JP3130110B2 - Minoxidil derivatives and medicaments containing them - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel minoxidil derivative or a pharmaceutically acceptable acid addition salt thereof having an excellent hair-growth effect, and a hair-growth agent containing the same.

[0002]

BACKGROUND OF THE INVENTION In recent years, alopecia has become one of the problems faced by many people. In addition to age-related alopecia, hair loss due to innate constitution, hair loss due to stress accompanying the complication of social mechanisms or side effects of drugs. Alopecia based is increasing. Various explanations have been made as to the cause of hair loss, but there are still many unclear points about the details of the onset mechanism. A typical example of the mechanism of hair loss onset is that sebum secretion from the sebaceous line increases and mixes with scalp dirt, etc., resulting in sebaceous leakage, which clogs pores and causes hair root nutritional disorders and circulatory disorders. A sebaceous leak theory, a hormonal theory of overproduction of the male hormone (testosterone), which results in a hormonal imbalance in the crown that was previously dominated by the balance of the sex hormones in men and women, or a genetic or nutritional claim. There are various theories such as the relationship. But neither can be the decisive cause.

[0003] Examples of these hair loss preventing agents, hair growth agents or hair tonics include blood circulation promoters such as hinokitiol and menthol; amino acids such as methionine; vasodilators such as minoxidil and acetylcholine derivatives; anti-inflammatory agents; estradiol - female hormonal agents such as Le; skin hyperactivity agents such as cepharanthine; -; vitamins such as vitamin B _6; 5.alpha. reductor peptidase inhibitors antiandrogen agent;
Alternatively, phthalide derivatives such as 4-hydroxy-3-heptylphthalide (JP-A-3-135907) are known. Of these, minoxidil (2,4-diamino-6-piperidinopyrimidine-3-oxide) is
It was originally used as an oral antihypertensive agent, but was developed with a focus on the effect of hair growth as a side effect.It has already been launched in Europe and the United States, and its development is currently ongoing in Japan. (JP-A-58-883)
No. 07 publication).

[0004]

However, although minoxidil has an excellent effect as a hair restorer, it has a disadvantage that it itself has high polarity and low transdermal absorbability.
Alternatively, it has safety problems such as the appearance of side effects such as palpitations due to continuous use, and there are some problems in its application as an external preparation for hair growth. The same applies to the above-mentioned 3-substituted-phthalide derivatives. Accordingly, an object of the present invention is to provide a novel minoxidil derivative and a salt thereof having improved transdermal absorption and an excellent hair-growth effect, and another object is a hair-growing agent containing these minoxidil derivative or a salt thereof. It is to provide.

[0005]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, have improved transdermal absorbability and an excellent hair-growth effect, particularly an initial hair growth rate, and A novel minoxidil derivative and a salt thereof with high safety have been found, and the present invention has been completed. That is, the present invention relates to the following general formula (I)

Embedded image (Wherein at least one of R ¹ and R ² is

Embedded image And the other represents a hydrogen atom), or a pharmaceutically acceptable acid addition salt thereof. Another object of the present invention is to provide a minoxidil derivative represented by the formula: Is to provide a hair restorer comprising the minoxidil derivative represented by the general formula (I) or a salt thereof. The compound of the present invention can be produced by various methods. One example of these production methods is as follows. [Method A]

Embedded image

[0006] Minoxidil represented by the general formula (1) is dissolved in an alcohol such as methanol, ethanol or isopropyl alcohol, or a solvent such as acetone, and then an appropriate amount of orthophthalaldehyde acid (2) is dissolved. ) Are mixed and reacted by stirring at room temperature to 60 ° C, preferably at 40 ° C to 50 ° C for 4 to 10 hours. After the reaction is completed, the dried crystal is purified using preparative liquid chromatography. By fractionation, general formulas (Ia), (Ib),
The compound represented by (Ic) can be obtained.

[Method B]

Embedded image In a solvent such as acetone or dimethylformamide (DMF), chlorophthalide or bromophthalide represented by the general formula (3) and minoxidil represented by the general formula (1) are mixed in the presence of a base such as anhydrous potassium carbonate. The reaction is carried out for 4 to 10 hours, washed, dried, and purified by silica gel column chromatography or the like to obtain the compound of the general formula (I-
Compounds represented by a), (Ib) and (Ic) can be obtained. The reaction temperature is from room temperature to 60 ° C, preferably 40 to 50 ° C. In the general formula (3), X is
It means a halogen atom such as a chlorine atom and a bromine atom.

The novel minoxidil derivative (I) of the present invention
Is a prodrug of minoxidil (1), which significantly improved transdermal absorption. Further, as is clear from the test examples described below, the minoxidil derivative of the present invention is gradually hydrolyzed into minoxidil and a phthalide derivative in the body such as skin after being absorbed percutaneously. Therefore, as compared with minoxidil (1), it is more reliably absorbed percutaneously, the initial hair growth rate is higher, and a large amount of minoxidil is absorbed into the body at a time even if a large amount is absorbed from the wound. There is no sudden drop in blood pressure or palpitations, and safety is excellent.

Minoxidil derivative (I) as hair restorer
Is not critical because its optimum amount varies depending on the application method or dosage form, but it is generally 0.01 to 1% by weight, preferably 0.1 to 0.5% by weight, as a dry matter in the total amount of the hair growth material. It is. In addition to the minoxidil derivative (I), the hair restorer according to the present invention may further comprise, for example, diazoxide, various antiandrogens such as oxendrone, 4-androsterone-
3,17-dione-17-cyclic ethylene digit
Derivatives), nicotinic acid and its derivatives, carpronium chloride, vitamin E acetate, vitamin E nicotine, pantothenic acid and its derivatives, biotin, glycyrrhizic acid, glycyrrhetinic acid, winter summer extract, Korean ginseng extract, Assembly extract, capsicum extract, cepharanthin, placenta extract, ethinyl estradiol, carpronium hydrochloride, photosensitizer, other vitamins and amino acids can be mixed together.

[0010] Further, additives usually used for hair restoration, such as hinokitiol, hexachlorophen, pheno-
Antibacterial agents such as benzalkonium chloride, benzalkonium chloride, cetylpyridinium chloride, undecylenic acid, trichlorocarbanilide and bitionol; cooling agents such as menthol;
Drugs such as salicylic acid, zinc and its derivatives, lactic acid and its alkyl esters, olive oil, squalane, liquid paraffin, isopropyl myristate, higher fatty acids,
Oils such as higher alcohols, other surfactants, fragrances,
Antioxidants, ultraviolet absorbers, dyes, lower alcohols such as ethanol and propyl alcohol, water, humectants, thickeners and the like can be appropriately compounded within a range that does not impair the effects of the present invention. .

The dosage form of the hair restorer of the present invention may be any dosage form applicable to the outer skin such as liquid, emulsion and ointment, and any dosage form applicable to subcutaneous injection such as liquid and suspension. Particularly, it is preferable to use a coating agent such as an ointment, lotion, tonic, spray, suspension, emulsion and the like. These preparations can be produced by a method known per se by dissolution, emulsification or suspension, and in addition to the above-mentioned active ingredients, distilled water; lower alcohols such as ethanol; Alcohols such as polyethylene glycol, propylene glycol, etc .; celluloses such as carboxymethyl cellulose; animal, vegetable and synthetic fats and oils; , Waxes, silicones, surfactants, fragrances and the like can be blended within a range that does not impair the effects of the present invention. The amount of the thus obtained hair restorer of the present invention applied to alopecia patients is not limited because it can vary depending on the degree of progression of the symptoms, other components used in combination, or the method of application, but is generally applied to the outer coat. For example, the minoxidil derivative (I) in one day
The application amount is about 1 × 10 ^-4 per 1 cm ^{2 of the} skin area to be applied.
g to 1 × 10 ⁻² g, preferably about 1 × 10 ⁻³ g to 5 × 1
0 ^-3 g. Since the compound of the present invention does not show any side effects transdermally, the number of operations per day is not limited.

[0012]

Next, the present invention will be described more specifically with reference to examples and test examples, but the present invention is not limited to these examples. The abbreviations used in the examples have the following meanings. ¹ H NMR proton nuclear magnetic resonance spectrum IR infrared spectrophotometer GC-MS gas chromatograph mass spectrometer

Example 1 Orthophthalaldehyde (150.13 mg) was dissolved in methanol (5 ml), and then minoxidil (10%).
5 mg), and reacted for 7 hours while stirring at a temperature of 50 ° C. After completion of the reaction, the residue dried under reduced pressure was purified by preparative liquid chromatography. The purification conditions were a chloroform-methanol system and a purification fraction. As a result, 4-amino-2-{(3-phthalidyl) amino} -6- represented by the general formula (Ia)
Piperidinopyrimidine-3-oxide, which has the general formula (I)
-B) 2-amino-4-{(3-phthalidyl) amino} -6-piperidinopyrimidine-3-oxide and 2,4-di- represented by the above general formula (Ic)
(3-phthalidyl) amino-6-piperidinopyrimidine-3-oxide was obtained at a yield of 17%, 12% and 6%, respectively. The overall yield from the crude extract was about 35%. Table 1 shows the physical property values of the three compounds (Ia), (Ib), and (Ic).

[Table 1]

Example 2 Anhydrous potassium carbonate (308 mg) was added to 2 ml of acetone, minoxidil (209.3 mg) and chlorphthalide (357 mg) were added, and the mixture was allowed to react at room temperature for 8 hours or more. The filtrate was evaporated to dryness, and the compound (I-
a), (Ib) and (Ic) were purified and collected. The purification conditions used were benzene-ethyl acetate. The yield of each compound was (Ia) 3%, (Ib) 7%,
(Ic) is 15% and the overall yield from the crude extract is
It was about 25%.

Next, the following tests were conducted to examine the pharmacological effects of the compounds of the present invention. Here, the product of the present invention is
10 mg of 4-amino-2-{(3-phthalidyl) amino} -6-piperidinopyrimidine-3-oxide represented by the general formula (Ia) obtained in Example 1 was added to ethanol.
In 10 ml. Minoxidil (2,4-diamino-6-piperidinopyrimidine-3-oxide) was similarly prepared as a control. Also,
Control means 10 ml ethanol solution.
The same applies to compounds (Ib) and (Ic).

Test Example 1 Using the product of the present invention, the effects of hair growth and hair growth on the back hair of C3H mice were evaluated. That is, the dorsal hair of a 12-week-old mouse (male) in a substantially resting period was shaved using an electric shaver so as not to damage the skin (4 × 4).
cm ² ). These mice were divided into groups of 5 mice, and from the next day, the compounds of the present invention and minoxidil and control as control drugs were added to each group at 100 μl / day (100 μg / day, 100 μg / day). Per animal) was applied to the back skin daily. Thereafter, the percentage of hair growth was evaluated with the naked eye and photographs over time. The result is shown in FIG.

According to the above test results, for example, the hair regrowth rate (about 48%) of the product of the present invention after 10 days is significantly higher than that of minoxidil (about 20%), that is, in terms of the initial hair growth rate. It turns out that it is excellent. Test Example 2 The following test was conducted for the purpose of comparing the transdermal absorption rate of the product of the present invention with the known substance minoxidil. That is, the back hair of an SD rat (15 weeks old) was shaved (6 × 8 cm ² ) with an electric shaver so as not to damage the skin.
ml / mouse, and after 15 hours and 40 hours,
g was collected, and 100 ml of dichloromethane was added and homogenized. Thereafter, the whole amount was centrifuged at 3000 rpm for 15 minutes. After the supernatant was evaporated to dryness, 5 ml of methanol was added to the residue, and the mixture was shaken with a vortex mixer.
20 μl of this sample was subjected to high performance liquid chromatography (HP
LC) to measure the absorption of the compound (Ia) of the present invention into the skin and muscle. A similar test was performed for the control drug. The measurement conditions of liquid chromatography are as follows.

HPLC measurement conditions Column: ODS 4.6 mφ × 150 mm Mobile phase: methanol / water UV wavelength: 260 nm Flow rate: 1.0 ml / min The results are shown in Table 2.

[Table 2] From the above test, it is clear that the compound of the present invention has superior transdermal absorbability as compared with the control drug minoxidil itself.

Test Example 3 In order to confirm that the compound of the present invention acts as a kind of prodrug, that is, to confirm the conversion of the compound of the present invention absorbed into skin to minoxidil in subcutaneous tissue, the following was carried out. Was tested. As in Test Example 2, an electric shaver was applied to the back hair of the SD rat so as not to damage the skin.
(6 × 8 cm ² ), 1 ml / animal of the present invention was applied exactly, and 0 hour, 15 hours, 30 hours, 45 hours, 6 hours
After 0 hour, 15 g of each skin was collected, and a 20 μl sample was prepared in the same manner as in Test Example 2. The sample was subjected to HPLC to leave the compound of the present invention as a prodrug and minoxidil as a converter thereof in the skin. The concentration was measured. The results are shown in FIGS. 2 and 3. Second
The figure is a graph showing the amount of the minoxidil derivative absorbed into rats and skin, and a part of the graph has already been converted to minoxidil. FIG. 3 is a graph showing the conversion ratio of the minoxidil derivative absorbed into the skin into minoxidil. According to this, for example, about 15 hours after application, about 26 μg of the compound of the present invention is absorbed into rat skin (see FIG. 2), and about 4% corresponding to about 15% thereof is converted to minoxidil. (See FIGS. 2 and 3).

[0020]

As is clear from the above test results, the compound of the present invention has improved transdermal absorbability and an excellent hair-growth effect, is highly safe, and can be applied as a hair-growth agent.

[0021]

[Brief description of the drawings]

FIG. 1 is a graph showing the hair regeneration rate when the product of the present invention is applied to C3H mice.

FIG. 2 is a graph showing the percutaneous absorption of the compound of the present invention into rat skin tissue.

FIG. 3 is a graph showing the conversion of the compound of the present invention to minoxidil in rat skin tissue.

────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Kenichi Sugimori 6-2 Umegaoka Midori-ku, Yokohama-shi, Kanagawa Japan Pharmaceutical Research Laboratories, Japan Tobacco Inc. (58) Field surveyed (Int. Cl. ⁷ , DB name) 405/14 A61K 7/06 A61K 31/506 A61P 17/00 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula (I) (Wherein at least one of R ¹ and R ² is And the other means a hydrogen atom), or a pharmaceutically acceptable acid addition salt thereof. 2. A hair restorer comprising a minoxidil derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof.