GB2183632A - Pyrimidine compounds for the growth of hair and cosmetic formulations containing such compounds - Google Patents
Pyrimidine compounds for the growth of hair and cosmetic formulations containing such compounds Download PDFInfo
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- GB2183632A GB2183632A GB08530065A GB8530065A GB2183632A GB 2183632 A GB2183632 A GB 2183632A GB 08530065 A GB08530065 A GB 08530065A GB 8530065 A GB8530065 A GB 8530065A GB 2183632 A GB2183632 A GB 2183632A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
- A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q7/00—Preparations for affecting hair growth
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D239/50—Three nitrogen atoms
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Abstract
New salts of general formula I: <IMAGE> in which R represents hydrogen or an SO3<(-)> group; R1 represents a piperidin-1-yl, 3-hydroxypiperidin-1-yl, 4-hydroxypipidin-1-yl or 4-carboxybutylamino grouping, with the condition that, when R is hydrogen, R1 is not piperidin-1-yl; when R is hydrogen A represents a compound of acid nature, selected from the group which comprises N-acetyl cysteine, thiosalicylic acid, S-carboxymethyl cysteine and 2-benzoymercapto-propionylglycine; when R is an -SO3<(-)> group, A represents, on the contrary, a compound of basic nature, selected from the group which comprises arginine, methyl cysteine, lysine or the dimethyl ester of the carboxy-cysteine; and groups A derived from amino acids may be in the L, D or D, L form, are useful as activators for the growth of hair and for the treatment of different forms of alopocia. Processes for the preparation of the free pyrimidines (I) are also claimed.
Description
SPECIFICATION
Compounds for the growth of hair and cosmetic formulations containing such compounds
The present invention relates to novel salts useful as activators for the growth of hair, a process for the preparation of the said salts and the formulations which contain them as active ingredients.
Products are already known which have been proposed for the treatment of changes of the scalp, these having an influence on the aesthetics of the person. Even if they have a doubtful result as regards the conservation of the head of hair, these products provide advantages in counteracting alopecia, baldness and seborrheic conditions, when they are employed at the time of the commencement of the pathological manifestations.
The formulations of such products are compounded with a hydro-alcoholic-glyceric medium which is balanced so as to favour the activity of the active ingredients, formed by active ingredients such as camphor, thymol, colloidal sulphur, resorcin, quinine salts, pilocarpine, acetyl resorcin, bactericides, fungicides and microergics (Vitamin A, Vitamin B6, pantothenic acid, oestrogens, placentary extracts, heparinoids).
In the cosmetic filed, there are also used other products capable of intervening in respect of damage to the hair follicle due to aesthetic treatments (permanent waving, bleaching, dyeing) or related to constitutional or ambient factors.
These products, of which the efficacy has been insufficiently documented, comprise first of all the proteic lysates of prolamines and scleroproteins (horny material, hair, feathers, collagen, horsehair) which, on account of the affinity for the elements of cornea production, act by forming a compensatory thin layer, capable of repairing mechanically the processes of wear. From a therapeutic point of view, the existing formulations have to be considered as means which have a simply symptomatic signification or a generally preventive effect.
A topical or local effect on the scalp has recently been shown in the case of a known medicament with a cradio-vascular effect, this being Minoxidyl or 6amino1 ,2-dihydro-1 -hydroxy-2-imino-4-piperidinopyrimidine (U.S. Patent No. 3382247).
The present invention is concerned with salts of the general formula I:
in which R represent hydrogen or an S03(-) group; R1 represents a piperidin-l -yl, 3-hydroxypiperidin-l -yl, 4-hydroxypiperidin-1 -yl or 4-carboxybutylamino group, with the condition that, when R is hydrogen, R1 is not piperidin-1 -yl;
When R is hydrogen A represents a compound of acidic nature, selected from the group which comprises
N-acetylcysteine, thiosalicyclic acid, S-carboxy-cysteine and 2-benzoylmercapto-propionylglycine; when R is an -S03(-) group, A represents, on the contrary, a compound of basic nature which is selected from the group which comprises arginine, methyl cysteine, lysine or the dimethyl ester of carboxy-cysteine; and A groups derived from amino acids may be in the L, D or D,L form.
Compounds I have shown a stimulating activity for the growth of hair.
The components having a pyrimidinic structure in the salts forming the subject of the present invention, i.e.
6-amino-i ,2-dihydro-1 -hydroxy-2-imino-4- (3-piperidinol) pyrimidine, 6-amino-i ,2-dihydro-1 -hydroxy-2- imino-4- (4-piperidinol) pyrimidine, 6-amino-I -hydroxy-2-imino-4- (4-carboxybutylamino) pyrimidine and 2,6-diamino-4-(1 -piperidinyl)-1 -(sulphoxy) pyrimidine, are the metabolites of Minoxidyl and are deprived of activity on the vascular system, with the exception of the 2,6-diamino-4- (1 -piperidinyl) -i - (sulphoxy) pyrimidine.
It has now surprisingly been found that all the metabolites retain the same activity on the hair as that of
Minoxidyl and that the novel salts of the metabolites forming the subject of the present invention show an action superior to that given by Minoxidyl by itself, in equivalent quantities, in the same cosmetic formulations.
As a consequence of prolonged daily use, for 2 to 3 months, we have found that the cosmetic formulations of the invention make it possible to obtain satisfactory responses ir; the treatment of different forms of alopecia and in the control of the functional states of "scaling" of the hair structures which cause the progressive process of the balding.
The novel salts which are the subject of the invention are conveniently added, in proportions between 0.2 and 10%, to balms, shampoos, creams and lotions, either individually, or mixed or combined with other active substances. As well as cosmetic formulations, the invention also seeks to provide processes for obtaining each compound and its novel salts.
The inactive metabolites may be obtained by reaction of 4-chloro-2,6-diaminopyrimidine with 3- or 4-hydroxy-piperidine or 5-aminopentanoic acid in excess, followed by an oxidation with hydrogen peroxide in a methanolic solution, this giving the corresponding N-oxides which, by being heated at 60 , are transformed into the desired hydroxy derivatives.
The sulphonated active metabolite (R = S03-, R, = 1 -piperidinyl) is obtained by the reaction of the
Minoxidyl in pyridine with chlorosulphonic acid at a temperature not above 5 . By distillation of the pyridine, acidification and treatment with acetonitrile, there is obtained the sulphoxy derivative.
According to the present invention, the salts of the non-vasoactive metabolites are prepared by reaction with
N-acetyl cysteine, thiosalicic acid, S-carboxymethyl cysteine, or N-(2-benzoyl thiopropionyl) glycine in a molar ratio of 1:1 in a solution or suspension in solvents which are preferably formed by the Ca-C4 alcohols, possible containing water in smaller proportions, at a temperature between 1 0 C and 100"C, preferably the boiling temperature of the solvent. The desired salts are obtained by cooling the solution or by evaporating the solvent.
The salts may be obtained by adding acetone to the cooled solution or by lyophilising the aqueous solutions which contain them.
The salts of the sulphonated vasoactive metabolite are prepared by causing it to react with methyl cysteine, arginine, lysine or dimethyl S-carboxycysteine in a molar ratio of 1:1 in a solution or suspension in solvents which are preferably constituted by Cr-C4 alcohols, possible containing water in smaller proportions, at a temperature which is between 10" and 100 , preferably the boiling temperature of the solvent. The desired salts are obtained by cooling the solutions as thus obtained or by evaporating the solvent.
The salts may also be obtained by adding acetone to the cooled solution or by lyophilising the aqueous solutions which contain them.
The Examples which follow hereafter illustrate the invention, without limiting it in any way.
EXAMPLE 1 (a) 2,6- diamino -4- (3-hydroxypiperidin -1 - yl) pyrimidine
3 g. of 4-chloro-2,6-diaminopyrimidine are heated at 100" for 121 hours with 30 g. of 3-hydroxypiperidine, re-cooled and filtered. The solid is mixed with vigorous stirring with 30 ml of NaOH alkaline solution.
Filtration is carried out, followed by extraction with boiling acetonitrile. After cooling and filtration, about 3.2 g. of the desired product are obtained. The structure is confirmed by elementary analyses.
Elementary analysis (M.W. = 209.25)
C H N
Calculated (%) 51.66 7.23 33.47
Found (%) 51.71 7.30 33.43 (b) 6-amino- 1,2-dihydro -1 1-hydroxy-2-imino-4-(3-hydroxypiperidin- 1 - yl) pyrimidine 30 ml of hydrogen peroxide (30%) are added to a solution of 18 g. of the compound prepared in (a) in 100 ml of methanol; the stirring is maintained for 1 hour, the solvent is evaporated and the residue is heated at 60 for 30 minutes. The latter is cooled and cystallised in absolute ethanol. 15 g. of the desired product are obtained. The structure is confirmed by spectral analyses.
Elementary analysis (M.W. = 225.25)
C H N
Calculated (%) 47.99 6.71 31.09
Found (%) 48.01 6.74 31.05
Examples 2-3
Using the operating procedure of Example 1, but replacing the 3-hydroxypiperidine by 4-hydroxypiperidine and 5-aminopenatnoic acid, there are obtained the products which are set out in the following Table.
TABLE
Compound Yield Mol. ELEMENTARYANALYSIS calc.
in weight found
g. C H N 6-amino-1,2-dihydro-1-hydroxy- 15 225.25 47.99% 6.71 YÓ 31.09% 2-imino-4- (4-hydroxypiperidin- 48.110% 6.81% 31.05% 1-yl) pyrimidine 6amino-1,2-dihydro-1-hydroxy- 15.5 242.26 44.62% 6.66% 28.91% 2-imino-4- (4-carboxybutylamino) - 44.70% 6.72% 28.94% pyrimidine
EXAMPLE 4 2,6-diamino -4- (1 -piperidinyl) -1- (sulphoxy) pyrimidine hydroxide
29.09 g. of 6-amino-I ,2-dihydro-1 -1 hydroxy-2-imino-piperidino-pyrimidine are dissolved in 100 ml of
pyridine.The solution is cooled to 0" and, while keeping the temperature at 0 C and while stirring, 12 g. of chlorosulphonic acid are slowly added. The stirring is maintained for 1 hour at 0", 100 ml. of water are added and the solution is distilled in vacuo to a reduced volume. The residue is dissolved in 50 ml of water, which contains 2% of sodium carbonate, extraction with chloroform is carried out the aqueous solution is acidified and then it is concentrated.
Crystallisation is allowed to take place at 10 , thereby obtaining 23 g. of product. The special analyses confirm the structure.
Elementary analysis (M.W. = 289.3)
C H N S
Calculated (%) 37.36 5.23 24.21 11.08
Found (%) 37.51 5.32 24.36 11.05
EXAMPLE 5 N-acetyl cysteinate of 6-amino- 7,2-dihydro- -hydroxy-2-imino-4 (3-hydroxypiperidin- 1 -yl) pyrimidine
(SKMIO 14) 21.69 g. of 6-amino-I ,2-dihydro-1 -hydroxy-2-imino-4-(3-hydroxypiperidin-1 -yl) pyrimidine and 16.32 g. of
N-acetyl cysteine are dissolved under heat in 100 ml of isopropyl alcohol. The solution is cooled, 300 ml of acetone are added and the formed precipitate is separated, this being washed with acetone and dried in an oven.
About 35 g. of product are obtained. The structure is confirmed by spectral analyses.
Elementary analysis (M.W. = 388.44)
C H N S
Calculated (%) 43.29 6.23 21.64 8.25
Found (%) 43.40 6.24 26.71 8.20
Examples 6-8
Operating as described in Example 5, but employing appropriate reactants instead of the N-acetyl cysteine, there are obtained the salts of 6-amino-I ,2-dihydro-1 -hydroxy-2-imino-4-(3-hydroxypiperidin-1 -yl) pyrimidine, which are set out in the following Table.
TABLE
Reactant used Yield Mol. ELEMENTARYANALYSIS calc.
in weight found
g. C H N S
Thiosalicylic acid 35 379.45 60.65% 5.58% 18.46% 8.45% (SKN/01 5) 61.56% 5.60% 18.41% 8.48%
S-carboxymethyl cysteine 37 404.44 41.58% 5.98% 20.78% 7.93% (SKM/O1 6) 41.61% 5.99% 20.78% 7.99% 2-benzoyl mercaptopropionyl 46 492.55% 51.21% 5.73% 17.05% 6.51% glycine (SKM/017) 51.30% 5.81% 17.10% 6.53%
EXAMPLE 9 N-acetyl cysteinate of 6-amino- 1.2-dihydro- 1-hydroxy-2-imino-4(4-hydroxypiperidin- 1 -yl) pyrimidine, SKM/018
21.69 g. of 6-amino-I ,2-dihydro-1 -hydroxy-2-imino-4- (4- hydroxypiperidin-l -yl) pyrimidine and 16.32 g. of
N-acetyl cysteine are dissolved under heat in 100 ml of isopropyl alcohol.The solution is colled, 300 ml of acetone are added and the formed precipitate is separated, this being washed with acetone and dried in an oven.
About 35 g. of product are obtained. The structure is confirmed by spectral analyses.
Elementary analysis (M.W. = 388.44)
C H N S
Calculated (%) 43.29 6.23 21.64 0.25
Found (%) 43.41 6.36 20.90 0.27
Examples 10-12
Using the operating procedure of Example 9, but replacing the N-acetyl cysteine by appropriate reactants, there are obtained the salts of 6-amino-I ,2-dihydro-1 -hydroxy-2-imino-4-(4-hydroxypiperidin-1 -yl) pyrimidine, which are grouped in the following Table.
TABLE
Reactant used Yield Mol. ELEMENTARY ANALYSIS calc.
in weight found
g. C H N S
Thiosalicylic acid 35 379.45 50.65% 5.58% 18.46% 8.45% (SKM/O1 9) 51.19% 5.61% 18.41% 8.42%
S-carboxymethyl cysteine 39 404.44 41.58% 5.98% 20.78% 7.93% (SKM/020) 41.62% 6.00% 20.71% 7.91% 2-benzoyl mercaptopropionyl 46.5 492.55% 51.21% 5.73% 17.05% 6.51% glycine (SKM/021) 51.31% 5.83% 17.10% 6.53%
EXAMPLE 13 N-acetylcysteinate of amino 1,2-dihydro- I-hydroxy-2-imino-C (4-carboxybutylamino) pyrimidine (SKM/022) 23.29 g. of 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-(4-carboxybutylamino) pyrimidine and 16.32 9. of acetyl cysteine are dissolved under heat in 80 ml of ethyl alcohol at 95 c.s.The solution thus obtained is concentrated in vacuo to about 30 ml; by cold crystallisation, about 37 g. of the desired salt are obtained. The structure is confirmed by spectral analyses.
Elementary analysis (M.W. = 390.44)
C H N S
Calculated (%) 43.07 6.20 17.94 8.21
Found (%) 43.12 6.18 18.05 8.28
Examples 14-16
Using the operating procedure of Example 3, but replacing the N-acetyl cysteine by appropriate reactants, there are obtained the salts of 6-amino-1,2-dihydro-1-hydroxy-4-(4-carboxybutylamino) pyrimidine grouped in the following Table.
TABLE
Reactant used Yield Mol. ELEMENTARY ANALYSIS calc.
in weight found
g. C H N S
Thiosalicylic acid 36 382.45 50.25% 5.80% 14.65% 8.38% (SKM/023) 51.16% 5.81% 14.63% 8.31%
S-carboxymethyl cysteine 37 406.44 8.41% 5.95% 17.23% 7.8% (SKM/024) 8.45% 6.01% 17.28% 7.8% 2-benzoyl mercaptopropionyl 46 494.55% 51.0% 5.71% 14.16% 6.48% glycine (SKM/025) 51.2% 5.80% 14.18% 6.41%
EXAMPLE 17 2,4- diamino -4- (1 -piperidinyl) -1 - (methylcysteine sulphoxylate) pyrimidine (SKM/026)
19.9 g. of methyl cysteine are added to a solution of 28.19 g. of 2,6-diamino-4-(1 -piperidinyl) -1 - (suiphoxy) - pyrimidine hydroxide in 100 ml of water. After solubilization, the solution is lyophilised. 40.09 9. of the desired product are obtained. The structure is confirmed by spectral analyses.
Elementary analysis (M.W. = 422.5)
C H N S
Calculated (%) 39.80 5.73 16.58 15.18
Found (%) 39.85 5.86 16.71 15.08
Examples 18-20
Using the operating procedure of Example 17, but replacing the methyl cysteine by appropriate reactants, there are obtained the salts of the 2,6-diamino-4-(1-piperidinyl)-1-(sulphoxy)pyrimidine which are included in the following Table.
TABLE
Reactant used Yield Mol. ELEMENTARY ANALYSIS calc.
in weight found
g. C H N S
Arginine 44.8 449.52 40.08% 6.50% 24.93% 7.1 3% (SKM/027) 40.01% 6.52% 24.96% 7.17%
Lysine 41.55 416.48 43.26% 5.81% 20.18% 7.70% (SKM/028) 43.31% 5.90% 20.1 5% 7.65%
Dimethyl carboxycysteine 48.1 482.56 39.83% 5.85% 14.51% 13.29% (SKM/029) 39.88% 5.91% 14.59% 13.21% EXAMPLES OF FORMULATATIONS
Example A - Shampoo
Sodium lauryl ethoxylate (27%) 600 9
Coconut diethanolamide (90%) 60 9
Ethylene glycol monostearate 20 9
Stearic diester of polyethylene glycol 20 9
Colour 2.5 9
Perfume 59 Preservative q.s.
SMK/020-SKM/021 -SKM/022 ana 2.0 9
Deionised water q.s.f. 1000
Example B - Shampoo
Sodium lauryl ethoxylate (27%) 600 9
Coconut diethanolamide (90%) 60 9
Ethylene glycol monostearate 20 9
Stearic diester of polyethylene glycol 20 9
Colour 2.5 9
Preservative q.s.
SKM/014-SKM/01 6-SKM/017-SKM/01 8-SKM/019 ana 2.0 9
Deionised water q.s.f. 1000
Example C - Lotion
Isopropyl myristate lOg PEG 6000 DS 20 9
Cetyl alcohol 20 9
Antioxidant 1.0 9
Carbopol 940 1.59 10% sodium hydroxide solution 3 ml
EDTA 0.5 9 Ethanol 30 ml
Perfumed composition 59 SKM/01 5 109 Deionised water q.s.f. 1000
Example D - Lotion
Isopropyl myristate 109 PEG 6000 DS 20 9
Cetyl alcohol 20 9
Antioxidant 1.0 g Carbopol 940 1.59 10% sodium hydroxide solution 3.0 ml
EDTA 0.5 9
Ethanol 30 ml
Perfumed composition 59 SKM/01 5-SKM/01 67-SKM/020 ana 0.335 9
Deionised water q.s.f. 1000
Example E- Lotion Isopropyi myristate 10g PEG 6000 DS 20 g Cetyl alcohol 20 g Antioxidant 1.0 g Carbopol 940 1.5g 10% sodium hydroxide solution 3.0 ml
EDTA 0.5 g
Ethanol 30 ml SKM/O1 4-SKM/O1 5-SKM/01 6 SKM/017-SKM/01 8-SKM/1 09-SKM/020 ana 0.56 g
Deionised water q.s.f. 1000
Example F - Balm
Cetyl alcohol 25 g
Solulan 10g Quarternary ammonium 109 Nesatol 109 Silicones 5g Monopropylene glycol 10 9 Glicam P10 lOg PEG 6000 DS 30 g Preserving mixture 5g Perfume 49 SKM/022-SKM/023-SKM/024-SKM/025 ana 2.5 g
Example G - Ointment
Cetomacrogal 189 Cetyl stearic alcohol 240 g Soiid paraffin 150g Liquid paraffin 60 g Perfume q.s.
Preservative q.s.
Monosodium and bisodium phosphate q.s. for pH 6.0 SKM/026-SKM/027-SKM/028-SKM/029 ana 1.0 g
Deionised water q.s.f. 1000
The novel salts according to the invention are provided with biological activities which activate the functions of the follicles, which are transformed into the prolongation of the "anagen" phase during the growth of the hair.
Local application of the compounds according to the present invention causes an acceleration of the growth of the hair or fur in rodents having alopecia induced by a chronic treatment with thallium slats. After suspension of the toxic treatment, the growth of the new fur in the zones which were attacked is found to be much faster as compared with that observed in the animals treated locally with other products in current use or in animals treated locally with equivalent quantities of Minoxidyl.
Another surprising observation concerns the effect which is shown by the salts of non-vasoactive metabolities, of which the activity, from a quantitive point of view, is shown to be more intense than that of the same
Minoxidyl applied locally in equivalent quantities.
Experiments carried out on New Zealand rabbits or Bourgogne rabbits have demonstrated that the local application of the compounds according to the invention determines a consistent improvement in the speed of growth of the hair or fur in previously shaved cutaneous zones and in addition decreases the entity of the spontaneous depilation in the intact cutaneous zones. In the treated zones, previously subjected to shaving, the average speed of growth of the hair or fur is shown to be 0.3 mm/die, this being about 35% greater than that found in the untreated zones.
These observations were made with a sample of 80 rabbits. The maximum activity was observed after 45-60 days of treatment with 1 mg/die of each salt in two applications per day.
The aforementioned experiments have confirmed the surprising efficacy in the local treatment with the salts of non-vasoactive metabolities, which is greater than that which was shown when employing equivalent quantities of Minoxidyl.
Claims (11)
1. Compounds of general formula I
in which
R represents hydrogen or an S03(-) group;
R, represents a piperidin-l -yl, 3-hydroxypiperidin-1 -yl, 4-hydroxypipidin-1 -yl or 4-carboxybutylamino grouping, with the condition that, when R is hydrogen, R, is not piperidin-l -yl; when R is hydrogen A represents a compound of acid nature, selected from the group which comprises N-acetyl cysteine, thiosalicyclic acid, S-carboxymethyl cysteine and 2-benzoylmercapto-propionylglycine; when R is an -S03(-) group, A represents, on the contrary, a compound of basic nature, selected from the group which comprises arginine, methyl cysteine, lysine or the dimethyl ester of the carboxy-cysteine; and groups A derived from amino acids may be in the L, D or D,L form.
2. Compound according to claim 1, selected from the group constituted by:
- N-acetylcysteinate of 6amino ,2-dihydro-l -hydroxy-2-imino-4- (3-hydroxypiperidin-1 -yl) pyrimidine;
- thiosalicylate of 6amino ,2-dihydro-l -hydroxy-2-imino-4(3-hydroxypiperidin-l -yl) pyrimidine;
- S-carboxymethylcysteinate of 6-amino-I ,2-dihydro-1 -hydroxy-2-imino-4- (3-hydroxypiperidin-1 -yl) pyrimidine;
- 2-benzoylmercaptopropionyl glycinate of 6-amino-1 ,2-dihydro-1 -hydroxy-2-imino-4- (4-hydroxypiperidin-1 yl) pyrimidine;
- N-acetyl cysteinate of 6-amino-1 ,2-dihydro-1 -hydroxy-2-imino-4-(4-carboxybutylamino) pyrimidine;;
- thiosalicylate of 6-amino-1 ,2-dihydro-l -hydroxy-2-imino-4- (4-carboxybutylamino) pyrimidine;
- S-carboxymethyl cysteinate of 6-amino-1 ,2-dihydro-l -hydroxy-2-imino-4- (4-carboxybutylamino) pyrimidine;
- 2-benzoylmercaptopropionyl glycinate of 6-amino-l ,2-dihydro-1 -hydroxy-2-imino-4- (4-hydroxypiperidin 1-yi) pyrimidine;
- N-acetyl cysteinate of 6-amino-1 ,2-dihydro-1 -hydroxy-2-imino-4-(4-carboxybutylamino) pyrimidine;
- Thiosalicylate of 6-amino-I ,2-dihydro-l -hydroxy-2-imino-4- (4-carboxybutylamino) pyrimidine;
- S-carboxymethyl cysteinate of 6-amino-I ,2-dihydro-l -hydroxy-2-imino-4- (4-carboxybutylamino) pyrimidine;;
- 2-benzoylmercaptopropionyl glycinate of 6-amino-l ,2-dihydro-1 -hydroxy-2-imino-4- (4-carboxybutylamino) pyrimidine;
- 2,6-diamino-4-(1 -piperidinyl)-l - (methyl cysteine sulphoxylate)-pyrimidine;
- 2,6-diamino-4-(l -piperidinyl) -1 - (arginine sulphoxylate) -pyrimidine; - 2,6-diamino-4-(l -piperidinyl) -1 - (lysine sulphoxylate)-pyrimidine;
- 2,6-diamino-4-(1 -piperidinyi)-l -(dimethylcarboxy cysteine sulphoxylate)-pyrimidine.
3. Process for the preparation of the compounds of formula I, comprising reacting the compounds of formula:
in which R and R1 have the meanings specified above, with the compounds A, in almost stoichiometric quantities in solution or in suspension in water Cr-C4 alcoholic solvents at the boiling temperature of the solvent, and isolating the salt I by crystallisation in the partially or entirely evaporated solvent, with addition of acetone, or by lyophilisation when the solvent is water.
4. Process for the preparation of the compounds of formula (lea), where R and R, have the meanings specified above, comprising reacting 2,6-diamino-4-chloropyrimidine at about 100" in pyridine with an excess of 3- or 4-hydroxypiperidine or 5-aminopentanoic acid and oxidising the product thus obtained by hydrogen peroxide in a methanolic solution and then heating for half an hour at 60"C.
5. Process for the preparation of the compounds of formula (Ib)
in which R1 represents piperidin-l-yl, comprising reacting 6-amino-l,2-dihydro-l-hydroxy-2-imino-4- piperidino-pyrimidine with chlorosulphonic acid in pyridine.
6. Cosmetic compositions for the growth of hair and for the treatment of alopecias, containing as active ingredient, one or more compounds according to claim 1 or 2.
7. Cosmetic compositions according to claim 6, in the form of shampoos, lotions, balms, ointments or creams.
8. Compositions according to claim 6 or 7, wherein the active ingredients are present in percentages which are between 1 and 10%.
9. A compound according to claim 1 substantially as described herein and exemplified.
10. A process for the preparation of compounds of formula I substantially as described herein and exemplified.
11. A cosmetic composition according to claim 6 substantially as described herein and exemplified.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8517798A FR2590897B1 (en) | 1985-12-06 | 1985-12-02 | NOVEL DERIVATIVES OF 6 AMINO 1,2-DIHYDRO-1-HYDROXY-2-IMINO-PYRIMIDINE, THEIR PREPARATION PROCESS AND COSMETIC COMPOSITIONS CONTAINING THEM |
| GB8530065A GB2183632B (en) | 1985-12-06 | 1985-12-06 | Dihydropyrimidine derivatives for the growth of hair and cosmetic formulations containing such compounds |
| DE19853544267 DE3544267A1 (en) | 1985-12-06 | 1985-12-14 | NEW CONNECTIONS FOR THE GROWTH OF HAIR, TREATMENT OF HAIR LOSS AND COSMETIC COMPOSITIONS CONTAINING THEM |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8530065A GB2183632B (en) | 1985-12-06 | 1985-12-06 | Dihydropyrimidine derivatives for the growth of hair and cosmetic formulations containing such compounds |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8530065D0 GB8530065D0 (en) | 1986-01-15 |
| GB2183632A true GB2183632A (en) | 1987-06-10 |
| GB2183632B GB2183632B (en) | 1990-04-04 |
Family
ID=10589338
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8530065A Expired - Fee Related GB2183632B (en) | 1985-12-06 | 1985-12-06 | Dihydropyrimidine derivatives for the growth of hair and cosmetic formulations containing such compounds |
Country Status (3)
| Country | Link |
|---|---|
| DE (1) | DE3544267A1 (en) |
| FR (1) | FR2590897B1 (en) |
| GB (1) | GB2183632B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990011762A1 (en) * | 1989-04-13 | 1990-10-18 | Kemios S.R.L. Bio Medical Research | 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-(4-hydroxypiperidin-1-yl)-pyrimidine hydroximinoxidil having antifibroblastic activity |
| EP0415598A1 (en) * | 1989-08-16 | 1991-03-06 | Unilever Plc | Cosmetic composition |
| US5300510A (en) * | 1988-09-23 | 1994-04-05 | Norchim | Salt of 6-piperidino-2,4-diaminopyrimidine 3-oxide and aceturic acid, its preparation and its dermato-cosmetological application |
| WO2006041204A1 (en) * | 2004-10-13 | 2006-04-20 | Shiseido Company, Ltd. | Anti-graying preparation |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| LU86547A1 (en) * | 1986-08-07 | 1988-03-02 | Oreal | SUSPENSION FOR INDUCING AND STIMULATING HAIR GROWTH AND REDUCING FALL FROM PYRIMIDINE DERIVATIVES |
| EP0417075B1 (en) * | 1988-02-18 | 1993-06-09 | The Upjohn Company | Minoxidil gel |
| US5225189A (en) * | 1988-02-18 | 1993-07-06 | The Upjohn Company | Minoxidil gel |
| FR2636840B1 (en) * | 1988-09-23 | 1990-12-21 | Norchim Sarl | SALT OF 6-PIPERIDINO-2,4-DIAMINOPYRIMIDINE-3-OXIDE AND ACETURIC ACID, THEIR PREPARATION AND THEIR DERMATOCOSMETOLOGICAL APPLICATIONS |
| FR2651122B1 (en) * | 1989-08-29 | 1994-10-28 | Oreal | COMPOSITIONS FOR USE IN BRAKING HAIR LOSS AND INDUCING AND STIMULATING THEIR GROWTH, CONTAINING 2-AMINO PYRIMIDINE OXIDE-3 DERIVATIVES AND NEW AMINO-2 PYRIMIDINE OXIDE-3 DERIVATIVES. |
| US7442369B1 (en) | 2000-08-09 | 2008-10-28 | Mcneil Ab | Compositions of minoxidil |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3461461A (en) * | 1965-11-01 | 1969-08-12 | Upjohn Co | 6-amino-4-(substituted amino)-1,2-dihydro-1-hydroxy-2-iminopyrimidines |
| CA1020558A (en) * | 1971-04-07 | 1977-11-08 | Richard C. Thomas (Jr.) | 6-amino-4-(substituted amino)-1,2-dihydro-1-hydroxy-2-iminopyrimidines |
| US4139619A (en) * | 1976-05-24 | 1979-02-13 | The Upjohn Company | 6-Amino-4-(substituted amino)-1,2-dihydro-1-hydroxy-2-iminopyrimidine, topical compositions and process for hair growth |
| US4287338A (en) * | 1980-03-10 | 1981-09-01 | The Upjohn Company | Sulfooxy-pyrimidinium, -pyridinium, and -triazinium hydroxide inner salts |
-
1985
- 1985-12-02 FR FR8517798A patent/FR2590897B1/en not_active Expired
- 1985-12-06 GB GB8530065A patent/GB2183632B/en not_active Expired - Fee Related
- 1985-12-14 DE DE19853544267 patent/DE3544267A1/en active Granted
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5300510A (en) * | 1988-09-23 | 1994-04-05 | Norchim | Salt of 6-piperidino-2,4-diaminopyrimidine 3-oxide and aceturic acid, its preparation and its dermato-cosmetological application |
| WO1990011762A1 (en) * | 1989-04-13 | 1990-10-18 | Kemios S.R.L. Bio Medical Research | 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-(4-hydroxypiperidin-1-yl)-pyrimidine hydroximinoxidil having antifibroblastic activity |
| EP0415598A1 (en) * | 1989-08-16 | 1991-03-06 | Unilever Plc | Cosmetic composition |
| WO2006041204A1 (en) * | 2004-10-13 | 2006-04-20 | Shiseido Company, Ltd. | Anti-graying preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2183632B (en) | 1990-04-04 |
| DE3544267A1 (en) | 1987-06-19 |
| FR2590897A1 (en) | 1987-06-05 |
| DE3544267C2 (en) | 1989-07-20 |
| FR2590897B1 (en) | 1988-02-19 |
| GB8530065D0 (en) | 1986-01-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19921206 |