JPS63135316A - Composition based on alkylenediaminoquinazoline derivative for causing and stimulating hair growth and controlling hair fall - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel compositions for inducing and stimulating hair growth and inhibiting hair loss based on alkylenediaminoquinazoline derivatives.

People have ioo, ooo to iso, ooo hair growth and commonly lose 50-100 hairs per day. This maintenance of hair growth is essentially due to the fact that hair undergoes a cycle known as the Pillary Cycle, at the beginning of which the hair is replaced by new components that appear in the same hair follicle. occurs, grows, and falls off.

In the course of the Pillary cycle, there are three successive phases: the anadene phase, the katadene phase and the telogen phase.

During the first phase, known as anagun, the hair goes through a period of active growth with intense metabolic activity in the hair root area.

The second stage, known as force tagging, is a transitional stage and is characterized by a decline in mitotic activity. During this phase, the hair on the head undergoes regression, and the atrophy of the hair follicle and its indentation on the skin become increasingly apparent.

The last stage, known as telogen, corresponds to a period of death of the hair follicle and hair debris by shedding, pushed by the new anadenic hair.

This process of continuous natural renewal undergoes a natural unfolding during the aging process, as the hair becomes progressively thinner and its cycle becomes shorter.

Alopecia occurs when the natural renewal process is accelerated or disturbed, i.e. the growth phase is shortened, the transition of the hair to the telogenic phase becomes faster and the number of hairs shed and shed increases. occurs; continuous growth cycles result in hair that becomes progressively thinner (shorter) and gradually turns gray.

Many factors can contribute to the Pillary cycle, resulting in more or less i'J alopecia. Among these factors, nutritional, endocrine, and neurological factors can be mentioned. Changes in different types of hair can be determined by tricograms.

In the cosmetics and pharmaceutical industry, there has been a search for compositions capable of eliminating or reducing the effects of alopecia and, in particular, inducing or stimulating hair growth, for many years.

6-Amino-1,2-nohydroa-1-human axy2-
Imino-4-piperitunopyrimidine and its derivatives,
Already proposals have been made for this purpose. Such compounds are described in particular in US Pat. No. tjIJ4,139,619.

Patent WO-A-83/02.558 L: Oite It
, combinations of retinoids and the above compounds have also been proposed.

Applicants have found that certain flukylenenoaminoquinazoline derivatives surprisingly induce and stimulate hair growth and reduce hair loss.

These compounds are known per se, in particular 7 Lance Supplementary Application No. 2,466.462 and! 72,46
No. 8,595.

Its compounds are known for their therapeutic activity as antihypertensive agents, especially in the cardiovascular field.

Applicants have found that these compounds, when used topically, exhibit activity on new hair growth and can induce or stimulate hair growth without promoting hair loss.

The subject of the present invention therefore consists of compositions for inducing hair growth and intensifying Iig and reducing hair loss, based on flukylenenoaminoquinazoline derivatives.

Another subject of the invention consists of the use of these compounds in the preparation of compositions having a therapeutic effect regarding the induction and stimulation of hair growth.

Further subject matter of the invention will become apparent from the following description and examples.

The composition according to the invention essentially comprises, in a physiologically acceptable medium, at least one of the formula: where R and R2 independently of one another contain hydrogen atoms, 1 to 4 carbon atoms represents an alkyl group or a benzyl group, 11 is equal to 2.3 or 4, and R is C1-C, a cyclofurkyl group, where q is 0.
1 or 2, a group of the formula: (III) (IV), or even a group of the formula: Particularly preferred compounds and which can be used according to the invention are compounds of the formula (I ), where n is equal to 3, R1 represents a hydrogen atom or a methyl group, R2 represents a methyl or benol group, and R is a tetrahydrofuryl, cyclopentyl, cycloprobyl, dihydrobenzo7lyl or benzo7lyl group This corresponds to equation (1), which represents

Particularly preferred compounds are those of formula (1) in which n is equal to 3 and R
It consists of a compound of formula (1) in which 2 represents a methyl group, R+ represents hydrogen and R represents a tetrahydrofuryl group.

The topical composition according to the invention comprises from 0.01 to 10% by weight, preferably from 0.1 to 5% by weight, relative to the total weight of the composition.
% of the compound of formula (1).

Particularly suitable m-acids are 0% by weight based on the total weight of the composition.
．． N-(4-amino-6゜7-simethoxy-2-quinzolyl)-N'-methyl-N#-(2
-tetrahydro7lyl) fluorobylennoamine -hydrochloride.

In one useful embodiment of the invention, the compound of formula (+) is a pyrimidine derivative having an effect on new hair growth, more particularly 6, also known by the name minoxidil. -amino-1,2-dihydro-
1-Hydroxy-2-imino-4-piperidi/pyrimidine, or for example patent specification WO-112102,83
It can also be used with retinoids, such as those described in No. 3, or a combination of both.

Particularly suitable retinoids include all-trans retific acid and (/13-cis retinoic acid) and their physiologically (pharmaceutically or cosmetically) acceptable salts or esters. These compounds can vary between 0.01 and 10% by weight in the case of pyrimidine derivatives and 0.001 and 2% by weight in the case of retinoids.

These compounds may be used in the same composition as the compound of formula (1) or separately, simultaneously or staggered, before or after the composition containing the compound of formula (I). It can also be used later.

The compositions according to the invention can be in the form of lotions, creams or gels, and optionally can also be pressurized as an aerosol.

They can be used in particular in treatments with compositions such as those mentioned above, with or without rinsing after their use, or they can be applied in the form of a shampoo. .

The cosmetically or pharmaceutically acceptable medium is an alcoholic or aqueous medium that is thickened, but may alternatively contain -m or more of a cosmetically or pharmaceutically acceptable solvent. It can be done.

Solvents include, for example, C, -C, such as ethyl alcohol, isopropyl alcohol and E-butyl alcohol.
-Alcohols, preferably selected from alkylene glycols such as propylene glycol and, for example, ethylene glycol monoethyl ether, propylene glycol monomethyl ether, tyrene glycol monoethyl ether no- and no-alkylene glycol furkyl ethers.

These compositions may contain other auxiliaries commonly used for topical compositions in the cosmetic and pharmaceutical fields, more particularly surfactants, thickeners, preservatives and alkalizing agents or An acidifying agent may be included. The 9H of these compositions can vary from 3 to 9, preferably from 5 to 8.

Thickeners or dilulating agents are in particular heterobiopolysaccharides, such as those containing mannose, glucose, glucuronic acid or lacturonic acid in the chain, more particularly xanthan gum or scleroglucan. You can choose from.

Among these substances, those sold by Kelco under the trade names Keltrol T or TF, Calzan S, Kelzan K 9 C57, Kelzan 8B12 and Kelzan 3B130, and Load Ball 2 from Lone Poulen.
3 and 233C, or Deuteron
CECA/SAT I, which is published under the trade name of
Examples of other heterobiopolysaccharides that can be used include those listed under the trade names CX9, C3lI and C56, and other heterobiopolysaccharides that can be used include, for example,
Patent specification, European Patent No. 8-23゜397, British Patent No. A-2-2,058,10G, No. A-2,058
, No. 107, U.S. Patent A, No. 4,454°316, European Patent-A-64,354 and German Patent A-3
, 224,547.

Other gelling agents can be chosen from cellulose derivatives such as, for example, methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, hydroxybutylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, methylhydroxyethylcellulose and methylhydroxypropylcellulose. These thickeners or gelling agents are preferably used in a proportion of 0.5 to 5% by weight, particularly 1 to 3% by weight, based on the total weight of the composition.

Thickeners that can be used, however, are polyacrylic acids crosslinked with polyfunctional crosslinkers, such as the product sold under the trade name Carpobol by Gutdrich, or water-soluble heptamer quaternary ammonium Thickeners may be selected from thickeners produced by the ionic interaction of a cationic polymer and a carboxyl anionic monomer consisting of a copolymer of cellulose or a cellulose derivative grafted with a salt. Among these latter products, in particular, hydroxyfurkylcellulose copolymers grafted with methacryloylenaltrimethylammonium, methacrylamidopropyltrimethylammonium or nomethylno7lylammonium salts and 7-tacrylic acid homopolymers or methacrylic acid by the Lanocal method. Copolymers of acrylic acid or methacrylic acid with monomers selected from 01-C, alkyl esters, acrylamide derivatives, maleic acid C1-C, monoalkyl esters, vinylpyrrolidone, and copolymers of ethylene and 7-leic acid anhydride. Mention may be made of thickeners produced by interaction with selected carboxyl group-containing anionic polymers. The weight relationship between the cationic polymer and the carboxyl anionic polymer is 1
8 to 58.

The thickener is present in an amount of 0.5-2% by weight, preferably 0.7-1.
Use at a rate of 5%.

Treatments for inhibiting hair loss mainly consist of administering a composition as described above to the bald areas of the scalp and hair of the patient, for example after washing the head or immediately after shampooing. A preferred method of administration is to administer 1 to 2 g of the composition according to the invention to alopecia areas of the scalp having a surface area of 200 to 300 cm2, 1 to 2 times per day, 1 to 7 days per week. It consists of

The effectiveness of this treatment is monitored once a month using hair photographs.

After two months of treatment, a significant increase in total hair density was observed with an increase in hairs in the 7-naden phase and a decrease in hairs in the telogen phase.

Another subject of the invention is the use of compounds of formula (1) for the preparation of compositions having the effect of inducing and stimulating hair growth and inhibiting hair loss.

This method of treatment is a measure that makes it possible to protect the hair and scalp within the point of view of cosmetic significance, i.e. to beautify it by endowing them with substances that are lacking in the hair and scalp. , has cosmetic properties.

Furthermore, this method also shows that the active substance is physiologically active in the Pillary cycle. Insofar as it has therapeutic activity with respect to its structure, it has the properties of a therapeutic treatment.

The following examples are intended to illustrate the invention, but include:
It is not intended to limit the essence of the invention.

Sentence m To prepare a lotion active in the inhibition of hair growth and hair loss, having the following composition:
-6,7-dimethoxy-2-quinazolyl)-N'-methyl-N'-(2-tetrahydrofuryl)propylenediamine-hydrochloride 1g - Preservative, fragrance Sufficient amount - Water
Sufficient Quantity 100g To determine the activity of the composition in stimulating new growth of hair relative to a placebo, the average yearly/? r40
The composition is evaluated by administering the composition once a day to the alopecia areas of the scalp of five subjects aged 5 years. After several months of treatment, the composition effectively improves the hair condition.

X1jL-A lotion active in inhibiting hair growth and hair loss is prepared having the following composition.

-N'-(4-amino-6.7-cymethoxy2-quinazolyl)-N'-methyl-N"-(cyclobentylcarbonyl)furopylenediamine-hydrochloride 2 g -Preservatives, fragrance Sufficient amount −Water
Sufficient quantity Nuts 1 eye-” - A gel having the following composition and active in stimulating hair growth and inhibiting hair loss? 'li made knee N'-(4-
Amino-6,7-simethoxy-2-quinazolyl)-N'
・Methyl-N"-(2-tetrahydro70yl)propylenediamine--hydrochloride 3g-Commercially available heteropolysaccharide from Kelf under the trade name Keltrol 1g-Isopropyl alcohol 30° water
Sufficient quantity 100g fruit]■L-(N'-(4-amino-6.7-dimethoxy-2- Quinazolyl)-N'-methyl-N'-(2-tetrahydro70yl)propylenezamine-hydrochloride 2g-Hydroxypropylcellulose, commercially available from Cures under the trade name Kurcel G 3g-Isopropyl alcohol ++ )jt 100gsu]1
No.-''-N'-(4-
Amino-6,7-simethoxy-2-quinazolyl)-N'
-Methyl-N'-(2-tetrahydro70yl)propylenediamine-hydrochloride 3g-Propylene glycol 20g-Ethyl alcohol 50g-Water
Sufficient amount: 1 per day for 100g scalp
When administered for two months at the rate of one dose, an improvement of about 15% in hair density is observed, with a marked increase in hair in the anaden phase and a decrease in hair in the telogen phase.

A tanning agent active in stimulating hair growth and inhibiting hair loss is prepared having the following composition.

-N'-(4-amino-6,7-simethoxy-2-quinazolyl)-N'-methyl-N"-(2-tetrahydro7
0yl) propylene diamine hydrochloride 1.5g-6-
Amino-1,2-dihydro-1-hydroxy-2-imino-4-biverino/pyrimidine 1.5g-Propylene glycol 20g-Ethyl alcohol 50g-Water
A rhosilane agent active in stimulating hair growth and inhibiting hair loss and having the following composition is prepared.

-N'-(4-amino-6,7-dimethoxy-2-quinazolyl)-N'-methyl-N"-(2-tetrahydro7
0yl) propylene diamine hydrochloride 0.3g-13
-cis retinoic acid 0.025g-
Ethyl alcohol 95g - Propylene glycol 100g -
Shadow

Claims (1)

[Claims] 1. In a cosmetically or pharmaceutically acceptable medium, there is a formula: ▲Mathematical formula, chemical formula, table, etc.▼(I) In the formula, R_1 and R_2 are, independently of each other, a hydrogen atom. , 1~
Represents an alkyl group or benzyl group containing 4 carbon atoms, n is equal to 2, 3 or 4, and R is a C_3 to C_6 cycloalkyl group, formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) Formula Where q is 0, 1 or 2, a group or formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) A group or formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) In the formula, m is 0, 1 or 2, p is 0, 1 or 2, and represents a group of at least one alkylenediaminoquinazoline corresponding to A composition for inducing and stimulating hair growth and inhibiting hair loss, characterized in that it contains derivatives and their addition salts with pharmaceutically or cosmetically acceptable acids. 2. In formula (I), n is equal to 3, R_1 represents a hydrogen atom or a methyl group, R_2 represents a methyl or benzyl group, and R represents a tetrahydrofuryl, cyclopentyl, cyclopropyl, dihydrobenzofuryl or benzofuryl group; Composition according to claim 1, characterized in that: 3. In the formula (I), n is equal to 3, R_2 represents a methyl group, R_1 represents hydrogen, and R represents a tetrahydrofuryl group, according to claim 1 or 2 Composition of. 4. Any one of claims 1 to 3, characterized in that the compound of formula (I) is present in a proportion of 0.01 to 10% by weight relative to the total weight of the composition. Compositions as described. 5. The composition according to any one of claims 1 to 4, characterized in that the pharmaceutically or cosmetically acceptable medium consists of a hydrous alcohol, water or an alcoholic medium. 6. The composition according to any one of claims 1 to 6, characterized in that it is present in the form of a gel containing a gelling agent selected from heterobiopolysaccharides and cellulose derivatives. 7. A cationic polymer consisting of a copolymer of cellulose or a cellulose derivative grafted with a thickener selected from acrylic acid polymers crosslinked with a polyfunctional crosslinking agent or with a quaternary ammonium salt of an aqueous monomer and a carboxyl anion. 7. A composition according to any one of claims 1 to 6, characterized in that it contains a thickening agent produced from the ionic interaction of a polypropylene polymer. 8. Composition according to any one of claims 1 to 7, characterized in that it also contains pyrimidine derivatives or retinoids or mixtures thereof having an effect on new hair growth. 9. The composition according to claim 8, wherein the pyrimidine derivative is 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperisinopyrimidine or minoxidil. . 10. Retinoid is all-trust retinoic acid, 13-
Composition according to claim 8, characterized in that it is selected from cis retinoic acid and physiologically acceptable salts or esters thereof. 11. Claims 8 to 11, characterized in that the pyrimidine derivative is present in a proportion of 0.01 to 10% by weight.
The composition according to any one of Item 10. 12. The composition according to any one of claims 8 to 10, characterized in that the retinoid is present in a proportion of 0.001 to 2% by weight. 13. Component (A) of the composition according to any one of claims 1 to 7, and a pyrimidine derivative or a retinoid, or both, which promote hair growth, in a physiologically acceptable medium. Component (B) containing mixture
for inducing and stimulating hair growth and inhibiting hair loss, characterized in that components (A) and (B) are scheduled to be administered separately or simultaneously or staggered in time. A combination of. 14. The pyrimidine derivative is 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine, and the retinoid is all-trans retinoic acid or 13-cis retinoic acid or their physiological Combination according to claim 13, characterized in that it is an acceptable salt or ester. 15. Use of a composition or combination according to any of claims 1 to 14 for preparing a medicament making it possible to induce and stimulate hair growth and to suppress hair loss. 16. A method for cosmetically treating hair, characterized in that at least one composition or combination according to any one of claims 1 to 14 is used on the hair or scalp.