CA2285886C - Compounds containing oxadiazolopyrimidines destined to be used for slowing down hair loss and for inducing and stimulating their growth - Google Patents

Abstract

The invention relates to a pharmaceutical or cosmetic composition, intended to be used in topical application to slow down hair loss and to induce and stimulate their growth. The composition according to the invention is characterized in that it contains, in a physiologically acceptable medium, at least one compound corresponding to the general formula: (see formula III) in which: R denotes a hydrogen atom, an alkyl radical , saturated and linear, in C1-C8 or form with the pyrimidine ring, a hydrocarbon ring of formula: (see formula above) 63 where n is equal to 1, 2 or 3; X denotes (i) a hydrogen atom; (ii) a group of formula: in which R1 and R2, identical or different, denote a hydrogen atom, a saturated C1-C12 alkyl group, linear or branched, unsubstituted or substituted by a halogen atom or a trifluoromethyl radical, a linear C2-C12 alkenyl group, a C3-C10 cycloalkyl group, a C7-C12 aralkyl group or an aryl group corresponding to the formula: in which R9 and R10, identical or different, denote an atom d hydrogen or halogen, or a C1-C4 alkyl, hydroxyl or C1-C4 alkoxy group; or else R1 and R2 form, with the nitrogen atom to which they are linked, a saturated or unsaturated heterocycle, chosen from the groups aziridino, azétidino, pyrrolidino, pipéridino, hexamethyleneimino, heptamethyleneimino octamethyleneimino, tetrahydropyridino, dihydropyridino, pyrrole, pyrrazole and thiomorpholino; (iii) a group -OR3, in which R3 denotes a saturated C1-C12 alkyl radical, linear or branched, unsubstituted or substituted by a halogen atom or a trifluoromethyl radical, a linear C2-C12 alkenyl radical, a C3-C10 cycloalkyl radical, a C7-C12 aralkyl radical, a phenyl radical optionally substituted by one or two groups, which, independently of one another, denote a halogen atom, a C1-C4 alkyl radical -C6, a C1-C6 alkoxy radical, or a trifluoromethyl radical; or (iv) a group -SR4, in which R4 has the same meaning as R3; or one of its physiologically acceptable acid addition salts.

Description

COMPOSITIONS FOR USE: USED TO BRAKE THE
HAIR LOSS AND TO INDUCE AND STIMULATE THEIR
GROWTH, CONTAINING OXADIAZOLOPYRIMIDINES
This application is a divisional application of Canadian application No. 2,024,156 filed on 28 August 1990 and relative of new compositions intended to be used, in particular in application topical, to curb hair loss and to lo induce and stimulate their growth, containing derivatives of 2-amino pyrimidine oxide-3, as well as new derivatives of 2-amino pyrimidine oxide-3 used in these compositions. This application divisional concerns new compositions also intended to be used in application topical to curb hair loss and to induce and stimulate their growth, but containing oxadiazolopyrimid_Lnes, as well as new oxadiazolopyrimidines used in these compositions.
We already know, in the state of the art, the diamino-2,4 piperidino-6 pyrimidine oxide-3 or Minoxidil for its properties of anti-agent hypertensive, mafia also for its use in the treatment of hair loss, alopecia areata, desquamating dermatitis and alopecia.
The Applicant has discovered new compositions for the treatment and prevention of hair loss, used in particular in application topical, particularly effective in the treatment 3o diseases of the scalp thanks to a family

2 particular of compounds derived from amino-2 pyrimidine oxide-3.
The compounds selected by the Applicant, in addition the fact that they are effective for regrowth of hair and in particular, to indure and stimulate their growth and curb their fall, present a antihypertensive activity substantially zero or more lower than that of Minoxidil.
These compounds have solubilities in 1o media usually used in cosmetics and pharmacy clearly superior to those of Minoxidil.
The subject of the invention is therefore new compositions for treatment and prevention hair loss, containing compounds individuals derived from 2-amino pyrimidine oxide-3.
The invention also. for new subject 2-amino pyrimidine oxide-3 derivatives used in these compositions.
Another object concerns the use of compounds according to the invention for the pz ~ separation of a drug intended for the therapeutic treatment of the fall of hair.
The composites = ions according to the invention are essentially characterized by the fact that they contain in a physiologically medium acceptable, at least one compound corresponding to the formula general:

3 Y
R NHR ' / ~
(I) X
in which:
R denotes a hydrogen atom, an alkyl radical, saturated and linear, in C1-C8 or form with the cycle pyrimidine, a hydrocarbon cycle of formula:
(CH2 ~~
where n is 1, 2 or 3; X denotes:
(i) a hydrogen atom;
(ii) a group of formula:

- /NOT

in which RL and R2 are identical or different, denote a hydrogen atom, a saturated alkyl group in C1-C12, linear or branched, can be substituted by a halogen atom or a trifluoromethyl radical, a linear Cz-C12 alkenyl group, a group C3-cycloalkyl - Clo a C ~ -C1z aralkyl group or a aryl group corresponding to the formula:

. \

4 in which R9 and Rlo, identical or different, denote a hydrogen or halogen atom, or a C1-C9 alkyl, hydro: ~ yl or C1-C9 alkoxy; or well R1 and R2 form with the nitrogen atom to which they are connected, a saturated or unsaturated heterocycle, chosen by the aziridino, azétidino, pyrrolidino groups, piperidino, hexamethyleneim: ino, heptamethyleneimino, octamethyleneimino, tetrahydropyridino, dihydropyridino, pyrrole, pyrrazole, imidazole, lo triazole, 4-alkyl piperazino in which the group alkyl has 1 to 4 carbon atoms, morpholino and thiomorpholino;
(iii) a group -OR3 in which R3 denotes a saturated C1 - C12 alkyl radical, linear or branched, can be sub ~, substituted by a halogen atom or a trifluoromethyl radical, a linear alkenyl radical in CZ-C12, a cycloalkyl radical in C3-Clo, a radical (cyclohexyl-1) methyl, a C ~ C12 aryl kyl radical, a phenyl radical optionally substituted with one or two groups which, independently of one another, denote a C1-C6 alkyl radical, an alkoxy radical in C1-C6, a halogen atom or a radical trifluoromethyl; or (iv) a group -SR4, in which R4 has the same meaning as R3 defined above;
Y denotes an oxygen atom or a group -OS030;
R 'denotes a hydrogen atom or one of the following groupings:

_II_RS. _II_O_R ~~. -II_N ~
0 O 0 R $
wherein:

RS and R6 will represent alkyl radicals lower in C1-Cq;
R ~ and Re denote a hydrogen atom or a C1-C4 lower alkyl radical, provided that they

5 do not simultaneously denote a hydrogen atom.
When Y denotes an oxygen atom, the compounds of formula (I), in accordance with the invention, can coexist with their form ~~ automere of formula (I2) according to the following balance:
X
~ I) (I2) Depending on the nature of the environment, one of the forms tautomers can be predominant over the other.
The compounds of formula (I), in accordance with the invention, can be transformed into their salts addition of acids cosmetically or pharmaceutically: acceptable ~ s, such as the salts of sulfuric, hydrochloric, hydrobromic acids, phosphoric, acetic, benzoic, salicylic, glycolic, succinic, nicotinic, tartaric, malefic, pamoic, sulphonic methane, picric, lactic, etc.
Among the compounds of general formula (I), one a number of compounds are known per se and have been described as antihypertensive agents or as synthesis intermediates.

6 They are especially described in patents American Nos. 3,464,987, 3,644,364, 4,013,778 and 4,287,338; French patent No. 2,087,936; the European patents Nos. 58.476 and 57.546 or cited in technical literature (C ~ rn. J. Chem. 1984, 62 (6), 1176-80), (Müller, Ramuz, Helv. Chim., Act. 65 (5), 1982, pages 1454-66).
The new compounds according to the invention have the following formula (I '):
Y
R NHR ' THIS')' X
in which:
R, R 'and Y have the same meanings indicated in formula (7.) above; and X denotes:
(i) a group -SR9, in which R4 denotes a saturated C1 - C12 alkyl radical, linear or branched, may be substituted by a halogen atom or a trifluorornethyl radical, a linear alkenyl radical in CZ-C12, a cycloalkyl radical in C3-Clo, a radical 2o C ~ -C1 ~ aralkyl, a phenyl radical optionally substituted by one or two groups which, independently of each other, denote an atom halogen, an alk ~~ C1-C6 radical, a radical C1-C6 alkoxy or a trifluoromethyl radical; or (ii) a group -OR3, in which R3 has the same meaning as R4, provided that when Y
denotes an oxygen atom, R an alkyl group and

7 R 'denotes a hydrogen atom, R3 does not denote a C1-C4 alkyl radical or a phenyl radical, optionally substituted ~~ ar one or two atoms halogen.
The new compounds of formula (I ') can be find in the form of acid addition salts physiologically acceptable.
Among the compounds pres = ered of formula (I ') above above, we can c_Lter more particularly:
lo - amino - 2 methyl-4 (2,2-dimethyl) propyloxy-6 pyrimidine oxide-3;
- amino - 2 methyl-4 (cyclohexyl-1) methyloxy-6 pyrimidine oxide-: 3;
- amino-2 methyl-4 (hexenyl-5) oxy-6 pyrimidine oxide-3;
- amino - 2 methyl-4 benzyloxy-6 pyrimidine 3-oxide;
- amino - 2 methyl-4 (2,4-dimethyl) phenyloxy-6 pyrimidine oxide- ~ 3 - 2-amino-4-methyl-6-methylthio pyrimidine 3-oxide;
- 2-amino-9-methyl: 6-ethylthio pyrimidine 3-oxide;
- 2-amino-4,5-tetramethylene butoxy-6 pyrimidine oxide-3;
- the internal salt of the amino-2 hydroxide 4-methyl-6-methoxy-3-sulfooxy pyrimidinium;
- the internal salt of the amino-2 hydroxide 4-methyl-6-ethoxy-3-sulfooxy: pyrimidinium; and - the internal salt of the amino-2 hydroxide tetramethylene-4, _ '~ butoxy-6 sulfooxy-3 pyrimidinium.

8 The compounds according to the present invention corresponding to the general formula (I), are obtained at from a substituted 2-amino pyrimidine oxide-3 derivative in position 6, of the following formula:

(II) Z
in which:
R has the meaning given in the formula general (I);
Z denotes a halogen atom chosen from chlorine or bromine, a sulfonate group such as tosylate, brosylate or mesylate or a group phenoxy substituted by electron-withdrawing groups, like halogen atoms or nitro groups.
The particular compounds according to the invention, meeting the formula (IA):

(IA) in which R has the meaning indicated in the formula (I) above, are obtained by hydrogenolysis compounds of formula (II), in which Z denotes 2o more particularly a chlorine or bromine atom.
The reduction is carried out according to the methods classics described in the technical literature (DJ
Brown, The Pyrimidines, Vol. 16, Supplement II,

9 Chapter X, 360). Their preparation process can be represented by the following diagram:

Pd / C, H2 I ~ ~ w ~ nTTl ww The particular compounds of formula (IB):
O

(IA) (IB) are obtained by reacting a solution of the alcoholate R30 ~ W ~, in which R3 has the same meaning as indicated for the formula general (I) and W denotes an alkali metal such as sodium, potassium or lithium, in alcohol corresponding, on the compounds of formula (II) in which Z denotes chlorine or bromine, or a phenoxy group substituted by electro-attractors.
We apply the Williamson method such that described in European Patent No. 57.546, to a temperature between 40 and 100 ° C.
The preparation of these compounds can be represented by the following diagram:

R OH
R 2 R 0 ~

(II) ~ (IB) DIAGRAM B
Compounds: specific formulas (IC) next:
T

(IC) are prepared by reacting on the compounds of formula (II) a thiolate of formula R4S ~, W ~, in which R4 and W have the meanings indicated previously, in the presence of a solvent chosen from

10 ethers, preferably METHYLCELLOSOLVE (brand of store) or ethylene glycol dimethyl ether, to a temperature of the order of 50 to 150 ° C.
We proceed according to the classic methods of literature (DJ Brown, The Pyrimidines, Vol. 16, Supplement II, Chapter VI, Section F).
The preparation of these compounds can be represented by E: following diagram:

11 Solvent: Eth ~

(II) (IC) SCHEM, ~ 1 C
Particular compounds of formula (ID) next:

(ID) are obtained by reacting an amine H-N ' 'R

in which Rl and RZ have the same meanings as those indicated for the general formula (I), on the lo compounds of formula (II). We proceed in the presence of a solvent which may be an alcohol, preferably ethanol, or the serving amine. of reagent and both solvent, at a temperature between 20 and 150 ° C, according to the processes described in the patents American Nos. 3,644,364 and 3,464,987.

12 The preparation of these compounds can be represented by the following diagram:

/ RZ
2 H_N / ~ P 2 R 'N' R

(II) (IDj SCHEME ~~ D
The compounds ~> particulic = rs according to the invention of formula (I), in which Y denotes an atom oxygen, obtained by different processes described above, can be transformed into their 1o 0-sulphate counterparts, by chemical sulphation, according to the classic methods described in the literature (J. Med. Chem. 1983, 26, p. 1791-1793).
The sulfation reagent used is sulfur trioxide-pyridine complexes, trioxide sulfur-triethy: Lamin or sulfur-ethyl trioxide diisopropylamine.
The solvents used are preferably dimethylformamide, acetonitrile, chloroform or their binary mixtures. The temperature is around 2o from 0 to 25 ° C and the reaction time varies between 1 hour and 24 hours.
The particular compounds, according to the invention, of formula (I) in 1_which Y denotes an oxygen atom, can be transformed into their amide counterparts, ureides or carbamates, according to conventional methods

13 described in the literature (J. MARCH, Advanced Organic Chemistry, Fifth Edition, p. 370) per share respectively an acid chloride, an anhydride acid, a carbamic acid chloride or a alkyl chloroformate; we proceed in the presence of a tertiary amine, such as pyridine.
The compounds thus obtained, of formula:

R NHR ' (IE) in which R, R ', X have the same meaning as lo that indicated for the formula (I) defined above, are easily hydrolyzable in potash medium alcoholic, for example, and can give birth to their precursors of formula (I), in which R ' denotes hydrogen.
The transformation of the compounds of formula (I) into which Y is 7_'oxygen ei. R 'is hydrogen, in their 0-sulfates, amides, ureides or carbamates, can be represented by the diagram next:

14 r sulfation XX
X ~ -lIE1 The compounds of formula (IE), in accordance with the invention, can constitute intermediaries for synthesis of oxadiazolopyrimidines of formula (III) next:
e.
(III) in which R and X have the meaning indicated in the general formula (I).
The compounds (III) are obtained by cyclization-lo internal elimination of carbamate or ureide derivatives of formula (IE) according to the methods described in the literature (JC. MÜLLER, Helvetica Chimica Acta, Vol.
66, 1983, p. 669-672).
The compounds of formula (III) and their salts are new, with the exception of 2-oxo-2,8-dihydro [1,2,4] oxa-diazolo [2,3-a] pyrimidine which is described in the document MÜLLER, RAMUZ, Helvetica Chimica Acta 65 (5), 1982, p.
1454-66, and constitute another object of the invention.
They can receive various applications and especially in the use for treatment and prevention of hair loss.
Ä as an example of a compound of formula (III), mention may be made of methyl-7-pyrrolidino-5-2H-oxadiazolo-1,2,4 [2,3-aJpyrimidine-oxo-2.
io The compositions in accordance with this invention, containing in a physiologically medium acceptable, at least one compound corresponding to the formula (I) or (III) or one of its acid addition salts physiologically acceptable, can be applied

15 in the cosmetic or pharmaceutical field, in particular topical application on goats or leather Scalp. They are intended for the treatment and prevention of hair loss and in particular of alopecia, alopecia and dermatitis 2o flaking.
These compositions may include, as physiologically acceptable medium, any medium suitable for topical application, either cosmetic, either in pharmacies, and which is compatible 2s with the active substance.
The compounds according to the invention can be find in this medium, either in the dissolved state, or at the dispersed state, in particular in micronized form.
The compositions intended to be used in 3o pharmacy are in the form of ointment, 15a tincture, cream, powder ointment, patch, soaked pad, solution, emulsion or dispersion gallbladder, lotion, gel, spray or suspension. They: can be either anhydrous or aqueous, according to the clinical indication.
The compounds: according to the invention are present in these pharmaceutical compositions at concentrations

16 preferably comprised enta = 0.1 and 10 ~ by weight, and in particular between 0.2 and 5 ~ by weight, relative to total weight of the composition.
The cosmetic compositions are in particular intended to be used in the form of lotion, gel, soap, shampoo, aerosol or foam and contain, in a cosmetically acceptable carrier, at least one compound of formu ~ _e (I) or one of its salts addition of acids.
1o The concentration of this ~ e compounds of formula (I) in these compositions is preferably included between 0.01 and 5% by weight, and in particular between 0.05 and 3 ~ by weight, compared to the total weight of the composition.
The compositions according to the invention can contain various additives usually used in cosmetic or pharmacy and in particular active substances, such as hydrating agents such as thiamorpholinone and its derivatives or urea; of the 2o antiseborrhoeic agents, such as S-carboxymethylcysteine S-benzylcysteamine, and their derivatives; thioxolone.
The compounds according to the invention can be associated with at least one compound further improving their activity on regrowth and% or on braking of the hair loss, such as especially following compounds:
- nicotinic acid esters, of which more particularly nicotin ~~ your C1-C6 alkyl and 3o in particular nicot: methyl inate;
- steroidal anti-inflammatory agents and non-steroid well known in the art

17 and in particular hydrocortisone, its salts and 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: e, palmitate or propionate, motretinide, etretinate, t-trans zinc retinoate;
- selected antibacterial agents more lo particularly among m <~ crolides, pyranosides and tetracyclines and in particular erythromycin;
- calcium antagonist agents, such as more particularly cinnarizine and diltiazem;
- hormones, such as estriol or analogues or thyroxine and its salts;
- antiandrogenic agents, such as oxendolone, spironolactone, diethylstilbestrol;
- OH radical sensors, such as dimethylsulfoxide.
It is also possible to combine with the compounds of the invention, possibly in admixture with the others, compounds such as Diazoxide corresponding to 3-methyl-7-chloro 2H benzot: hiadiazine 1,2,4-dioxide-1.1; Spiroxasone or 7- (acetylthio) -4 ', 5'-dihydrospiro [androst 4-ene-17.2 '- (3'H) furan] -3 one;
phospholipids, such as lecithin; acids linoleic and linolenic; salicylic acid and its derivatives described more particularly in the patent French No. 2,551,542, and more particularly the 3o salicylic acid derivatives bearing a group alkanoyl having 2 to 12 atoms: carbon in position 5 the benzene cycle; hydroxycarboxylic acids or

18 ketocarboxylates and their esters, lactones and their corresponding salts; anthralin or the trihydroxy-1,8,9 anthracene, carotenoids, eicosatetraynoic acids-5,8,11,14 or eicosa-triynoic-5,8,11, their esters and amides.
The compounds according to the invention can also be associated with surfactants including more particularly those chosen from the agents nonionic and amphoteric surfactants.
1o Among the nonionic surfactants, mention will be made more particularly polyhydroxypropyl ethers described in particular in: ~ French patents Nos.
1.477.048, 2.091.516, 2.169.787, 2.328.763 and 2,574,786; oxyethylenated (C8-C9) alkyl phenols containing from 1 to 100 moles of ethylene oxide and preferably 5 to 35 moles of o ~; yde of ethylene; the alkyls polyglycosides of formula:
CnH2n + 1 (C6Hlo ~ 5) x ~~ ~ A) in which n varies from 8 to 15 inclusive and x from 1 to 10 included .
Among the amphoteric surfactants, will more particularly mention the amphocarboxyglycinates and the amphocarboxypropionates defined in the CTFA dictionary, Sème edition, 1982, and sold, in particular, under the trade mark MIRANOL by the MIRANOL company.
The compounds according to the invention can be introduced in supports = s which further improve regrowth activity, presenting to the times advantageous properties in terms of cosmetics, such as volatile ternary mixtures of alkylene glycol alkyl ether, in particular of alkyl C1-C4, C1-C4 alkylene glycol ether or

19 dialkylene glycol, preferably C1-C9 dialkylene glycol, ethyl alcohol and water, the solvent glycolic designating more particularly the monoethyl ether of ethylene glycol, monomethyl ether propylene glycol, monomethyl ether diethylene glycol.
Compounds conform; to the invention can also be int: roducts in gelled supports or thickened, such as essentially aqueous supports lo gelled by heterobiopo7_ysaccharides, such as that xant gum: hane or the cellulose derivative, hydroalcoholic supports gelled with polyhydroxy ethylacrylates or methacrylates or carriers essentially aqueous thickened in particular by polyacry_Liques acids crosslinked by an agent polyfunctional, such as those: sold under the brand of CARBOPOL trade by GOODRICH Company.
These compositions can also contain at least minus a pharmaceutically or cosmetically adjuvant 2o acceptable chosen from the ~~ group formed by preservatives, stabilizers, pH regulating agents, modifiers of osmotic pressure, emulsifying agents, UVA and UVB filters and antioxidants, such as a-tocopherol, butylhydroxyanisole, butylhydroxytoluene.
The physiologically acceptable medium can be consisting of water or a mixture of water and at least minus one solvent, the solvent being chosen from cosmetically acceptable organic solvents or pharmaceutical and chosen more particularly among lower C1-C4 alcohols, such as alcohol ethyl, isopropyl alcohol, alcohol tert-butyl, alkylene glycols, alkyl ethers alkylene glycol and: dialkylene glycol, such as monoethyl ether of ethylene glycol, the monomethyl ether of propylene glycol, the diethyleneglycol monomethyl ether collar. Solvents: when they are present s in proportic:> ns preferably between 1 and 80% by weight relative to the total weight of the composition.
Physiologically acceptable media can be thickened with thickening agents and / or io gelling agent: used: It is used in cosmetics or pharmacy, and we can more particularly cite the heterobiopolysaccha: wrinkles such as gum xanthan, scleroglucans, cellulose derivatives like ether: cellulose, polymers 15 acrylic, crosslinked or not.
The thickeners are preferably present in proportions of between 0.1 and 5% by weight, and in particular ent.rs ~ 0.4 and 3% by weight, relative to total weight of the composition.
2o The invention also relates to a method of cosmetic treatment of hair or scalp, consisting in applying to them at least one composition as defined: above, to improve the aesthetics of the hair.
2s Another object: of the invention consists of the use of ~ ..a composition containing the compounds of formu7_e (I) defined above, for the preparation a drug that has the effect of inducing or stimulate hair growth and curb their 3o fall.
The treatment. mainly involves applying on the al.opecic areas of the scalp of a 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, during 1 to 7 days a week and CE? C1. for a period of 1 at 6 months.
The compositions can. especially be used in the treatment of alopecia areata, the fall of hair, peeling dermatitis.
The following examples: bridge intended to illustrate l0 the invention without presenting a character limiting.
PREPARATION EXAMPLES

Amino-2 methyl-4 piperidino-6 pyrimidine oxide-3 O

NH

Procedure:
15 g (9.35'10-2 mole) 2-amino-4-methyl chloro-6 pyrimidine oxide-3 are introduced in suspension in 150 ml piperidine. The mé: iange is heated to 100 ° C
for 8 hours. After cooling of the medium reaction, the precipitate is. filtered, washed with piperidine then ethyl ether. I1 is then added to 35 ml of an aqueous sodium hydroxide solution at 10 ~

containing 6 g of sodium chloride; we let shake 1/2 hour then the resulting precipitate is filtered which, after drying, is recrystallized from the water system ethanol (80/20).
Mass obtained = 12.5 g Yield = 64%
Mp = 262 ° C
Elementary analysis for C1oH16N40; PM = 208.
CHNO
Calculated 57.69 7.69 26.92 7.69 Found 57.76 7.73 26.81 7.71 1 H and 13 C NMR spectra as well as the l0 mass spectrum conform to the structure.

Amino-2 methyl-4 pyrrolidino-6 pyrimidine oxide-3 Procedure:
In a 250 ml knitted fabric provided with an agitator magnetic, thermometer and refrigerant, we place 9 g (5.61 ~ 10-2 mole) 2-amino-4-methyl-chloro-6 pyrimidine oxide-3 suspended in 90 ml of pyrrolidine. The reaction medium is stirred for 2 2o hours at room temperature, i.e. 25 ° C. After having cooled to 5 ° C, the precipitate is filtered on glass sintered. It is washed with 100 m = L of acetone then with 2x100 ml of ethyl ether. Mass obtained = 8.85 g.
The precipitate is recrystallized from a mixture acetonitrile-water (95/5). A precipitate is obtained in white glitter.
Mass obtained = 4.70 g Yield = 43 ~
Mp = 260 ° C (decomposition).
Elementary analysis for C9H19N40; PM = 194 Calculated 55.67 7.22 28.86 8.25 Found 55.69 7.29 29.03 8.37 13C NMR and mass spectra are consistent to the structure.

Amino-2 methvl-4 morpholino-6 pvrimidine oxvde-3 Procedure:
In a 100 ml three-necked flask fitted with an agitator 1o magnetic, a thermometer and a coolant, we place 5 g (3.12'10-2 mole) of 2-amino-4-methyl-chloro-6 pyrimidine oxide-3 extra: oension in 50 ml of morpholine. The reaction medium is stirred for 2 hours at room temperature, i.e. 25 ° C. After having cooled to 5 ° C, the precipitate is filtered on glass sintered. It is washed with 2x50 ml of acetone and then with 2x50 ml of ethyl ether. Mass obtained = 9.10 g.
The precipitate is taken up in 90 ml of potash alcoholic at 10 ~. Stir 1 hour then filter on 2o a sintered glass previously filled with silica. The solution is evaporated to dryness.
The precipitate is recrystallized from a mixture acetonitrile-water (90/10).
Mass obtained = 2.1 g Yield = 35 ~
Mp> 260 ° C
Elementary analysis for C9H19N402; PM = 210 Calculated 51.43 6.66 26.67 15.24 Found 51, 48 6, 7.L 26, 57 15, 48 NMR spectra of 13C ~~ t mass are consistent to the structure.

Amino-2 methyl-4 t; hiomorpholino-6 pyrimidine oxide-3 The procedure described in Example 3 is followed, but using thiomorpholine.
Temperature: 25 ° C
lo Time: 2 hours Recrystallization from acetonitrile-ethanol (90/10) Yield = 42 ~
Mp = 243 ° C
Elementary analysis for C9H14N40S; PM = 226 Calculated 47.78 6.19 24.78 7.08 14.16 Found 47.88 6.25 24.86 7.22 14.03 NMR spectra of 13C ~~ t mass are consistent to the structure.

2o Amino-2 methyl-4 (N-méthy7_pipérazino) -6 pyrimidine 3-oxide The procedure described in Example 3 is followed, using N-methylpiperazine.
Temperature: 30 ° C
Time: 18 hours Recrystallization from the acetonitrile system-ethanol (50/50) Yield = 36 ~
Mp = 220 ° C
Elemental analysis for CloH1 ~ N50'1 / 4H20; PM = 223 CHNO
Calculated 52, 75 7, 6 ~~ 30, 77 8, 79 Found 52, 90 7, 6 ~ 30, 95 8, 83 Calculated with 0.25 mole H ~ 0 13C NMR and mass spectra are consistent to the structure.

Amino-2 methvl-4 diethvlamino-6 pvrimidine oxide-3 Procedure:
In a 250 ml three-necked flask fitted with an agitator 1o magnetic, a thermometer and a coolant, we place 10 g (6.24'10-2 mole) 2-amino-4-methyl-chloro-6 pyrimidine oxide-3 suspended ~; ion in 70 ml of ethanol.
10 equivalents of diethylamine, i.e. 60 ml. he reaction medium is 15 heated at 50 ° C for 24 hours. Cool to 5 ° C
then 70 ml of alcoholic potash are added to 10 ~.
Shake for 1 hour. We f_Lltre on a sintered glass previously filled with silica. The solution is evaporated to dryness.

20 Mass obtained = 9.5 g.
The precipitate is recrystallized from acetonitrile.
Mass = 7.15 g Yield = 58 ~
25 mp = 188 ° C
Elementary analysis for CgH16 ~ 40: PM = 196 Calculation 55.10 8.16 28.57 8.16 Found 54.93 8.13 28.77 8.40 NMR spectra of 13C ~~ t mass are consistent to the structure.

Amino-2 methyl-4 dimethylamino-6 pyrimidine oxide-3 The procedure described in Example 6 is followed, using dimethylamine.
Temperature: 25 ° C
lo Time: 3 hours Recrystallization from the acetonitrile-water system (90/10) Yield = 67 ~
Mp = 222 ° C
Elementary analysis for C ~ HlzN40% PM = 168 Calculated 50.00 7.14 33.33 9.52 Found 49.99 7.16 33.29 9.64 The 13C, 1H and mass NMR spectra are conform to the structure.

2o-Amino-2 methyl-4 diallylamino-6 pyrimidine oxide-3 Procedure:
In a 100 ml three-necked flask fitted with an agitator magnetic, thermometer and refrigerant, we place 5 g (3, 1210-2 mole) 2-amino-4-methyl-chloro-6 pyrimidine oxide-3 suspended ~; ion in 50 ml of ethanol.
2.2 equivalents of diallylamine, or 6.7 g. The reaction medium is heated at 60 ° C for 24 hours.
Cool to 5 ° C and then filter the precipitate corresponding to the rest of the amino-2 methyl-4 chloro-6 pyrimidine oxide-3. The solution is evaporated to dryness. We adds et; hanol hydrochloric until acid pH.
By addition of ethyl ether, the 2-amino-4-methylally diallylamino-6 hydrochloride pyrimidine oxide-3.
This precipitate is recrystallized from a mixture acetone / ethanol.
Mass obtained = 1 g Yield = 12 Mp = 166 ° C
The derivative is isolated in the form of its hydrochloride.
Elementary analysis for C11H1 ~ N40C1: PM = 256.5 Calculated 51.45 6.63 21.83 6.23 13.84 Found 51, 56 6, 65 21, 92 6, 38 13, 72 NMR and mass spectra conform to the structure.

Amino-2 methyl-4 (n-butylamino) - 6 pyrimidine oxide-3 We follow the procedure described in the example 2, using n-butylamine.
2o Temperature: 55 ° C
Time: 18 hours Recrystallization from _The acetonitrile-water system (70/30) Yield = 49 ~
Mp = 216 ° C
Elementary analysis for C9H16N40; PM = 196 Calculated 55.10 8.16 28.57 8.16 Found 54.91 8.22 28.72 8.25 1H NMR and mass spectra are consistent to the structure.

Amino-2 methyl-4 benzylamino-6 pyrimidine oxide-3 We follow the procedure described in the example 2, using benzylamine.
Temperature: 60 ° C
Time: 6 hours 1o recrystallization in the water-ethanol system (75/25) Yield = 53 ~
Mp = 226 ° C
Elementary analysis for ClzH1 ~ N40; PM = 230 C 1-i N 0 Calculated 62, 60 6, 09 24, 35 6, 95 Found 62.69 6.02 24.43 7.06 1H NMR and mass spectra are consistent to the structure.

Ethoxycarbonylamino-2 methyl-4 ~ 6-iperidino pyrimidine 3-oxide H3C \ NH2 H3C / O ~ /
NE: t + C2H50COC1 -NOT
By the action of ethyl chloroformate on amino-2 methyl-4 piperidino-6 pyrimidine oxide-3, in presence of triethylamine, carbamate is obtained ethyl ethyl expected.
Procedure:
In a 50 ml knitted fabric provided with an agitator magnet, a thermometer and a light bulb addition, place 2 g (1.2510-2 mole) of amino-2 lo methyl-4 piperidino-6 pyrimicline oxide-3 in suspension in 20 ml of dichloromethane previously dried on molecular sieve. We add 1 equivalent of triethylamine, i.e. 1.35 ml. We cool the medium reaction at 0 ° C. and 1 dropwise added equivalent of ethyl chloroformate, that is 1.05 g. We let return to room temperature (25 ° C) and shakes for 2 hours.
10 ml of water are added to the reaction medium. The organic phase is extracted by:
- 10 ml of hydrochloric acid 1 ~
- 10 ml of a sodium carbonate solution 1 ~
- 2x10 ml of water then dried over sodium sulfate.
After filtration on paper, the solution is evaporated. A white precipitate is obtained.

Mass obtained = 2 g This precipitate is recrystallized from 45 ml of water.
Mass obtained = 1.60 g Yield = 60 ~
5 PF = 1 34 ° C
Elementary analysis for Cl3HZON403: PM = 280 Calculated 55.71 7 .14 20.00 17.14 Found 55.80 7, .18 20.09 17.05 NMR spectra of 13C ~~ t mass are consistent 10 to the structure.

2-acetamido-4-methyl-6-dimethylamino pyrimidine oxide-3 According to the procedure described in the example 11, acetyl chloride is reacted in the presence 15 of triethylamine, on 2-amino-4-methyl-dimethylamino-6 pyrimidine oxide-3.
Temperature: 25 ° C
Time: 2 hours Recrystallization from ethyl methanol acetate 20 (50/50) Yield = 10 ~
Mp = 208 ° C
Elementary analysis for C9H14N402; PM = 210 Calculated 51, 43 6, 67 26, 67 15, 24 Found 51, 32 6, 66 26, 66 15, 36 25 13 C NMR and mass spectra are consistent to the structure.

7-methyl-pyrrolidi.no-5-2H-oxa ~~ iazolo-1,2,4 [2,3a pyrimidine-oxo-2 H3 (~ H2 C1-CN (CH3) 2 HC
NOT /
(And) 3N ~
Procedure:
In a 50 ml knitted fabric provided with an agitator magnet, a thermometer and a light bulb addition, place 2 g (1.25'10-2 mole) of amino-2 4-methyl-6-pyrrolidino pyrimidine oxide-3 in suspension 1o in 20 ml of dichloromethane previously dried on molecular sieve. We add 2 equivalents of triethylamine, i.e. 2.9 ml. We cool the medium reaction at 0 ° C. We add drop by drop 2 equivalents of di.methylcarbamoylchloride, i.e. 2.2 g.
Leave to return to room temperature (25 ° C) and shakes for 2 hours.
Cool to 0 ° C and then filter the precipitate corresponding to triethylamine hydrochloride. The solution is evaporated to dryness. We take the solid obtained in ethanol. After stirring for 1 hour, we filters the precipitate. This precipitate is recrystallized in ethanol.
Mass obtained = 0.5 g Yield = 23 ~

Mp = 255 ° C (decomposition) Elemental analysis for CloHlaN402 ~ 1isH20; PM = 220 Calculated 53.66 5.54 25.05 15.74 Found 53.96 5.51 25.25 15.66 1H NMR and mass spectra are consistent to the expected structure.

Amino-2 methyl-4 methoxy-6 pyrimidine oxide-3 OO
H3 ~ VHZ CH30Na H3C NH2 10 g of sodium are dissolved in 750 ml of methanol.
lo We add 50 g of amino-2 met ~ hyl-4 chloro-6 pyrimidine oxide-3 and the reaction medium is brought to reflux for 4 hours. The solvent is evaporated, the mixture is dissolved in 250 ml of E = _au and 30 ml of acid concentrated hydrochloric acid, filtered and then basified by addition of soda. The white precipitate obtained is recrystallized from water.
Yield = 43 ~
Mp = 210 ° C
Elementary analysis for C6H9r1302'0, 15 HzO; PM = 155 C 1 ~ N 0 Calculated 45.66 5.90 26.63 21.81 Found 45.77 5.93 26.56 21.84 13C NMR and mass spectra conform to the expected structure.

EXAMPLE: 15 Amino-2 methvl-4 ethoxy-6 pyr: imidine oxide-3 The procedure described in Example 14 is followed, using ethanol.
Temperature: 80 ° C
Time: 4 hours After the reaction mixture has dried and addition of ether, the precipitate obtained is filtered. We 1o evaporates the mother liquors and precipitates with acetone. The white precipitate: obtained is recrystallized in an ac: etone / water mixture.
Yield = 25 ~
Mp = 155 ° C
Elementary analysis for C ~ H11N302% PM = 169 C f ~ N 0 Calculated 49.70 6.51 24.85 18.93 Found 49, 34 6, 6 24, 63 18, 69 1H, 13C NMR and mass spectra are consistent to the expected structure.

2o Amino-2 methyl-4 butyloxy-6 pyrimidine oxide-3 We follow the operato = _re mode described in example 14, using butanol.
Temperature: 118 ° C
Time: 4 hours Recrystallization from an ether mixture of Oil / Acetone.
Yield = 34 ~

Mp = 137 ° C
Elementary analysis for C9H15 ~ '~ 302% PM = 197 Calculated 54.82 7.61 21.32 16.24 Found 54.74 7.65 21.20 16.41 1H NMR and mass spectra are in accordance with the expected structure.
EXAMPLE: 17 Amino-2 methyl-4 (methyl-1) eth: yloxy-6 pyrimidine oxide-3 The procedure described in Example 14 is followed, but using isopropan ~~ l.
lo Temperature: reflux Time: 48 hours Recrystallization from an acetonitrile-water mixture (98/2) Yield = 10 ~
Mp = 190 ° C
Elementary analysis for CgH13N302% PM = 183 Calculated 52.46 7.10 22.95 17.49 Found 52.44 7.20 22.92 17.58 1H NMR and mass spectra are in accordance with the expected structure.

Amino-2methyl-4 (2,2-dimethyl) propyloxy-6 pyrimidine 3-oxide 0.32 g of sodium is dissolved in 50 ml of 2,2-dimethyl-2 propanol-1 hot. 2 g are added (0.0125 mole) of amino-2 methyl-4 chloro-6 pyrimidine oxide-3 and the reaction medium is brought to 105 ° C for 22 hours. Pour the still hot mixture into 300 ml of an aqueous solution of sodium hydroxide at 10 ~. We extract with ethyl acetate and the organic phase is dried with sodium sulfate. We concentrate and we get 5 a brown oil. Filtered on silica gel in using an elution gradient with ethyl acetate and methanol. After evaporating ~~ n, we obtain a product solid crude which is rewritten: ~ tallized in a mixture acetonitrile-water (98/2).
lo Yield = 17.%
Mp = 213 ° C
Elementary analysis for C1oH17N302; PM = 211 C ~ N 0 Calculated 56.87 8.06 19.90 15.16 Found 56.74 8.04 19.80 15.15 1H NMR and mass spectra are in accordance with the expected structure.
15 EXFMPI ~ i's 19 Amino-2 methyl-4 (cyclohexyl - 1) methyloxy-6 pyrimidine 3-oxide We follow the operato_Lre mode described in example 14, using cyclohexylmethanol.
20 Temperature: 85 ° C
Time: 5 hours Recrystallization from an acetonitrile-water mixture (98/2) Yield: 30 ~
25 mp = 161 ° C
Elemental analysis for C12H19N302, '0.1 H20; PM = 237 Calculated 60.25 8.04 17.57 14.13 Found 60.26 8.05 17.60 14.10 The 1 H NMR and ~~ mass spectra are in accordance with the expected structure.
EXAMPLE: 2 0 Amino-2 methyl-4 (hexenyl-5) ox; y-6 pyrimidine oxide-3 The procedure described in Example 14 is followed, using hexene-5 0l-1.
Temperature: 85 ° C
Time: 3 hours, 15 minutes Recrystallization from acetonitrile 1o Yield = 27 Mp = 103 ° C
Elemental analysis for C11H1 ~ N302, 0, 1'H20; PM = 223 Calculation 58, 66 7, 18, 66 15, O1 Found 58.68 7.65 18.52 14.93 1H NMR and mass spectra are in conformity of the expected structure.

Amino-2 methvl-4 benzyloxy-6 pyrimidine oxide-3 The procedure described in Example 14 is followed, using benzyl alcohol.
2o Temperature: 83 ° C
Time: 2 hours 30 minutes Recrystallization from an acetonitrile-water mixture (98/2) Yield = 45 ~
Mp = 188 ° C

Elementary analysis for Cl2Hi: 3N302% PM = 231 Calculated 62.33 5.62 18.18 13.85 Found 62.40 5.59 18.06 13.89 1H NMR and mass spectra are in accordance with the expected structure.
EXAMPLE: 2 2 Amino-2 methyl-4 (2,4-dimethyl) phenyloxy-6 pyrimidine 3-oxide The procedure described in Example 14 is followed, using 2,4-dimethyl: phenol.
l0 Temperature: 7 5 ° C
Time: 4 hours Recrystallization from an acetonitrile-water mixture (95/5) Yield = 60 ~
Mp = 214 ° C
Elementary analysis for Cl3HisN30z% PM = 245 CI ~ NO
Calculated 63.67 6.12 17.14 13.06 Found 63.60 6.16 17.16 13.19 13C, 1H NMR and mass spectra are consistent to the expected structure.

Amino-2 methvl-4 methvlthio-6 pvrimidine oxvde-3 OO
H3 2 CH3SC ~ Na ~ H3 2 W (1) Compound (I) is obtained: naked by the action of methyl-sodium thiolate, hot, on 2-amino-4-methyl 6-chloro pyrimidine oxide-3.
Procedure:
5 g (3.12'10-2 mol) 2-amino-4-methyl-chloro-6 pyrimidine oxide-3 are introduced into 75 ml of 1,2-dimethoxy ethane; 5.46 g (7.81'10-2 mole) are added sodium methylthiolate and then brought to reflux 1o until the starting substrate disappears (reaction = 55 hours). The precipitate obtained, after filtration of the reaction medium, is dissolved in methanol and added with ethanol chlorh ~~ drique until pH = 2; the hydrochloride of compound (1) is isolated, then the base associated is released by adding a solution of sodium methylate at 30 ~ in methanol; after having removing the salts by precipitation with ethyl ether, the resulting filtrate is evaporated to dryness and then recrystallized from the acetonitrile-ethanol system (70/30). 1.55 g of compound (1) are obtained.
Yield = 29 ~
Mp = 172 ° C
Elementary analysis for C6H9N30S; PM = 171 Calculated 42.10 5.26 24.56 9.35 18.71 Found 42.17 5.31 24.65 9.45 18.47 13C NMR and mass spectra conform to the expected structure.
EXAMPLE: 2 4 Amino-2 methvl-4 ethvlthio-6 ~ yrimidine oxide-3 5 g (3.1210-2 mole) 2-amino-4-methyl chloro-6 pyrimidine oxide-3 are introduced in suspension in 75 ml of 1,2-dimethoxyethane; we add 3.92 g (4,68'10-z mole) of ethylthio: Sodium latex, then reflux up to di: ~ appearance of the substrate lo departure (towing = 18 hours). The precipitate from the middle stirred in suspension in 30 ml of water then filtered, dried and recrystallized in acetonitrile. 2.1 g of the expected compound are obtained.
Yield = 36 ~
Mp = 152 ° C
Elementary analysis for C ~ H11N30S; PM = 185 Calculated 45.40 5.94 22.70 8.65 17.29 Found 45, 33 5, 9-'i 22, 82 8, 78 17, 32 The 1 H NMR and mass spectra conform to the expected structure.
2 o EXAMPLE 2 5 Amino-2-methyl-4 pyrimidine oxide-3 H ~ MeOH / Na2C03 H
3 2 ~ 3 2 Pd / C H2 15 g of a: mino-2 methyl-4 chloro-6 are mixed pyrimidine oxide-3, 11 g of ~~ sodium arbonate, 2, 4 g of palladium / carbon at 10 ~ da: zs 1 liter of methanol. We hydrogenolysis in a PARR device at 2x105 Pa for 2 hours 30 minutes. We filter the medium reaction then the solvent is evaporated. The precipitate 5 is extracted with boiling ethyl acetate.
Yield = 20 ~
Mp = 145 ° C
Elementary analysis for CSH ~ N30; PM = 125 Calculated 48.00 5.6 33.6 12.8 Found 47.97 5.6 33.7 12.87 1o 13C NMR and mass spectra conform to the expected structure.
EXEMPI ~ F: 2 6 Internal salt of hydroxide: 2-amino-methyl-4 dimethvlamino-6 sulfooxy-3 pyrimidinium ~. ~ H ~

~ N H3 ~ ~ FH3 0 ~ OO ~ SO- QN
~ H ~ p ~ ~ ~ CH

15 H3 H3 (2) Ä a solution of 1.03 ml (0.006 mole) of N, N-diisopropylethyl amine in 8 ml of chloroform cooled in ice, 0.2 0.2 g is added with stirring ml (0.003 mole) of chlorosulfonic acid. After waiting 20 of 30 minutes, 0.252 g (0.0015 mole) of amino 2-methyl-4-dimethylamino-pyrimidine oxide-3 and one maintains 2 hours between 0 "and 5 ° C, under nitrogen.

filters the white precipitate that has formed, and then wash with a little chloroform.
After recrystallization from a mixture dimethylformamide-water, 0.11 g of compound (2) is obtained which decomposes at 250 ° C. The efficiency is 30 ~.
Elementary analysis for C ~ H12: N409S; PM = 248 Calculated 33.88 4.84 22.58 25.80 12.90 Found 33.90 4.86 22.62 25.82 12.81 Mass spectrum: compliant.

1o Internal salt of hvdroxvde of amino-2 methyl-4 pyrrolidino-6 sulfooxy-3 pyri: midinium NH2 ~ 0 NO = ~ = O

0 ~

In a suspension of 0.194 g (0.001 mole) of 2-amino-4-methyl-6-pyrrolidino-3-pyrimidine oxide, 0.32 g (0.002 mole) of complex is added with stirring of sulfur trioxide-pyridine and maintained at room temperature for: 3 hours. We dilute the solution obtained with 15 g of ice water. We filter the white precipitate, then washed with a little water 2o frozen.
After recrystallization from a dimethyl-formamide-water, 0.085 g of compound (3) is obtained which decomposes at 260 ° C.
The yield is 31 ~.
Elementary analysis for C9H14N4O4S; PM = 274 CHNOS
Calculated 39.42 5.11 20.44 23.36 11.68 Found 39.35 5.16 20.33 23.36 11.61 Mass spectrum: compliant.
EXAMPLE: 2 8 Internal salt of 2-amino-4-methyl hydroxide piperidino-6 sulfooxy-3 pyrimidinium The procedure described in Example 27 is followed, using 2-amino-4-methylpiperidino-6 pyrimidine 3-oxide.
The product obtained recrystallized from a mixture lo dimethylformamide-water is a monohydrate which decomposes at 184 ° C.
The yield is 73s.
Elementary analysis for C1oH18N905S% PM = 306 Calculated 39.21 5.88 18.30 26.14 10.46 Found 39.27 6.08 18.48 26.02 10.44 Mass spectrum: compliant.
1H NMR spectrum: compliant.

Internal salt of 2-amino-4-methyl hydroxide 6-morpholino-3-sulfooxy pyrimidinium 2o The procedure described in Example 26 is followed, using 2-amino-4-methyl-6-morpholino pyrimidine 3-oxide.
The reaction time is. 3 hours and the temperature the temperature is maintained between 5 and 10 ° C.
The product obtained recrystallized from a mixture dimethylformamide-water decomposes at 250 ° C.

The yield is 56 ~.
Elementary analysis for C9HIqNqOSS; PM = 290 CHNOS
Calculated 37.24 4.83 19.31 27.59 11.03 Found 37.29 4.81 19.39 27.83 10.96 Mass spectrum: compliant.

Internal salt of 2-amino-4-methyl hydroxide thiomorpholino-6 sulfooxy-3 pyrimidinium We follow the operating mode described in Example 26, using 2-amino-4-methyl thiomorpholino-6 lo pyrimidine oxide-3.
The reaction time is 1 hour 30 minutes.
The product obtained recr_ ~ stallized in a mixture dimethylformamide-water decomposes above 260 ° C.
The yield is 74%.
Elementary analysis for C9H14N904S2; PM = 306 Calculated 35.29 4.57 18.30 20.91 20.91 Found 35.15 4.50 18.35 21.10 20.88 Mass spectrum: compliant.
EXAMPLE's 31 Internal salt of 2-amino-4-methyl hydroxide (4-methylpiperazin) -6-3-sulfooxy pyrimidinium We follow the operating mode described in Example 26, using 2-amino-methyl-4 (4-methyl-piperazino) -6 pyrimidine oxide-3.
The reaction time is 3 hours.
The product obtained recrystallized from a mixture dimethylformamide-water decomposes at 265 ° C.

The yield is 20 ~.
Elemental analysis for CloH1vN504S, '0.15 H2O; PM = 303 Calculated 39.27 5.65 22.91 21.68 10.47 Found 39.18 5.72 23.01 21.68 10.46 Mass spectrum: compliant.

Internal salt of 2-amino-4-methyl hydroxide 6-methoxy-3-sulfooxy pyrimidinium The procedure described in example 26 is followed, using 2-amino meth; 4-yl-6-methoxy pyrimidine lo oxide-3.
The reaction time is 1 hour 30 minutes.
The yield of crude product is 60 ~.
Mass spectrum: compliant.

Internal salt of 2-amino-4-methyl hydroxide ethoxv-6 sulfooxy-3 pyrimidinium Ä a solution of 1.03 ml (0.006 mole) of N, N-diisopropylethylamine in 8 ml of chloroform cooled in ice, 0.2 0.2 g is added with stirring 20 ml (0.003 mole) of chlorosulfonic acid. After one wait 30 minutes, add 0.253 g (0.0015 mole) amino-2 methyl-4 ethoxy-6 pyrimidine oxide-3 and maintains 2 hours between 0 ° ~~ and 5 ° C, under nitrogen. The solvent is evaporated. The residue taken up in a little water leaves a white product to crystallize which is filtered and dried.
The yield of crude product is 25 ~.
Mass spectrum: compliant.

EXAMPLE: 3 4 2-amino-4,5-tetramethylene-6 piperidino-pyrimidine 3-oxide 1st part:
5 Preparation of the 2-amino tet: 4,5-ramethylene-6-hydroxy pyrimidine.
In a three-necked vehicle, equipped with a refrigerant, a therm mometer and an entry of ~ irgon, we dissolve 2.15 g (9.35'10-2 m) of sodium in 70 ml of absolute ethanol then 10 8.95 g (9.3710-2 mole) of chloride are added guanidinium in solid portions while maintaining the temperature at 25 ° C.
We then proceed to a gradual pouring of 16.66 ml of ethylcyclohexanone-2 carboxylate at 90 ~
15 (9, 3710-2 m) previously introduced into an ampoule bromine; the flow time is 20 min and the temperature of the exothermic reaction develops up to 45 ° C.
When the temperature of the reaction medium is 2o returned to ambient, we filter the precipitate, we wash thoroughly with water to remove chloride sodium then with ethanol; the gross mass thus obtained is recrystallized from water.
Recrystallized mass: 11.84 g 25 Yield = 76.3%
Analyzes:
Mp = 300 ° C
Elementary analysis for C $ H11N30; 0.1H20; PM = 165 Calculated 57.55 6.65 25.18 10.55 Found 57.57 6.73 25.09 10.56 1H NMR spectra and ~~ e mass are in accordance with the expected structure.
Part 2:
Preparation of 2-amino-4,5-chloro-6 tetramethylene pyrimidine.
In a knitted fabric of 250 rr.l, fitted with a thermometer, a refrigerant topped with a chloride guard calcium and magnetic stirring, we introduce 10 g (6 '10-2 m) of 2-amino tet ~ ramethylene-4, 5 hydroxy-6 pyrimidine in 1C) 0 ml of phosphorus oxychloride.
The medium is heated at 100 ° C. for 1/2 hour, then allowed to return to room temperature.
The phosphorus oxychloride is evaporated; the oil obtained is poured slowly over an aqueous solution 6.6% ammonia (300 ml) while maintaining the temperature below 10 ° C.
Stir 1/2 hour and filter the white precipitate obtained by washing with water until neutral.
The gross mass thus re ~: raised is recrystallized in ethanol.
Recrystallized mass = 4 g Yield = 36.4 Analyzes:
Mp = 207 ° C
Elementary analysis for C $ HloN3Cl; PM = 183.5 Calculated 52.32 5.45 22.89 19.34 Found 52.27 5.49 22.98 19.46 1H NMR and mass spectra are consistent to the expected structure.
Part S:
Preparation of 2-amino-4,5-chloro-6 tetramethylene pyrimidine oxide-3 In a one liter knitted fabric fitted with a thermometer and of magnetic stirring, 30 g are introduced (16.34'10-2 mole) of amino-2 tE = tramethylene-4,5 chloro-6 lo pyrimidine suspended in 600 ml of methanol; we then add 76.2 g (1.5 equivalents) of acid metachloroperbenzoic at 55 ~ maintaining the temperature at 5 ° C.
Then leave to stir for 4 hours at room temperature (25 ° C).
The reaction medium is filtered and the precipitate isolated is washed with cold methanol, then with ether ethyl.
Mass obtained = 28.5 g 2o Yield = 87%
Analyzes:
Mp = 188 ° C
Elementary analysis for C $ HloC1N30; PM = 199.5 CHN 0 Cl Calculated 42.12 5.01. 21.05 8.02 17.79 Found 48.07 5.0 ~~ 21.09 7.95 17.85 1H NMR and mass spectra are consistent to the expected structure.

4th part Preparation of 2-amino-4,5-tetramethylene-ridino-6 pyrimidine oxide-3 H (NH ~ NH
2 ~ 2 Procedure:
g (510- 'mole) of 2-amino-4,5-tetramethylene chloro-6 pyrimidine oxide-3 are introduced into 100 ml piperidine; the reaction medium is heated to reflux for 8 hours, re: cooled to ambient, then lo filtered on sintered. The precipitate obtained is added in solid portions to a 30 cc refrigerated solution of water in which 2 g of sodium hydroxide and 3 g of sodium chloride. Shake for 1 hour, filter, then washing with water until neutral; white crystals are recrystallized from a water / ethanol mixture (50/50).
Mass obtained = 5.4 g Yield = 43.5 Analyzes:
Mp = 178 ° C
Elementary analysis for Cl3HZON40; 0.3 H20 PM = 248 Calculated 61.56 5, .13 22.09 8.21 Found 62.02 8, .11 22.19 8.24 1H NMR and mass spectra are consistent to the expected structure.
EXAMPLE: 3 5 2-amino-4,5-tetramethylene-6-butoxy-pyrimidine oxide-3 Procedure:
In a knitted fabric, fitted with a coolant, a therm mometer and an entry of argon, add 1.72 g (7.5'10-2 m) of sodium in 100 ml of anhydrous butanol, shake for 3/4 of an hour while allowing to develop the exothermicity linked to the formation of butylate sodium. Then added by solid portions, 10 g (510-2 m) 2-amino-4,5 tetramethylene chloro-6 pyrimidine oxide-3 then heated to reflux of butanol for 1 hour.
After the reaction medium has cooled, filter and the neutrality filtrate is adjusted by addition of hydrochloric ethanol; sodium chloride is removed, then the organic phase is washed with 30 ml of distilled water, evaporated to dryness and the residue 2o resulting oily is precipitated by addition of ether ethyl. It is stirred in an ice-water bath for 1/2 hour, then filter.
The gross mass obtained (9 g) is recrystallized in an acetonitrile / ethanol mixture (50/50), thus collects 4.65 g of the pure compound.
Yield = 39 ~
Analyzes:
Mp = 166 ° C
Elementary analysis for C12H19N302; PM - 237 Calculated 60.76 8.02 17.72 13.50 Found 60.76 8.06 17.78 13.69 13C NMR and mass spectra are consistent to the expected structure.
EXAMPLE: 3 6 Amino-2 methvl-4 anilino-6 pyrimidine oxide-3 5 In a three-necked vehicle, equipped with a refrigerant, a therm mometer and magnetic stirring, place 20 g amino-2 methyl-4 chloro-6 pyrimidine oxide-3, 25.65 g aniline and 100 ml of ethanol. The reaction medium is brought to 55 ° C for 4 hours.
lo After returning to room temperature, filter on paper, then evaporate to dryness, the oil is taken up in 10 m: l of ethanol, then brought to pH = 4 by addition of hydrochloric ethanol. 100 ml are added ethyl ether. A beige product precipitates. This The precipitate is filtered, washed with ethyl ether, dried under vacuum, then taken up in 50 ml of sodium hydroxide. After 1 hour of stirring, the precipitate is filtered, washed with water until neutral, vacuum dried on phosphorus pentoxide. We recrystallize from 120 ml of 2o dimethylformamide and 3.1 g of 2-amino methyl-4 anilino-6 pyrimidine oxide-3.
Yield = 11.5 Analyzes:
Mp = 260 ° C
Elementary analysis for C11Hi2N20; PM = 216 CHNO

Calculation 61.12 5.50 25.92 7.40 Found 61.12 5.50 25.82 7.62 1H NMR and mass spectra are in conformity the expected structure.

Amino-2 methyl-4 (N-methylphenethylamino) -6 pyrimidine 3-oxide The procedure described in Example 36 is followed, using N-methylphenethylamine.
Temperature = 40 ° C
Time: 3 hours Recrystallization from acetonitrile Yield = 33 ~
PF = 170C

1o Elementary analysis for C14H1gN9O; PM = 258 C ~ NO

Calculation 65.12 6.98 21.70 6.20 Found 64.82 6.96 21.50 6.64 Mass and 1H spectra are consistent NMR

the expected structure.

2-amino-4-methyl hexamet: 6-nyleneimino pyrimidine 3-oxide The procedure described in Example 3 is followed, using hexamethyleneimine.
Temperature = 80 ° C
Time: 3 hours Recrystallization from acetonitrile / ethanol (70/30) Yield = 7 Mp = 218 ° C
Elementary analysis for C11H18N40; PM = 222 Calculated 59.46 8.10 25.22 7.20 Found 59.47 8.21 25.40 7.30 The 1H NMR and mass spectra are in accordance with the expected structure.
EXAMPLE: 3 9 Internal salt of 2-amino hydroxide tetramethylene-4,5 butoxy-6 sulfooxy-3 pyrimidinium Ä a solution of 1.2 ml (0.007 m) of N, N-diisopropylethylamine in 6 ml of chloroform cooled in ice, is added, with stirring, 0.12 ml (0.003 m) of chlorosulfonic acid. After 1o wait 30 minutes, on, play 0.237 g (0.001 m) 2-amino tetramet = 4,5-hylene-6-butoxy-pyrimidine oxide-3 and maintained for 2 hours between 0 ° and 5 ° C, under nitrogen.
The solvent is evaporated. The: residue is taken up in a little water, we get a white crystalline product that we filter. After recrystallization from a mixture of dimethylformamide / water, 0.13 g of crystals is obtained whites which decompose at 122 ° C.
Yield = 41 ~
Elementary analysis for C12H19N305S; 0.21 HzO; PM = 317 Calculation 44.89 6.05 13.09 25.9 9.97 Found 44.89 6.08 13.09 26.02 9.93 1H NMR and mass spectra are in conformity the expected structure.

Internal salt of 2-amino-4-methyl hydroxide N-methvlphenethvlam: ino-6 sulfooxy-3 pyrimidinium 1st method:

CH3 ~ _H3 \ HC.- ~ - C: / \
CH3 / 0 = S = 0 CH3 yN / CH3 \ O ~ O / CH3 0 -0- ~ ld O ~ N '~ ~ CH -CH \ r \ CH z-- CH 2 ~ \ /

Ä a solution of 0.7 '<? ml (0.0042 m) of N, N-diisopropylethylamine in 6 ml of chloroform cooled in ice, es ~~~ added, with stirring, 0.133 ml (0.002 m) of acid: chlorosulfonic. After wait 30 minutes, add 0.258 g (0.001 m) amino-2 methyl-4 N-methylplzenylamino-6 pyrimidine oxide-3 and maintained for 3 hours between 0 ° and 5 ° C, under nitrogen. The solvent is evaporated. We resume the 1o residue in a little water, we get a product white lens that is filtered. After recrystallization from a mé: acetonitrile / water mixture, 0.27 g of internal salt is obtained which decomposes at 213 ° C.
Yield = 80%
Elementary analysis for C14H18N40qS; 0.25 H2O; PM = 338 CHNOS
Calculated 49, 05 5, 40 16, 35 19, 85 9, 34 Found 48.98 5.2 ~~ 16.27 19.94 9.43 The 1H NMR and mass spectra are in accordance with the expected structure.
2nd method:
In a suspension of 0.258 g (0.001 m) of amino-2 2o methyl-4 N-methyl: Lphenethylamino-6 pyrimidine oxide-3 in 3 ml of dimethylformamide is added under stirring 0.32 g (0.002 m) this complex of trioxide sulfur / pyridine. After 2 heL.res at 15-20 ° C, add 0.16 g (0.001 m) of the complex and leave for another 1 hour at 15-20 ° C. The solution obtained is diluted with 15 g of water Ice. The white precipitate obtained is filtered and wash with ice water. After recrystallization in a acetonitrile / water mixture, 0.24 g of sulfate is obtained internal which decomposes at 213 ° C.
Yield = 7 J.

lo Internal salt of hydroxide: 2-amino-methyl-4 anilino-6 sulfooxy-3 pyrimidinium We follow the operating mode of the first method described in Example 40 using 0.216 g of amino-2 4-methyl-6-anilino pyrimidine oxide-3. The product obtained recrystallized from an acetonitrile / water mixture, decomposes above 260 ° C.
Yield = 64 ~
Elementary analysis for CllHiaN404S% PM = 296 Calculated 44.59 4.05 18.92 21.62 10.82 Found 44.68 4.07 18.95 21.54 10.69 The 1H NMR and mass spectra are in accordance with the expected structure.

Internal salt of hydroxydE = 2-amino-methyl-4 hexamethvineneimino-6 sulfooxy-3 pyrimidinium We follow the procedure of the first method described in Example 40 using 0.222 g of amino-2 4-methylhexamethyleneimine-6 pyrimidine oxide-3. The product obtained recrystallized in a mixture acetonitrile / water, decomposes above 195 ° C.

Yield = 46 ~
Elementary analysis for CllHisN404S: PM = 302 Calculated 43.71 5.96 18.54 21.19 10.60 Found 43.79 6.04 18.71 21.20 10.40 The 1H NMR and mass spectra are in accordance with 5 the expected structure.
FORMULATION EXAMPLES
A lotion intended for the treatment of hair loss, having the following composition:
Lotion 1 - 2-amino-4-methyl-piperidino-6 pyrimidine oxide-3 (example 1) 5.0 g - Propylene glycol 23.0 g - Ethanol 55.0 g - Water qs 100.0 g T .. ~ ~ .v .-.
- 2-amino-4-methyl-piperidino-6 pyrimidine oxide-3 (example 1) 2.0 g - Ethanol 49.0 g - Water qs 49.0 g T .-. i- s - Amino-2-methyl-4 morpholin ~~ -6 pyrimidine oxide-3 (example 3) 2.0 g - Propylene glycol. 4.9 g - Ethanol 93.1 g Lotion 4 - 2-Amino-4-methyl-dimethylamino-6 pyrimidine oxide-3 (example 7) 5.0 g - Propylene glycol. 23.0 g - Ethanol 55.0 g - Water qs 100.0 g Lotion 5 - 2-amino-4-methyl dimethyla: mino-6 pyrimidine oxide-3 (example 7) 2.0 g - Propyleneglyco7_ 4.9 g - Ethanol 93.1 g T. ~ 1-. ~.
- 2-amino-4-methyl-butyloxy-6 pyrimidine oxide-3 (example 16) 8.0 g - Propylene glycol 23.0 g - Ethanol 55.0 g - Water qs 100.0 g Lotion 7 - 2-amino-4-methyl-6-methoxy pyrimidine oxide-3 (example 14) 1.0 g - Propylene glycol 5.0 g - Ethanol 94.0 g T ~ 1 s - 2-amino-4-methyl-6-ethoxy 5.0 g pyrimidine oxide-3 (example 15) - Ethanol 47.5 g - Water 47.5 g Lotion 9 - 2-Amino-4-methylpyrimidine 3-oxide (example 25) 3.0 g - Ethanol 30.0 g - Propylene glycol 20.0 g - Water qs 100.0 g .... ~ n - 2-Amino-4-methylpyrimidine oxide-3 (example 25) 2.0 g - Propylene glycol 4.9 g - Ethanol 93.1 g Apply 1 to 2 g of each of these lotions to alopecic areas of the scalp, due to a application per day for = 7 days per week and this for 3 months = is.

Claims (5)

The embodiments of the invention, in respect of which a exclusive right of ownership or lien is claimed, are defined as follows: 1. Pharmaceutical or cosmetic composition, intended to be used topically to slow down the hair loss and to induce and stimulate their growth, characterized by the fact that it contains in combination with a pharmaceutically adjuvant or cosmetically acceptable, at least one compound responding to the general formula:
in which:
R denotes a hydrogen atom, an alkyl radical, saturated and linear, in C1-C8 or form with the cycle pyrimidine, a hydrocarbon ring of formula:
where n is equal to 1, 2 or 3;
X denotes:
(i) a hydrogen atom;
(ii) a group of formula:

in which R1 and R2, identical or different, denote a hydrogen atom, a saturated alkyl group in C1-C12, linear or branched, unsubstituted or substituted by a halogen atom or a radical trifluoromethyl, a linear C2-C12 alkenyl group, a C3-C10 cycloalkyl group, an aralkyl group in C7-C12 or an aryl group corresponding to the formula:
in which R9 and R10, identical or different, denote a hydrogen or halogen atom, or a C1-C4 alkyl, hydroxyl or C1-C4 alkoxy group; or good R1 and R2 form together with the nitrogen atom to which they are linked, a crossed out or unsaturated heterocycle, chosen from the groups aziridino, azetidino, pyrrolidino, piperidino, hexamethyleneimino, heptamethyleneimino octamethyleneimino, tetrahydropyridino, dihydro-pyridino, pyrrole, pyrrazole, imidazole and thio-morpholino;
(iii) a group -OR3, in which R3 denotes a linear or branched C1-C12 saturated alkyl radical, unsubstituted or substituted by a halogen atom or a trifluoromethyl radical, an alkenyl radical linear C2-C12, a cycloalkyl radical C3-C10, a C7-C12 aralkyl radical, or a phenyl radical optionally substituted by one or two groups, which, independently of one another, designate an atom halogen, a C1-C6 alkyl radical, a radical C1-C6 alkoxy, or a trifluoromethyl radical; or (iv) a -SR4 group, in which R4 has the same meaning that R3;
or one of its acid addition salts physiologically acceptable. 2. Composition according to claim l, characterized in that it contains as a compound of formula (III) 7-methyl-pyrrolidino-5-2H- oxadiazolo-1, 2, 4 [2, 3-a] pyrimidin-oxo-2. 3. The compounds corresponding to the general formula:
in which:
R denotes a hydrogen atom, an alkyl radical saturated and linear, in C1-C8 or form with the cycle pyrimidine, a hydrocarbon ring of formula:
where n is equal to 1, 2 or 3;

X denotes:
(i) a hydrogen atom (ii) a group of formula:
in which R1 and R2, identical or different, denote a hydrogen atom, a saturated alkyl group in C1-C12, linear or branched, unsubstituted or substituted by a halogen atom or a radical trifluoromethyl, a linear C2-C12 alkenyl group, a C3-C10 cycloalkyl group, an aralkyl group in C7-C12 or an aryl group corresponding to the formula:
in which R9 and R10, identical or different, denote a hydrogen or halogen atom, or a C1-C4 alkyl, hydroxyl or C1-C4 alkoxy group, or good R1 and R2 form together with the nitrogen atom to which they are linked, a crossed out or unsaturated heterocycle, chosen from the groups aziridino, azetidino, pyrrolidino, piperidino, hexamethyleneimino, heptamethyleneimino, octamethyleneimino, tetrahydropyridino, dihydropy-ridino, pyrrole, pyrrazole, imidazole and thiomorpholino;
(iii) a group -OR3, in which R3 denotes a linear or branched C1-C12 saturated alkyl radical, unsubstituted or substituted by a halogen atom or a trifluoromethyl radical, a linear alkenyl radical C2-C12, a C3-C10 cycloalkyl radical, a radical C7-C12 aralkyl, or a phenyl radical optionally substituted by one or two groups which, independently one from the other, designate a halogen atom, a C1-C6 alkyl radical, a C1-C6 alkoxy radical, or a trifluoromethyl radical; or (iv) a -SR4 group, in which R4 has the same meaning that R3;
with the proviso that 2-oxo-2,8-dihydro [1,2,4] oxadia-zolo [2,3-a] pyrimidine is excluded; and their salts addition of physiologically acceptable acids. 4. 7-methyl-7-pyrrolidino-5-2H-oxadiazolo-1,2,4 [2,3-a] pyrimidin-oxo-2. 5. Cosmetic treatment process for the hair or scalp, characterized by the fact that one applies on the hair or the scalp a composition such as defined in claim 1 or 2.