JP2000178163A - Skin preparation for external use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a skin preparation for external use, having an activity for preventing and improving skin-aging phenomena such as the generation of wrinkles, an activity for inhibiting the growth of hair, etc., by adding a new compound. SOLUTION: This skin preparation for external use contains a compound of formula I [R1 is H, a 1-12C alkyl; R2, R4 are each H or a lower alkyl; R3 is H, a (substituted) alkyl or aralkyl; R5 is H, or is combined with R3 and the adjacent nitrogen atom to form a heterocyclic ring] (for example, a compound of formula II) preferably in an amount of 0.0001-40 wt.%, especially preferably 0.01-20 wt.%. The compound of formula I is obtained, for example, by reacting a glycinamide derivative of formula III with a halocarboxylic acid derivative of formula IV in the presence of a base such as sodium hydroxide at 20-200 deg.C for 10 min to 24 hr, neutralizing the reaction product with an acid such as hydrochloric acid, properly drying the product, and then isolating the product.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to the prevention of skin aging.
The present invention relates to a skin external preparation having an improving effect, a hair growth suppressing effect, and the like, a skin aging preventive / improving agent, a hair growth suppressing agent, an elastase inhibitor, and a novel carboxyalkylamine derivative having these effects.

[0002]

2. Description of the Related Art Aging, drying, oxidation, sunlight (ultraviolet rays) and the like are mainly cited as causes of skin aging represented by generation of wrinkles and sagging skin. . Skin aging is recognized by a decrease in collagen and elastin in the skin dermis and a decrease in mucopolysaccharides such as hyaluronic acid.

[0003] With regard to the prevention of wrinkles and the like, for example, a collagen-containing cosmetic has not been sufficiently effective. As for skin aging caused by ultraviolet irradiation, cosmetics containing an ultraviolet absorbent and an ultraviolet protective agent having sufficiently satisfactory effects have not yet been developed.

It is thought that when elastin is denatured or destroyed by overexpression of elastase, the elasticity of the skin is reduced and the generation of wrinkles is promoted. However, elastase inhibitors 1,10-orthophenanthroline and Euphorbiaceae (Euphorbiaceae) are considered. Phyllanthus (Phyllanthus)
s) An extract of Meniran (P. niruri L.) belonging to the genus
No. 87136), its effect is not always sufficient, or it takes a long time for extraction, and has a problem in terms of safety.

[0005] In terms of aesthetic appearance, treatment of body hair is particularly performed on limbs and the like. For example, a mechanical removal method using a hair remover or the like, a removal method using a depilatory agent, and the like are used. However, since these removal methods involve physical or chemical irritation to the skin and regenerate the body hair, a more preferable body hair removal method is desired.

[0006] The present invention relates to an external preparation for skin having an effect of preventing and improving skin aging such as the generation of wrinkles, and an effect of inhibiting hair growth, an agent for preventing and improving skin aging, an agent for suppressing hair growth, an elastase inhibitor, An object of the present invention is to provide an inhibitor of an enzyme having an activity of decomposing succinyl-Ala-Ala-Ala-p-nitroanilide (STANA) to generate p-nitroaniline, and a novel compound having these effects.

[0007]

The present invention provides the following general formula (1):

[0008]

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(Wherein R ¹ is a hydrogen atom and has 1 to 12 carbon atoms)
R ² and R ⁴ represent a hydrogen atom or a lower alkyl group; R ³ represents a hydrogen atom or an alkyl group or an aralkyl group which may have a substituent; and R ⁵ represents a hydrogen atom. Or together with R ³ to form a ring with the nitrogen atom. The above object has been achieved by providing a skin external preparation containing a carboxyalkylamine derivative represented by the formula (1) or a salt thereof as an active ingredient. The present invention has also achieved the above-mentioned object by providing a skin aging preventive / improving agent comprising a carboxyalkylamine derivative (1) or a salt thereof as an active ingredient. The present invention has also achieved the above-mentioned object by providing a hair growth inhibitor containing a carboxyalkylamine derivative (1) or a salt thereof as an active ingredient. The present invention has also achieved the above-mentioned object by providing an elastase inhibitor comprising a carboxyalkylamine derivative (1) or a salt thereof as an active ingredient. The present invention also provides an activity of decomposing N-succinyl-Ala-Ala-Ala-p-nitroanilide (STANA) to produce p-nitroaniline, which comprises a carboxyalkylamine derivative (1) or a salt thereof as an active ingredient. (Hereinafter referred to as “STA”)
NA degrading enzyme inhibitor ").
The above object has been achieved. The present invention also provides the following general formula (2)

[0010]

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(Wherein R ⁶ is a hydrogen atom or a group having 1 to 1 carbon atoms)
4 represents an alkyl group, R ⁷ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an aralkyl group having 7 to 10 carbon atoms which may be substituted by a carbamoyl group, and R ⁸ represents a hydrogen atom Or R ⁷ together with an adjacent nitrogen atom to form a pyrrolidinyl group or a piperidinyl group. )) Or a salt thereof.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION In the general formula (1), R ¹ is preferably a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and is preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, or an n-alkyl group. Butyl and isobutyl are particularly preferred.
R ² is preferably a hydrogen atom and an alkyl group having 1 to 4 carbon atoms, and particularly preferably a hydrogen atom and a methyl group. R ³ represents a hydrogen atom, a carbon atom number 1 to which a carbamoyl group may be substituted;
An alkyl group having 4 and an aralkyl group having 7 to 10 carbon atoms are preferable, and an isopropyl group, an isobutyl group, a sec-butyl group, a benzyl group and a 2- (carbamoyl) ethyl group are particularly preferable. R ⁴ is particularly preferably a hydrogen atom. R ² and R
⁴ may be the same or different. R ⁵ is particularly preferably a hydrogen atom or, together with R ³ , forms a pyrrolidinyl group or a piperidinyl group together with an adjacent nitrogen atom.

Examples of the salt of the carboxyalkylamine derivative (1) include alkali metal salts such as sodium salt, alkaline earth metal salts, amine salts, amino acid salts and the like.
Of these, salts wherein R ¹ is sodium are particularly preferred. Note that the carboxyalkylamine derivative (1) may have optical activity, and the configuration may be either R or S, or may be a racemic form, but an S form is preferred. It may be in the form of a hydrate.

The following compounds are most preferred as the carboxyalkylamine derivative (1) or a salt thereof.

[0015]

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The carboxyalkylamine derivative represented by the general formula (2) is a novel compound among the carboxyalkylamine derivatives (1). In the carboxyalkylamine derivative (2), R ⁶ represents R ² ,
R ⁷ is preferably the above-mentioned R ³ , and R ⁸ is particularly preferably the above-described R ⁵ . The most preferred compounds of the carboxyalkylamine derivatives (2) are those exemplified as the most preferred compounds of the carboxyalkylamine derivative (1).

Carboxyalkylamine derivative (1)
Can be produced, for example, by the following method.

[0018]

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Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵
Is the same as above. The glycinamide derivative (3) and the halocarboxylic acid derivative (4) are reacted in the presence of a base such as sodium hydroxide. The reaction temperature is preferably −20 to 200 ° C., and the reaction time is preferably 10 minutes to 24 hours. Then, the carboxyalkylamine derivative (1) is obtained by neutralizing with an acid such as hydrochloric acid and drying and isolating as appropriate.

[0020] The carboxyalkylamine derivative (1) or a salt thereof according to the present invention for external use on the skin, an agent for preventing or improving skin aging, a hair growth inhibitor, an elastase inhibitor or STAN.
The compounding amount in the A-degrading enzyme inhibitor is 0.0001 to 40% by weight (hereinafter simply referred to as%), particularly 0.01 to 20%.
Is preferred.

It is particularly preferable to administer the external preparation for skin of the present invention for the purpose of improving or preventing wrinkles, sagging, abrasion, etc. caused by aging of the skin, or preventing hair growth. The agent for preventing and improving skin aging and the agent for suppressing hair growth of the present invention can be administered as an external preparation for the skin, an oral preparation, an injection and the like. Of these, skin external preparations are preferred.

The elastase inhibitor of the present invention can be used for various symptoms and diseases caused by elastin denaturation and overproduction, such as improvement of skin elasticity, suppression of wasted hair, improvement of inflammation,
Treatment of lupus and psoriasis, treatment of rheumatoid arthritis, improvement of respiratory diseases (emphysema, pulmonary fibrosis, pneumonia, bronchitis, bronchiectasis, asthma, etc.), cardiovascular diseases (arteriosclerosis, arteritis, myocardial infarction) Etc.), renal failure / liver failure, periodontitis improvement, rejection of organ transplant rejection, etc. can be administered as an external preparation for skin, oral preparation, injection, etc. Of these, skin external preparations are preferred. The STANA-degrading enzyme inhibitor of the present invention is N-succinyl-Ala- at a concentration of 100 mM or less.
In an enzyme activity measurement system using Ala-Ala-p-nitroanilide as a substrate, it is preferable to show an inhibitory activity of 25% or more, particularly 30% or more.

The external preparation for skin of the present invention,
Improving agent, hair growth inhibitor, elastase inhibitor and stan
The A-degrading enzyme inhibitor may contain, in addition to the above-mentioned active ingredient, conventionally used pharmaceutical ingredients according to the purpose.

The external preparation for skin, the agent for preventing / improving skin aging, the inhibitor for hair growth, the inhibitor for elastase and the inhibitor for STANA-degrading enzyme of the present invention can be formed into various forms by a conventional method. , Ointment, stick, solution with organic solvent or purified water, pack, gel and the like. The skin aging prevention of the present invention
Improving agent, hair growth inhibitor, elastase inhibitor and stan
The A-degrading enzyme inhibitor can be in the form of tablets, granules, solutions, foods and drinks, aqueous injections, non-aqueous injections, emulsion or suspension injections, etc. in addition to the above forms.

The skin external preparation, skin aging preventive / improving agent, hair growth inhibitor, elastase inhibitor and STANA-degrading enzyme inhibitor of the present invention comprise a carboxyalkylamine derivative (1) or a salt thereof, and other additives. It can be obtained by mixing, stirring and the like in a conventional manner.

[0026]

EXAMPLES Synthesis Example 1 Synthesis of Compound 1 200 mL of water and phenylalanine amide 2 were placed in a flask.
0 g (0.12 mol), 9.7 g of sodium hydroxide
(0.24 mol) and 14 g of sodium chloroacetate
(0.12 mol) and heated at 50 ° C. for 5 hours.
After completion of the reaction, about 7 g of hydrochloric acid was added for neutralization. Subsequently, drying under reduced pressure was performed to obtain a mixture 44 of compound 1 and sodium chloride.
g was obtained. Compound 1 was isolated by recrystallization (H ₂ O) (yield 67%).

2.75-3.34 ppm (4H, m), 3.75 ppm (1H, t, J = 6.7
Hz), 7.27ppm (5H, m), 7.57ppm (1H, s), 7.76ppm (1H, s)

Synthesis Examples 2 to 9 Compounds 2 to 9 shown in Tables 1 and 2 were synthesized according to the method of Synthesis Example 1 using glycinamide derivatives shown in Tables 1 and 2.

[0029]

[Table 1]

[0030]

[Table 2]

Test Example 1 Test for Elastase Activity Inhibition of Cultured Human Fibroblasts Normal human fibroblasts commercially available from Dainippon Pharmaceutical Co., Ltd. were subcultured in a DME medium containing 10% fetal bovine serum, and used in this test. did. The cells detached from the petri dish using a rubber policeman were suspended in saline, the cells were collected using a low-speed centrifuge, and washed three times with saline. Cells are 0.1% Triton X-100 / 0.2M Tris-HCl buffer
The suspension was suspended in [pH 8.0] and sonicated to prepare an enzyme solution.
125 mM N-Suc- (Al
a) ₃ -p-Nitroanilide was used. Enzyme solution 1 to which compounds 1 to 9 were respectively added so as to have the concentrations shown in Table 3.
1 μl of the substrate was added to 00 μl, reacted at 37 ° C. for 1 hour, and stopped by adding 5 μl of acetic acid (Test Nos. 1 to 9). The amount of nitroaniline produced was measured by measuring the absorbance at 405 nm with a spectrophotometer to determine the elastase activity inhibition rate. Table 3 shows the results.

[0032]

[Table 3]

Compounds 1 to 9 significantly inhibited elastase activity.

Test Example 2 Wrinkle Inhibition Test Using Hairless Mice A hairline mouse (HR / ICR, 6 weeks old at the start of the experiment) was irradiated on the back with a health line lamp (manufactured by Toshiba, SE20) at a dose of 1 MED. Adjust UV-B as follows
Light irradiation was performed. Immediately thereafter, 100 μl of an 80% ethanol solution containing Compounds 1 to 9 in the amounts shown in Table 4 was applied (Test Nos. 11 to 19). This work was performed for 20 weeks. As a control, an 80% ethanol solution containing no carboxyalkylamine derivative (1) or a salt thereof was similarly applied (Test No. 10). The irradiation energy amount is UV-Radiometer (TOKYOOPT)
It was measured using ICAL Co., Ltd., UVR-305 / 365D). After completion of the test, the frequency of the formed wrinkles was visually evaluated according to the following criteria (wrinkle index). Table 4 shows the results. ◎ Wrinkle index 0: No wrinkle formed 1: Wrinkle slightly formed 2: Wrinkle trace formed 3: Slight wrinkle formed 4: Wrinkle formed firmly

[0035]

[Table 4]

Compounds 1 to 9 had a remarkable inhibitory effect on wrinkle formation, and exhibited excellent effects of preventing and improving skin aging.

Test Example 3 Test for Maintaining Skin Elasticity Using Rats Both soles of 3-week-old SD male rats were divided into four groups. After UV-B light (1 MED or less) was irradiated to the third and fourth groups, 10 μl of an 80% ethanol solution containing the compound 1 or 3 in an amount shown in Table 5 was applied per foot. This work is 1
The test was performed three times a week every other day or every other day for 6 weeks (test numbers 22, 23). The second group includes 80% containing no carboxyalkylamine derivative (1) or a salt thereof.
An ethanol solution was similarly applied (Test No. 21). Nothing was applied to the first group (test number 20). The elasticity of the skin was measured by using a cute meter SES575 (manufactured by Courage Kazaka), suctioning it at 500 mb for 3 seconds, releasing it, and then measuring the displacement for 3 seconds for a total of 6 seconds. The measurement was performed five times per foot, and the Ue value and the Uf value were determined. Next, the sole of the rat was taken from Melcox (Dainippon Ink Co., Ltd.)
The solution was fixed by refluxing, digested with formic acid, and analyzed for linearity of the elastic fiber by a scanning electron microscope (SEM). Analysis was performed by the method of Imokawa et al. (J. Invest. Dermatol., 10
5, 254-258 (1995)). That is, for each sample, 10 representative SEM photographs were extracted from a 1000-fold SEM photograph, enlarged, copied, and then equally divided into 16 parts. An arbitrary elastic fiber was extracted from each region, and was traced on a transparent film with a line having a constant thickness (8 pixels width). The linearity of the elastic fiber is represented by A / (B ×
C). For example, if the torres of the elastic fibers are straight, the linearity is 1. Table 5 shows the results.

[0038]

[Table 5]

Compounds 1 and 3 have the effect of strongly preventing the elasticity of the skin from being reduced by UV-B light and the denaturation of the three-dimensional structure of the elastic fiber which causes the UV-B light, and can maintain the skin beam. .

Test Example 4 Mouse Hair Growth Inhibition Test The back hairs of 10 6-week-old C3H mice were shaved using an electric clipper and an electric shaver over 2 × 4 cm ² without damaging the skin. Compound 1 on shaving site
An 80% ethanol solution containing 9 in the amount shown in Table 6 was applied twice a day in 100 μl portions for 4 weeks (test numbers 24-32). As a control, an 80% ethanol solution containing no carboxyalkylamine derivative (1) or a salt thereof was similarly applied (control group). Three weeks later, the shaved portions of the test numbers 24-32 and the control group were photographed at a fixed magnification.
The regenerated hair was observed using an image analyzer, the regenerated hair area ratio (regenerated hair area / shaved area) was determined, and the hair growth inhibition rate (1-
(Regenerated hair area ratio of each test number / regenerated hair area ratio of control group)) × 100 (%) was calculated. Table 6 shows the results.

[0041]

[Table 6]

Compounds 1 to 9 had an excellent hair growth inhibitory effect.

Example 1 A cream for preventing and improving skin aging was prepared according to a conventional method with the composition shown in Table 7. This showed an excellent effect of preventing and improving skin aging.

[0044]

(%) Compound 1 0.2 stearic acid 2.0 cetanol 4.0 squalene 8.0 petrolatum 5.0 hydrogenated palm oil 4.0 polyoxyethylene sorbitan monostearate (20E.O.) 4 Lipophilic glyceryl monostearate 2.4 butyl paraben 0.1 glycerin 3.0 L-arginine 10.0% potassium hydroxide 0.2 fragrance 0.1 purified water Total balance 100.0

Example 2 The components belonging to A shown in Table 8 were dissolved, and the components belonging to B were separately dissolved. Add B to A, stir and mix uniformly,
A hair growth inhibiting lotion was manufactured. This showed an excellent hair growth inhibitory effect.

[0046]

Table 8 (%) Polyoxyethylene hydrogenated castor oil 0.8 ethanol 30.0 B. Compound 3 1.0 Sodium dodecyl sulfate 0.12 Dodecylmethylamine oxide 0.18 Isopropyl alcohol 15.0 Benzyl alcohol 12.0 Glycerin 2.0 Purified water Balance total 100.0

[0047]

The external preparation for skin of the present invention exhibits excellent effects particularly in preventing and improving skin aging such as generation of wrinkles and in suppressing hair growth. Further, the skin aging preventive / improving agent of the present invention has an excellent skin aging preventing / improving effect, a hair growth inhibitor has an excellent hair growth inhibiting effect, an elastase inhibitor has an excellent elastase inhibitory effect, and a STANA degrading enzyme inhibitor. Shows an effect of effectively inhibiting an enzyme having an activity of decomposing STANA to generate p-nitroaniline. Such effects are remarkable when the carboxyalkylamine derivative (2) or a salt thereof is used.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 43/00 A61K 31/00 643B A61K 31/40 31/40 31/445 31/445 C07C 237/06 C07C 237/06 C07D 207/16 C07D 207/16 211/34 211/34 (72) Inventor Yukihiro Ohashi 2606 Kagabacho, Haga-gun, Tochigi Prefecture Kao Corporation Research Institute (72) Inventor Shigeru Moriwaki, Haga-gun, Tochigi 2606 Akabane, Kao Corporation Research Laboratory (72) Inventor Naoko Tsuji 2606, Kaigamachi, Kaga-cho, Haga-gun, Tochigi Prefecture Kao Corporation Research Laboratory F-term (reference) AC102 AC122 AC152 AC242 AC402 AC432 AC482 AC562 AC582 AC621 AC622 AC782 AC851 AC852 CC02 CC05 CC37 DD23 DD31 EE06 EE12 EE22 4C086 AA01 AA02 AA03 BC07 BC21 MA01 MA01 MA 04 MA63 NA14 ZA89 ZB02 ZC20 4H006 AA01 AA03 AB12 AB20 BJ50 BS10 BU32 BU38 BV21 BV51

Claims (7)

[Claims] 1. The following general formula (1): (Wherein, R ¹ represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms, R ² and R ⁴ represent a hydrogen atom or a lower alkyl group, and R ³ has a hydrogen atom or a substituent A good alkyl group or an aralkyl group, and R ⁵ represents a hydrogen atom or may form a heterocyclic ring with an adjacent nitrogen atom together with R ³ ) or a carboxyalkylamine derivative represented by the formula: An external preparation for skin containing the salt as an active ingredient. 2. R¹Is a hydrogen atom or an atom having 1 to 4 carbon atoms.
A alkyl group, R ^TwoIs a hydrogen atom or a group having 1 to 4 carbon atoms
An alkyl group;^ThreeIs a hydrogen atom, a carbamoyl group is
An optionally substituted alkyl group having 1 to 4 carbon atoms or carbon
An aralkyl group having a prime number of 7 to 10,^FourIs a hydrogen atom
Yes, R^FiveIs a hydrogen atom, or R^ThreeTogether with
A pyrrolidinyl group together with an adjacent nitrogen atom or
2. The skin according to claim 1, which forms a piperidinyl group.
External preparation for skin. 3. A skin aging preventive / improving agent comprising a carboxyalkylamine derivative represented by the general formula (1) according to claim 1 or 2 or a salt thereof as an active ingredient. 4. A hair growth inhibitor comprising a carboxyalkylamine derivative represented by the general formula (1) according to claim 1 or a salt thereof as an active ingredient. 5. An elastase inhibitor comprising a carboxyalkylamine derivative represented by the general formula (1) according to claim 1 or a salt thereof as an active ingredient. 6. A carboxyalkylamine derivative represented by the general formula (1) according to claim 1 or 2 or a salt thereof as an active ingredient, wherein N-succinyl-Ala-Ala- is used.
An inhibitor for an enzyme having an activity of decomposing Ala-p-nitroanilide (STANA) to produce p-nitroaniline. 7. The following general formula (2): (Wherein, R ⁶ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R ⁷ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms which may be substituted by a carbamoyl group, or a 7 to 4 carbon atom.
10 represents an aralkyl group, R ⁸ represents a hydrogen atom,
Alternatively, it indicates that together with R ⁷ forms a pyrrolidinyl group or a piperidinyl group together with an adjacent nitrogen atom. Or a salt thereof.