g of product.

Yield = 76%
PF = 2060C
Elemental analysis for C9H18N3O2; M = 193
CHNO
Calculated 55.96 5.70 21.76 16.58
Found 56.02 5.70 21.92 16.74
The 1 H NMR and mass spectra are consistent with the structure.

 2 * 6-Diacetamido pyridine 1 oxide (II).

 37 g of 2,6-diacetamido pyridine are dissolved in 750 ml of acetic acid.

 70 g of magnesium monoperoxyphthalate (M.M.P.P.) are added little by little.

 It is heated at 450 ° C. for 3 hours.

 After distillation under vacuum, 800 ml of water are added to the residue.

 The mixture is extracted with 800 ml of dichloromethane and then twice with 200 ml, and the organic phase is washed with water saturated with NaCl.

 After drying and evaporating, the product obtained is taken up in 100 ml of acetone.

 The precipitate is filtered and washed with acetone.

 34.9 g are obtained.

Yield = 87%
PF = 2130C
Elemental Analysis for C11H11N3O3; M = 209
CHNO
Calculated 51.67 5.26 20.10 22.97
Found 51.76 5.29 20.10 23.11
The 1 H NMR and mass spectra are consistent with the structure.

2.6-diamino pyridine 1oxide (m)
34 g of 2,6-diacetamidopyridine 1-oxide are dissolved in 200 ml of 10% sodium hydroxide in water.

 Refluxed for 3 hours.

 After acidification with dilute HCl, the mixture is dried.

 The residue is taken up in 300 ml of ethanol and filtered through celite.

 The solution is dried, the residue is impasted with the minimum amount of ethanol and diluted with ether.

 The precipitate obtained is filtered and washed with ether.

Yield = 60%
PF = 2060C
Elemental analysis for C5H7N30; M = 125
CHNO
Calculated 47.32 5.68 33.12 13.90
Found 47.39 5.67 33.13 13.55
The 1 H NMR and mass spectra are consistent with the structure.

EXAMPLE 3 2.6-Lutidine 1-oxvde

2,6-lutidine 2,6-lutidine 1-oxide
5 g of 30% hydrogen peroxide in 5 g of 2,6-lutidine dissolved in 40 ml of acetic acid are added.

 The mixture is heated at 70-800 ° C. for 3 hours and then 4 g of hydrogen peroxide are added again.

 The temperature is maintained at 70-800C for 9 hours.

 The mixture is concentrated under vacuum. Water is added to the residue and concentrated to a maximum.

 The residue is treated with sodium carbonate and rendered strongly alkaline.

 The minimum amount of water is added until the dissolved salts are dissolved and the mixture is extracted with dichloromethane.

 The organic phase is dried over sodium sulfate and dried.

 The oil obtained is distilled under vacuum.

PE15mmHg 1150C
4 g of product are obtained.

Yield = 70%
Elemental analysis for C7H9NO 0.25 H20; M = 123
CHNO
Calculated 65.88 7.45 10.98 15.69
Found 65.68 7.43 10.92 15.53
The 1 H NMR and mass spectra are consistent with the structure.

EXAMPLE 4 4-methoxy 2-picoline N-oxide

<tb><SEP> HNO <SEP> CH <SEP> ONa
<tb><SEP> CH3 <SEP> H2S <SEP>. <SEP> s <SEP> CH? 3oH <SEP> N
<tb> dr '"<SEP> I <SEP> 48h <SEP> 1H3
<tb><SEP>Ref'.ux<SEP>'\ H3
<tb><SEP> * 2 <SEP> (5CH3
<Tb>
Step 1: 4-nitro 2-picoline N-oxide
In a mixture of 130 ml of sulfuric acid (d = 1.83) and 52.5 g of nitric acid (d = 1.4), 50 g of 2-picoline N-oxide are introduced.

 It is heated for 6 hours at 1150-1200C. The mixture is poured on 1 liter of water and ice.

 After neutralization with sodium hydroxide, the mixture is extracted 3 times with 1 liter of dichloromethane. The organic phase is dried over sodium sulphate and dried.

 Recrystallization from 450 ml of acetone gives 38.5 g of yellow product.

Yield = 55%
PF = 1540C.

Elemental analysis for C6H6N2O3; M = 154
CHNO
Calculated 46.75 3.90 18.18 31.17
Found 46.85 3.94 18.08 31.10
The 1 H NMR and mass spectra are consistent with the structure.

Step 2: 4-methoxy 2-picoline N-oxide
In a solution of 1.5 g of sodium methoxide, 2 g of 4-nitro-2-picoline N-oxide are introduced.

 It is heated for 48 hours under reflux. After the reaction mixture has been dried, 30 ml of dichloromethane are added and the precipitate of sodium nitrite obtained on celite is filtered off.

 The dichloromethane is evaporated and the residue is taken up in 20 ml of water.

The precipitate corresponding to the starting material is removed. The mother liquors are again extracted with dichloromethane, concentrated and precipitated by addition of ether.

 After filtration, a second purification by precipitation dichloromethane / ether provides 280 mg of product.

Yield 15%
PF = 720C (hydrate).

Elemental analysis for C7H11NO3 (hydrate)
CHNO
Calculated 53.50 7.00 8.91 30.57
Found 53.76 6.76 8.84 30.52
The 1 H NMR and mass spectra are consistent with the structure.

Retape 1 : 4-chloro 2-picoline N-oxyde
On additionne 30 g de 4-nitro 2-picoline N-oxyde dans 150 ml de chlorure d'acétyle à -100C. EXAMPLE 5 4-thiomethoxy 2-picoline N-oxvde

Retape 1: 4-chloro 2-picoline N-oxide
30 g of 4-nitro-2-picoline N-oxide are added in 150 ml of acetyl chloride at -100 ° C.

 The ice bath is maintained for 1 h 30 and then allowed to rise to room temperature. Leave stirring for another hour.

The mixture is poured on 1 liter of water and ice, neutralized with sodium hydroxide and extracted with 1 liter of dichloromethane.

 After drying, the residue is taken up in 300 ml of absolute ethanol.

 35 ml of a solution containing 8 mol / l of hydrochloric ethanol are added.

 The solution is evaporated under vacuum, the residue is taken up in the minimum dichloromethane and precipitated by addition of isopropyl ether.

After recrystallization in acetone, we obtain
11 g as hydrochloride.

 Yield = 31%.

 Mp = 1250C.

Elemental analysis for C6H7NOCl2; M = 180
CHNO Cl
Calculated 40.00 3.89 7.78 8.89 39.44
Found 40.06 3.90 7.82 9.05 39.29
The 1 H NMR and mass spectra are consistent with the structure.

Step 2: 4-thiomethoxy 2-picoline N-oxide
A solution of 6 g of 4-chloro-2-picoline hydrochloride
N-oxide is basified with 3.7 ml of 10N sodium hydroxide. After extraction with dichloromethane and dry, 4 g of 4-chloro-2-picoline are obtained.
N-oxide. 15 ml of a 15% aqueous solution of sodium thiomethylate are added and brought to 900 ° C. for 3 hours.

 After extraction with 100 ml of dichloromethane, washing with water, the organic phases are dried over sodium sulfate and evaporated to dryness.

 The oily residue obtained is precipitated with ether and then washed with ether. 1.3 g are obtained.

Yield = 29%
PF = 700C.

Elemental analysis for C7HgNOS; M = 155
CHNOS
Calculated 54.19 5.81 9.03 10.32 20.65
Found 54.19 5.87 8.91 10.45 20.56
The 1 H NMR and mass spectra are consistent with the structure.

EXAMPLE 6 2-Diamino-4-piperidino-1-sulfooxv pyridine

<tb><SEP> zSO3
<tb><SEP> ol <SEP> o <SEP> 3
<tb> HN <SEP> H2
<tb><SEP> 2 <SEP> ClSO3H <SEP> NN + 1NH2
<tb><SEP>> F / <SEP> N, <SEP> N-diisopropyl-ethylamine
<tb><SEP> TO <SEP> AT
<Tb>
Operating mode:
1.2 ml of N, N-diisopropylethylamine are dissolved in 10 ml of chloroform and cooled to -50 ° C.

 0.2 ml of chlorosulphonic acid is then slowly introduced while keeping the temperature below OOC.

 The mixture is stirred for 30 minutes at 0 ° C. and then 0.21 g of 2,6-diamino-4-piperidinopyridine N-oxide is added. 0.7 ml of N, Ndiisopropylethylamine is then added to bring the medium to a basic pH. Stir 1 h 30 between 0 and + 50C.

 The reaction medium is evaporated under vacuum without heating, and the oil obtained is then taken up with a minimum of ice-cold acetonitrile. Then 4 volumes of water are added and cooled in ice. The white solid obtained is filtered and dried in vacuo to give 0.13 g of the expected product.

Yield = 45%
PF = 1650C (decomposition)
Elemental analysis for C10H16N4O4S; 0.3 H2O; M = 288
CHNOS
Calculated 41.23 5.63 19.24 23.09 10.99
Found 41.05 5.62 19.06 23.20 11.06
The 1 H NMR and mass spectra are consistent with the structure.

EXAMPLE OF COMPOSITION 1
The following composition is prepared - 2,6-diamino-4-piperidino pyridine
l-oxide 2.0 g - Propylene glycol 20.0 g - Ethanol 950 50.0 g - Water qs 100.0 g
This composition is in the form of a lotion.

EXAMPLE OF COMPOSITION 2
The following composition is prepared: 2,6-diamino pyridine 1-oxide 1.0 g - Ethanol 950 65.0 g - Water qs 100.0 g
This composition is in the form of a lotion.

 1 to 2 ml of this lotion are applied to the alopecic areas of the scalp at a rate of two applications per day, in the morning and evening for 4 months of treatment.

Claims (15)

 1. A composition for braking hair loss and for inducing and stimulating their growth, characterized in that it contains, in a physiologically acceptable medium, at least one compound of the following formula

 in which R1 and R2, which may be identical or different, denote a hydrogen atom, a C1-C4 alkyl radical, a group -NHR6, where R6 denotes a hydrogen atom or a C1-C4 alkyl radical, or one of following groups of formulas

 in which R7 and Rg, which may be identical or different, denote a C1-C4 alkyl; R4 denotes a hydrogen atom; a group -ORg or -SR9, wherein Rg denotes a C1-C8 alkyl radical, C3-C8 alkenyl, phenylC1-C4 alkyl; or R4 denotes a group -NR1OR11 where RIo and R11, which may be identical or different, denote a C1-C8 alkyl, C3-C8 alkenyl or phenylC1-C4 radical or form, with the nitrogen atom, a heterocycle chosen from pyrrolidino, piperidino, morpholino, 4-alkylpiperidino, said heterocycle possibly containing C1-C3 alkyl radicals; R3 and R5, identical or different, denote a hydrogen atom, a methyl radical, a nitro group, amino, a chlorine or bromine atom; Y is O or OSO3; as well as its cosmetically or pharmaceutically acceptable acid addition salts.  2. Composition according to Claim 1, characterized in that the compound of formula (I) is chosen from 2,6-diamino pyridine oxide, 2,6-diamino-4-piperidino pyridine oxide, 2,6-diamino 4-piperidino-1-sulfooxy pyridine.  3. Composition according to claim 1 or 2, characterized in that it is in the form of ointment, tincture, cream, ointment, powder, patch, impregnated buffer, solution, emulsion. , vesicular dispersion, lotion, gel, spray or anhydrous or aqueous suspension for pharmaceutical application.  4. Composition according to Claim 3, characterized in that the compound of formula (I) is present in concentrations of between 0.1 and 10% by weight relative to the total weight of the composition.  5. Cosmetic composition according to claim 1 or 2, characterized in that it is in the form of lotion, gel, soap, shampoo, aerosol or mousse and that it contains, in a cosmetically carrier acceptable, at least one compound of formula (I) at a concentration of between 0.01 and 5% by weight.  6. Composition according to any one of claims 1 to 5, characterized in that it further contains moisturizing agents and antiseborrheic agents.  7. Composition according to any one of claims 1 to 6, characterized in that it also contains agents which further improve the activity of the compounds of formula (I) in the regrowth and / or braking of the fall. hair.  8. A composition according to claim 7, characterized in that it contains as agents further improving the activity of regrowth and / or braking of hair loss, nicotinic acid esters, anti-inflammatory agents, steroidal or non-steroidal inflammatories, retinoids, antibacterial agents, calcium antagonists, hormones, anti-androgenic agents, OH radical scavengers.  9. A composition according to claim 8, characterized in that it contains as compounds further improving the activity on the regrowth and / or the braking of hair loss, compounds selected from diazoxide, spiroxazone, phospholipids, linoleic and linolenic acids, salicylic acid and its derivatives, hydroxycarboxylic or ketocarboxylic acids, their esters, lactones and their corresponding salts, anthralin, carotenoids, eicosatétrainoic acids-5,8,11,14 and eicosatriynoYque-5,8,1 1, their esters and amides.  10. Composition according to any one of claims 1 to 9, characterized in that it also contains surfactants chosen from nonionic surfactants and amphoteric surfactants.  11. Composition according to any one of claims 1 to 10, characterized in that the physiologically acceptable medium consists of water, a mixture of water and one or more organic solvent (s) or by a mixture of organic solvents, the organic solvents being pharmaceutically or cosmetically acceptable.  12. Composition according to Claim 11, characterized in that the solvents are chosen from C1-C4 lower alcohols, alkylene glycols and mono- and diaikylene glycol aikyl ethers.  13. Composition according to any one of claims 1 to 12, characterized in that the physiologically acceptable medium is thickened by means of thickening agents and / or gelling agents and contains preservatives, stabilizing agents, pH-regulating agents. , osmotic pressure modifying agents, emulsifying agents, UV-A and UV-B filters, antioxidant agents.  14. Use of Compounds of General Formula (I)

 wherein R1, R2, R3, R4, R5, Y, are as defined in claim 1 or their pharmaceutically acceptable acid addition salts for the preparation of a medicament for the therapeutic treatment of alopecia , alopecia areata, hair loss and desquamating dermatitis.  15. Process for the cosmetic treatment of hair and scalp, characterized in that a composition as defined in any one of Claims 5 to 1 3 is applied.