JPH10212231A - Oxa-diacid for treating dermal state and related compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a local coating composition useful for xeroderma, ichthyosis, pimple, psoriasis, eczema, wrinkle, etc., by using a specific oxa-diacid as an active component. SOLUTION: This composition used a suitable local coating excipient and a compound of the formula [R4 is (CR5 R6 -CR7 R8 X1 )n -CR9 R10 -C(=X2 )X3 R11 (n) is 1-18; R1 to R11 are each H, a substitute of a non-hydrogenous atom; X, X1 to X3 , Y and Z are each O, NH or S]. Preferably, 3,6-dioxaoctadioic acid, 3,6,9-trioxaundecanedioic acid, 3,6,9,12-tetraoxatetradecanedioic acid, etc., is used as the compound of the formula. A blending amount of the compound of the formula into the composition is about 0.1-95wt.%. The composition is effective for abnormal corneal layer of epidermis, dandruff, a simple chronic disease of lichen, Darier's disease, cornified fiber, lentigo, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION The present invention relates to a new class of compounds used as active agents for local treatment of skin conditions, compositions containing these compounds, and care of skin conditions using these compounds and compositions. It is about the method. Compounds of this type have the formula (I)

[0002]

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(Where R ₄ is (CR ₅ R ₆ -CR ₇ R ₈₎
X ₁ ) _n —CR ₉ R ₁₀ —C (＝ X ₂ ) X ₃ R ₁₁ ; n is an integer from 1 to 18; R ₁ , R ₂ , R
₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are a substituent by a hydrogen atom or a non-hydrogen atom; the substituent of the non-hydrogen atom is preferably an alkyl, alkene , oxa - alkyl includes aralkyl and aryl _{groups; X, X 1, X 2} , X 3, Y and Z are each independently O, NH or S, preferably X, X _1, X
₂ , X ₃ , Y and Z each represent an oxygen atom, R ₁ , R ₂ ,
R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are each a hydrogen atom. )including.

[0004] For all background related art use on the skin of the α- hydroxy acid is a compound consisting of carbon skeleton, U.S. Patent U. S. P. N
o. B15,091,171, and cosmetic compositions using 2-hydroxyalkene-based acids are described in U.S. Pat. S. P. No. 5,108,751
Is well known. Such a compound always has an α-hydroxy group which cannot be substituted at the position of all these carbon skeletons due to its chemical structure,
Therefore, it is used intentionally because it has a beneficial effect on the skin. However, α which requires a low pH range for use known to cause skin irritation in the most common form, such as glycolic acid and lactic acid
The use of hydroxy acids has departed from this trend.

It has been proposed to replace the currently prevalent α-hydroxy acids with topical compositions consisting of dicarboxylic acids with a straight-chain, all-carbon skeleton. For example, U.S.
S. P. Nos. 4,292,326,4,386,1
04 and 5,385,943 claim that dicarboxylic acids having 7 to 13 carbon atoms should be used for various skin indications. Similarly, U.S. S. P. No.
No. 4,885,282 states that dicarboxylic acid compounds having 4 to 18 carbon atoms are effective for skin roughness.

A disadvantage of using these dicarboxylic acids is that their bulk is inherently insoluble in the aqueous solution required when combined with cosmetic excipients. A dicarboxylic acid composed entirely of a carbon skeleton is solid at normal temperature. It is very difficult to work with water-soluble liquids, and even if a possible solution is produced, it is unsuitable for use as a cosmetic product, which results in an aesthetically unpleasant mixture.

There is a need in the art for a class of compounds that can be used as mild and exfoliating when applied topically to the skin.

[0008] Furthermore, in this field, there is a mild, exfoliating topical agent which contains a water-soluble compound which does not cause problems when producing cosmetic or dermatological agents which are aesthetically acceptable. There has been a need for a coating composition.

OBJECTS OF THE INVENTION It is an object of the present invention to provide a composition for topical application with a number of skin care benefits.

Another object of the present invention is to provide water-soluble compounds which are aesthetically acceptable for application to the skin and which have no problem in producing a composition which is gentle on the skin and has an exfoliating action. It is in.

It is a further object of the present invention to make oxa diacids and related compounds new and dermatological and cosmetically usable. These and other objects will become apparent from the present disclosure provided below.

[0012] The method with the active compounds used in the composition of the cleaning SUMMARY The present invention provides compounds of formula (I)

[0013]

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(Wherein R ₄ is (CR ₅ R ₆ -CR ₇ R ₈₎
X ₁₎ is indicated by _{n -CR 9 R 10 -C (=} X 2) X 3 R 11; n is an integer from 1 to 18, preferably from 2 1
R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R
₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are each independently a substituent by a hydrogen atom or a non-hydrogen atom. ).

Preferably, the non-hydrogen atom substituent includes an alkyl, alkene, oxa-alkyl, aralkyl and allyl group. Non-hydrogen atom substituents include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, hexyl, heptyl, octyl, nonyl, dodecanyl, methoxy, ethoxy, propoxy,
Includes butoxy, cyclohexenyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclobutyl and cyclohexanyl.

X, X ₁ , X ₂ , X ₃ , Y and Z are each independently O, NH or S. Preferably, X, X ₁ , X ₂ , X ₃ , Y and Z in these compounds are all oxygen atoms. Most preferably, X, X ₁ , X ₂ , X ₃ , Y and Z in each of these compounds are all oxygen atoms, and R ₁ ,
R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R
₁₀ and R ₁₁ are all hydrogen atoms.

As defined herein, all compounds of this class identified as Formula (I) above, even if any or all of X, X ₁ , X ₂ , X ₃ , Y and Z Regardless of whether they are independently oxygen, sulfur or amino groups, they belong to the "oxa diacid" and / or "oxa compound" as an aggregate.

The treatment method and the composition for local application of the present invention can further comprise a mixture comprising two or more of the formula (I).

The present invention relates to a composition for topical application containing a compound of the formula (I), a method of skin treatment using a compound of the formula (I), and a method of treating a compound of the formula (I) and a corresponding epidermis from the epidermis. It provides a method for skin treatment using a composition composed of possible excipients.

[0020] DETAILED DESCRIPTION finding the present invention surprisingly the invention, the group of compounds represented by Formula (I) is dry skin, ichthyosis, back of the hand and foot instep excessive Kawamizo small mole, age Purple spots, black spots,
Injured skin, acne, psoriasis, eczema, prurigo, inflammatory dermatitis, muscle swelling (ie stretch marks),
It can be used as an active ingredient in topical applications to cure various advanced or pathological skin conditions caused by abnormal scaling, including "warts" and "octopus" It has become.

Including fine wrinkles around the eyes, or "crow's feet", or fine wrinkles around the mouth, irregular pigmentation, soil color, skin wrinkles due to loss of skin elasticity or elasticity, etc. It has been unexpectedly and surprisingly found that this compound is effective as an active agent in the form of "skin polish" to suppress the signs of aggressive, aggressive dermatopathological progression.

The compound of the present invention represented by the formula (1) and the composition for skin coloring containing the same can further be used for diseases such as nails, scalp, and hair that penetrates into the hair, such as hair, hair follicles and pseudo-hair follicles. It is also useful for curing. The compounds of the present invention have been found to be useful for softening hair, helping to eliminate hair ingrowth, and also for shaving.

The representative compound of the chemical structure (I) for the method of treatment and the composition for topical application of the present invention are 3,3
6-di oxa oct dioic acid (HOOC-CH ₂ -O
_{-CH 2 -CH 2 -O-CH 2} -COOH); 3,6,9- trio key sound decane-oic click acid (HOOC-CH ₂ -
_{O-CH 2 -CH 2 -O-} CH 2 -CH 2 -O-CH 2
-COOH); 3,6,9,12 tetraoxatetracosane decane-oic click acid _{(HOOC-CH 2 -O-CH} 2 -CH 2 -
_{O-CH 2 -CH 2 -O-} CH 2 -CH 2 -O-CH 2
-COOH); 3,6,9,12,15- penta-oxa hepta-decane-oic click acid _{(HOOC-CH 2 -O-CH} 2 -CH
_{2 -O-CH 2 -CH 2 -O} -CH 2 -CH 2 -O-C
_{H 2 -CH 2 -O-CH 2} -COOH); 2- methyl-3,
6,9-trioxaundecandioic acid (HOOC-C
_{H 2 -O-CH 2 -CH 2} -O-CH 2 -CH 2 -O-
_{CH (CH 3) -COOH);} 2- ethyl - 3,6,9-12- tetraoxatetracosane decane-oic click acid (HOOC-CH
_{2 -O-CH 2 -CH 2 -O} -CH 2 -CH 2 -O-C
_{H 2 -CH 2 -O-CH (} C 2 H 5) -COOH); 2-
Phenyl-3,6,9-trio key sound decane-oic click acid (HOOC-CH (Ar) -O -CH 2 -CH 2 -O-
CH ₂ —CH ₂ —O—CH ₂ —COOH); 3,6,9-trioxaundecandioic acid / diethyl ester (H
_{2 C 2 -OOC-CH 2 -O} -CH 2 -CH 2 -O-C
H ₂ —CH ₂ —O—CH ₂ —COO—C ₂ H ₅ );
9-triaminoundecandioic acid (HOOC-CH
_{2 -NH-CH 2 -CH 2 -NH} -CH 2 -CH 2 -N
H-CH ₂ -COOH); 3,6,9,12- tetramethyl aminotetralin decane-oic click acid (HOOC-CH ₂ -NH-CH
_{2 -CH 2 -NH-CH 2 -CH} 2 -NH-CH 2 -C
_{H 2 -NH-CH 2 -COOH)} ; 3- amino-6,9-di oxa undecanedicarboxylic oic click acid (HOOC-CH ₂ -NH
_{-CH 2 -CH 2 -O-CH 2} -CH 2 -O-CH 2 -
COOH); 3,6-diamino-9-oxa-undecane-oic click acid _{(HOOC-CH 2 -NH-CH} 2 -CH 2 -N
_{H-CH 2 -CH 2 -O-} CH 2 -COOH); 3,6,9-
Trithiadiaza Own decane-oic click acid (HOOC-CH ₂ -
_{S-CH 2 -CH 2 -S-} CH 2 -CH 2 -S-CH 2
—COOH); 3,6-dithio-9,12-dioxatetradecandioic acid (HOOC—CH ₂ —S—CH ₂ —C
_{H 2 -S-CH 2 -CH 2} -O-CH 2 -CH 2 -O-
CH ₂ -COOH); 3- amino-6,9-di oxa undecanedicarboxylic oic click acid monoamide (HOOC-CH ₂ -NH
_{-CH 2 -CH 2 -O-CH 2} -CH 2 -O-CH 2 -
CO-NH ₂ ); 3-amino 6,9-dioxaundecandioic acid diamide (H ₂ N—OC—CH ₂ —NH—
_{CH 2 -CH 2 -O-CH 2} -CH 2 -O-CH 2 -C
ONH ₂ ); 3,6,9-trioxaundecandioic acid monoamide (HOOC—CH ₂ —O—CH ₂ —CH ₂
—O—CH ₂ —CH ₂ —O—CH ₂ —CONH ₂ );
6,9-trioxaundecandioic acid diamide (H
_{2 NOC-CH 2 -O-CH} 2 -CH 2 -O-CH 2 -
CH ₂ —O—CH ₂ —CONH ₂ ); 2,10-dimethyl-
3,6,9-Trioxaundecandioic acid (HOOC-
_{CH (CH 3) -O-CH} 2 -CH 2 -O-CH 2 -C
H ₂ —O—CH— (CH ₃ ) —COOH);
0-dimethyl-3,9-dithio-6-oxa-undecane-oic click acid _{(HOOC-CH (CH 3)} -S-CH 2 -CH 2
_{-O-CH 2 -CH 2 -S-} CH (CH 3) -COO
H). The method and the composition of the present invention exert a better effect by mixing two or more different compounds among the substances having the “formula (1)”.

Compounds belonging to this class are used as intermediates in preparing a curing agent for epoxy resin. S. Patent
Nos. 5,017,675 and 5,319,00
4, both of which are assigned to Hoechst. Application No. published in Germany. DE-A-
2936123 describes a method for preparing such an epoxy resin intermediate. Such compounds are also commercially available from Hoechst.

Other compounds of this class are similarly prepared from commercially available polyamines, polyols and polythiols via conventional chemical reactions.
They are well known in the art for amidation, catalytic oxidation, esterification and other well-known chemical reactions and other organic chemistry synthesis books by Advanced Or
ganic Chemistry: Reactions, Mechanisms, and Structur
e, 3rd ed., John Wiley Interscience (1985) and Carey
et al., Advanced Organic Chemistry, 3rd.ed., Parts A
and BPlenum Press, New York (1990).

The oxa compound may be neutralized with a free acid or an organic or inorganic base such as triethanolamine, algin, lysine, potassium hydroxide, sodium hydroxide, lithium hydroxide, ammonium hydroxide or the like. The corresponding salts derived from are also incorporated into the composition. The pH of the oxa diacid composition is adjusted by adding a water-soluble salt formed by a strong base (eg, KOH, NaOH, NH ₄ OH) and a weak acid (eg, phosphoric acid, acetic acid, lactic acid, carboxylic acid). Can also be adjusted. Such salts include, for example, potassium biphosphite, sodium phosphate, sodium acetate, sodium lactate and the like. Other methods of adjusting the pH of the topical compositions of the present invention are well known to those skilled in the art.

The care method and topical application composition of the present invention are used in the form of a derivative, such as glycosidase, phosphates, esterase, amidase, which is reverted to the acid by the action of a hydrolase in the skin. It is also possible. Examples of preferred derivatives of oxa diacid include esters with aliphatic alcohols or esters with carbohydrates, amides, lactones and anhydrides.

As used herein, "topical use" means that the composition is directly diffused or applied to the surface of the skin, and "topical application composition" A composition intended to lay or spread directly on the surface of the skin; an "effective amount" of which has caused, developed or deteriorated an abnormal exfoliating effect In the condition of the skin treated
Means an amount of the compound or composition sufficient to effect a positive change (eg, normal exfoliation); and also, a “physiologically acceptable excipient” or a “preferred topical excipient”. Is intended to mean that the term is a drug, cosmetic, pharmaceutical, or inert ingredient suitable for use without undue toxicity when in direct contact with human tissue.

The present invention includes formulations in which these compounds can be used to treat the aforementioned skin conditions. Such methods usually apply to the affected skin area
Once or twice daily applying to the epidermis an effective amount of one or more compounds of formula (I). Such methods include physiologically acceptable excipients for the affected epidermis, usually once or twice daily, in an effective dose of one or more compounds of formula (I). And a composition for topical application containing The method of the present invention is applicable when the compound of formula (I) is topically applied at concentrations up to 100% and the oxa compound is used for skin or to soften hair. Such compounds are liquid at room temperature (eg, 3,6,9-trioxaundecandioic acid).

When used in combination with a physiologically acceptable excipient to form a topical composition, the effective amount of the compound of formula (I) ranges from about 0.1% to 95%. Is possible. The condition of each person's skin, the effective amount and number of treatments when used, the age and physical condition of the person at the time of care, the severity of the condition, the time of care, the nature of the treatment used together The properties of the compounds and compositions used, the properties of the excipients used to carry the compounds and compositions, and within the knowledge and experience of the person skilled in the art, also depending on similar factors. Will.

The efficacy of these compounds in caring for the condition of the skin is also affected by the pH of the composition. It is desirable to maintain the pH in the range <7.0, preferably <5.0, and most preferably 3.5 to 4.0.
It is good to be in the range.

The compound of formula (I) used in the treatment method of the present invention and in the composition for topical application is another known compound which has been used for improving skin condition, α-hydroxy. Compounds such as acids and dicarboxylic acids are structurally different substances. Compared to the formula of α-hydroxy acids, the substances according to the invention derive a group of compounds which have the distinct advantage of being much milder on the skin. Substances of chemical structure with α-hydroxy acids, such as glycolic acid and lactic acid, sometimes cause their own discomfort and sometimes rough skin symptoms for facial use. For example, a composition containing 4.0% glycolic acid, when tested on 20 respondents at pH 3.7, shows a degree of skin irritation (PI
I) The score showed 0.23. In contrast, 10
The composition containing% 3,6,9-trioxaundecandioic acid had a PII score of only 0.13 at pH 3.7. (See Example 2 below)

Compounds with a PII score equal to or less than 0.15 are considered non-irritant;
Those with a II score between 0.15 and 0.3 are considered to be moderately stimulating; a PII of 3.0.
Compounds derived from respondents who test the above scores are considered to be difficult stimulants. The score based on the PII is a value obtained by dividing the number of respondents who complained of irritation in the test by the number of all respondents who took the test.

Oxa diacids are considerably more gentle on the skin than compositions of glycolic acid, while the compositions, on the other hand, have a high metabolic upper stratum corneum, which is necessary to relieve the condition of the skin as described above. Very effective in normalizing the peeling action.

The advantages of the oxa compound as compared to the dicarboxylic acid are that it has better solubility in water and excellent activity for exfoliating the stratum corneum. Oxa diacids are readily soluble in water, at least up to a concentration of 20 to 30% by weight, and thus can provide flexibility over a fairly wide range of compositions. All are carbon skeletons and medium length linear carbon dicarboxylic acids are essentially insoluble in water or apparently insoluble in other acceptable excipients. This limits the choice of penetration solvent to dissolve the dicarboxylic acid to severe. All carbon skeleton dicarboxylic acids are also problematic in terms of the activity of the stripping action. For example, it is known that compositions containing 5% and 10% dodecanedioic acid do not have any normalizing effect on the exfoliation of the stratum corneum beyond the effect of its excipients.

The oxa-diacid compound of the present invention can be used alone or in combination with other cosmetics, pharmacologically active substances, excipients and the like. Oxa diacids are other cosmetics and drugs, such as antibacterial agents, stain removers, sunscreen agents, retinoids, antiallergic agents, depigmenting agents, anti-inflammatory agents, anesthetics, emulsifiers, wetting agents,
Release agents, surfactants, stabilizers, preservatives, antiseptic agents, emollients, thickeners, lubricants, wetting agents, chelating agents, fragrances,
It is already used in compositions containing colorants, skin penetration enhancers and the like. The use of an oxa compound in admixing with any one of the above classes of actives is a particular dermatology that could not be obtained when the above actives were used without the oxa compounds of the present invention. And / or cosmetic benefits.

The composition simultaneously comprises a cation, an anion,
Nonionic or amphoteric types, or a combination of these surfactants. Nonionic surfactants are preferred. Representative commercially available nonionic surfactants are sorbitans, alkoxylate fatty alcohols and alkyl polyglycosides. Anionic surfactants include soaps, alkyl sulfates, monoalkyl and dialkyl phosphates, alkyl sulfonates and acyl isethionates. Other suitable surfactants are described by McCutcheon, Detergentsand Emul
sifiers, North American Edition, pp. 317-324 (1986), and its use concentration is incorporated therein as a reference.

Where the compositions of the present invention require preservatives, suitable preservatives include alkanols, especially ethanol, phenol, paraben, sorbate, diazolidinyl urea and isothiazolinone.

Preferred thickeners for use with the oxa diacids of the present invention are xanthan gum, salt water resistant xanthan gum, hydroxypropyl cellulose,
Contains hydroxyethyl cellulose, Carbopol and gum acacia, Sepigel 305 (available from Seppic, France), veegum or magnesium aluminum silicate. Oxa diacids can be used in combination with humectants and their use is, for example, in urea, PCA,
Enhanced by amino acids, certain polyols and other compounds that are hygroscopic.

The compounds of the present invention are most commonly used as emollients, for example, mineral oil, petroleum wax, paraffin, ceresin, ozokerite, microcrystalline wax, perhydrosqualene, dimethylpolysiloxane, methylphenylphenyl. Polysiloxane, silicone glycol copolymer, triglyceride ester,
Acetylate monoglyceride, ethoxylate glyceride, alkyl fatty acid ester, fatty acid and alcohol, lanolin and lanolin derivative, polyhydric alcohol ester, sterol, beeswax derivative, polyhydric alcohol and polyester, and It can be combined with fatty acid amides. Other suitable emollients are Cosmeti by Sagarin
cs, Science and Technolo-gy, 2nd.Ed., Vol.1, pp.32-43
(1972), the concentration of which is also incorporated therein for reference.

Another advantage of oxa diacid is that
When used in combination with a drug that acts on the stratum corneum in a composition for topical application, a compound such as salicylic acid or benzoyl peroxide, or a drug that gives fluorescence to the skin, for example, kojic acid, benzoquinone, a licorice derivative, Ascorbic acid and its derivatives (for example, magnesium ascorbyl phosphate), glycerhetinic acid and its derivatives can be used in combination. Oxa diacid is also an organic and inorganic sunscreen, for example, titanium dioxide, zinc oxide,
Bentilidene camphor, anthranyl compounds (methyl, menthyl, phenyl, bentyl, phenylethyl, linalyl, terpinyl, esters of cyclohexenyl and cycloheptenyl, and o-amino-benzoate),
Salicyl compounds (amyl, phenyl, ventil, menthyl, glyceryl, octyl, dipropylene glycol,
Esters and cholesteryl salicylate), cinnamic acid derivatives (menthyl, octyl, 2-ethylhexyl, benzyl, alphaphenyl, cinnamnitrile and butyl cinnamoyl pyruvate), dihydroxycyanamic acid derivatives (umbelliferone, methylumbellium) Ferron, methylacetoumbelliferone), trihydroxycinnamic acid derivatives (esculetin, methyl esculetin, daphnetin, and glycoside compounds thereof)
Esculetin, methyl esculetin, daphnetin and its glucoside compound, esculin and dafuran), naphthol sulfonate compound (2-naphthol-
3,6-disulfonic acid and salts of 2-naphthol-6,8-disulfonic acid), dihydroxynaphthoic acid and its salts, ortho- and para-hydroxybiphenyldisulfonates, non-toxic coumarin derivatives, diazole compounds (e.g. 2-acetyl-3-benzothiazole compounds, quinone derivatives (8-hydroxyquinoline, 2-phenylquinoline), quinates, urea and violuric acid, tannic acid and its derivatives, dioxybenzone, benzoresorcinol, 2,2 ', 4,4'-tetrahydroxybenzophenone, ethacrylene, etc. Among these, a cyanamic acid derivative is preferred.

The utility of oxadiacids is based on (i)
In the case of retinoid compounds (vitamins),
Retinol, retinol acid, retinyl palmitate,
Retinyl propinate, retinyl acetate, isotretionin equivalent to synthetic pseudo-retinoid; (ii) formonal compounds (hormones), examples of which include estriol, estradiol, estrone or conjugated estrogen compounds; (iii) α-hydroxyl Acids or polyhydroxy alpha-hydroxy acids, such as glycolic acid, lactic acid, tartaric acid, gulonic acid and other carboxylic acids, and their monomers, polymers, cyclic or acyclic derivatives, free or A non-substituted amine group at the α-position linked to a substituted hydroxy-, thiol-, selenyl-, or carboxyl group; (iv) those having an α-keto acid such as pyruvic acid, 2-oxa Propionic acid, 2-oxabutyric acid, 2-oxapentane Quick an acid and the like.

Oxadiacide is also compatible with the following substances in topical coating compositions and can produce additional advantages when used in combination: That is,

(I) Vitamins and enzyme cofactors
For example, vitamin B6 (pyro-doxine-HCl), vitamin B12 (Cyanocobalamin), vitamin D3 (cholecalci
pherol), 1,25-dihydroxy vitamin D3, vitamin B1 (thiamine), vitamin B2 (riboflavin),
Vitamins K _n , vitamin E (tocopherol), tocopheryl hemisuccinate, tocopheryl ascorbyl phosphate, tocopheryl linoleate, tocotrienol and its derivatives, nicotinic acid and its esters, panthenol, folic acid and its Derivatives, choline, carnitine and normal vitamin status or substances without "fake vitamins" such as vitamin F or cis, cis-linoleic acid, vitamin M or pteroylglutamic acid, vitamins B10 and B11, vitamin T Vitamin T, Thermitin, Penicin, Insectin, Hypomycin, Mycoin, Vitamin L or Anthranilic acid, Vitamin L2 or Adenylthiomethylpentose, Myo-inositol or also known as "sesame seed factor" Shi 1,2,3,5-trans-4-6-cyclohexanehexol and its esters, especially phytic acid, laetrile or 1-mandero-nitrile β-glucuronic acid, amygdalin, vitamin B15 or pangamic acid, vitamin B13 or Orotic acid, vitamin H3 or procaine hydrochloride, vitamin U or the methylsulfonium salt of methionine, and pyrroloquinonoline quinone;

(Ii) an effective amount of an antibacterial agent, specifically
Clotrinazole, ketoconazole, miconazole, naftifine, tolnaftate, amphotericin B, nystatin, 5-fluorocytosine, griseofulvin, haloprogine, among these, tolnaftate,
Haloprogine and miconazole are most often used;

(Iii) Self-massage agents include dihydroxyacetone and laurin, of which the former is most preferred;

(Iv) antibacterial agents, such as erythromycin, tetracycline and related compounds, especially doxycycline and metacycline, cephalosporins, penicillins, phenazines, especially clohadimin, rifamycins, especially rifampins, especially sulfones, Diaminodiphenyl sulfone, hiradineamide, thiosemicarbazone, especially benzaldehyde thiosemicarbazone, thiourea, especially diphenylthiourea having 4,4-2 substituents, biomycin, macrolide, aminoglycoside and peptide compound, Noopiocin, vancomycin, oleandomycin, paromomycin, leucomycin, fortimycin, colistin, clicloserine, dactinomycin, bicyclomycin, polypeptide compounds Ri amphomycin, quinolone derivatives having a macrolide molecules of choice, especially Narijikishikku acid, oxolinic acid, norfloxacin, ciprofloxacin and Furumekine, and cell wall synthesis bacteria, membrane potential function, RN
A metabolism, synthesis of purines, pyrimidines and proteins,
Other compounds that interfere with respiratory action or the superphosphate reaction;

(V) Skin analgesics such as lidocaine, benzocaine, butamben, butacaine, dimethisoquin, diperodone, diclonin, pramoxine, tetracaine, chlorobutanol, clove oil, eugenol, etc., among which benzocaine and lidocaine Is most preferred;

(Vi) lipid compounds which are essential for the protective function of the skin, such as ceramides, essential fatty acids and their esters, in particular derived from glycerides, alkanols via carboxylic hydroxyls or omega-hydroxyls. Ω-hydroxy fatty acids derived from other fatty acids in the form of
In this case, the latter type is most preferred, for example, cholesterol / hemisuccinate and cholesterol / phosphate, which include cholesterol / hemisuccinate and cholesterol / phosphate, in which cholesterol / phosphate and essential fatty acids are included. The most preferred is the human steroid, cholestanol and its derivatives. The lipid compound can be added to the topical composition, whether it is a single molecule itself or a complex mixture of lipids derived from animal or plant sources by chemical synthesis;

(Vii) Antiallergic agent and H1 and / or
Or H2 antihistamines such as, for example, diphenylhydramine, clemizole, antazoline, tenaldine, phenyltroxamine citrate, doxylamine and its salts, diphenylpyralin, medrilamine, clemastine, phenylamine and its halogenated derivatives and their derivatives. Salts, especially maleate of phenylamine, bacridine, triprolidine and its salts, phenothiazine and related analogues, especially phenesazine hydrochloride and parathiazine hydrochloride, debenz [b, e] azepine, Trapane, another tricyclic anti-allergic agent, ketotifene, dithiadene and thiadene 3-thienyl sulfide, H2-receptor blocker, especially Mamaido, Mechiamaido, Shimechijien, Kuromorikku acid and its salts, Kerin,
Chiethylcarbamadine, hiliprost;

(Viii) An anti-dermatitis agent which relieves inflammation at a concentration of 0.025% to 10%, preferably 0.5-1%, adjusted up and down according to the efficacy of the drug used. Examples of steroidal dermatitis inhibitors used when oxadiacid is used in the present invention include hydrocortisone, hydroxytriamcilone, α
-Methyl dexamethasone, dexamethasone phosphate, beclamethasone dipropionate, clobetasol valerate, dezonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone,
Dichlorisone, di-florazone diacetate, diflucortron and its derivatives, fluadrenolone, fluchloron acetonide, fluocinonide, flucortin butyl ester, fluocortron, flupredonidine acetate, flulandrenolone, halcinonide, hydrocortisone acetate , Hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, medolizone, amcinafide,
Betamethasone and its esters, chloroprednisone, chloroprednisone acetate, crocorterone, crescinolone, dichlorisone, difluprednate, fluchloronide, flunizolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentolpropionate hydrochloride, hydrocortisone cyclopentylpropionate hydrochloride , Including meprednisone, parameterzone, prednisolen, and mixtures thereof, the most preferred being prednisolone and hydrocortisone; and

(Ix) Rainsford, Antiinflammatory
and Anti-Rheumatic Drugs, Vols. I-III, CRC Press, Bo
As in ca Raton, Florida (1985), non-steroidal dermatitis inhibitors may also be employed. And the appropriate NSA
Specific examples of IDs include enolic acid, oxicams (eg, proxicam, isooxicam), phenamic acid derivatives, meclofenamic acid derivatives (eg, sodium salt of meclofenamic acid), flufenamic acid derivatives ( For example, N- (α,
α, α-trifluoro-m-tolyl) anthranilic acid), mefenamic acid derivatives (for example, N- (2,3-
Xylyl) anthranilic acid), propionic acid esters such as ibuprofen, naproxen, benoxaprofen, flubiprofen, ketoprofen, saprofen (of which ibuprofen is the most preferred), feprazone, trimetasone, oxyhembutazone , Pyrazolidinediones such as sulhynpyrazone, phenylbutazone (of which the phenylbutazone is the most preferred), diclofenac, fenclofenac, indomethacin, salindac, tolmetin, isosepac, flofenac, cridanac, Acetic acid derivatives such as Zomepirac, Asematricin (of which indomethacin is the most preferred), Aspirin, Safaprine, Disalasid, Benolylate, Tricile Doo (among which aspirin and Jisarashiddo is most preferred) is salicylic acid derivatives such as.

The composition of the present invention comprises an aloe vera extract,
Extract from the genus Rubis (Rubia Cordifolia), Commiphom
(Commiphora Mukul) For anti-inflammatory like extracts from bark of the genus, eel bark, Matricaria flower, Arnica flower, Finflower root, Roller seed and its analogs known in the art as perfected technology Includes safe anti-inflammatory products made from natural ingredients that have been shown to have activity.

The compositions of the present invention contain an antioxidant having a phenolic hydroxy functional group, such as a gallic acid derivative (eg, propyl gallate), a bio-flavonoid compound (eg, quercetin, Rutin, daidzein, genistein),
Ferric acid derivatives (eg, ethyl ferulate, sodium ferrate), 6-hydroxy-2,5,7, tetramethylchroman-2-carboxylic acid. The compositions also contain effective concentrations of water-soluble antioxidants, for example, uric acid, redactic acid, tannic acid, rosmarinic acid and catechin compounds. Moreover and beneficially, oxa diacids combine with nitric oxide to redden skin, especially in response to electromagnetic and ionic emissions or to chemically and biochemically active compounds. Synthesize inhibitors as a way to reduce vasodilation and inflammatory responses. The nitric oxide synthesis inhibitor can be added at a concentration of 0.05% to 10%,
Most preferably from 1% to 3%, and especially monoamino and methyl guanidine, L-arginine derivatives, especially ^NG -nitro-L-arginine and its esters, ^NG -monomethyl-L-arginine,
It can be selected from the group consisting of guanidine derivatives such as 2-iminopiperidine and other 2-iminoazaheterocycles.

The compositions of the present invention comprise from 0.025% to 5%, preferably from 0.5% to 2%, most preferably from 0 to 25% of these compounds known to be electron spin complements. 0.5 to 1%, for example, a nitrone compound, N-tert-butylnitrone and α- [4-pyridyl-1-oxide] -N-tert-butylnitrone or a half reduction of 1 minute or more. And other compounds known to form aging free radicals.

Other possible antioxidants contained in the composition are in either reducing or non-reducing forms such as glutathione, lipoic acid, thioglycolic acid, thiolactic acid, thioglycerol and kristine. One or more thiol groups (-S
H). The level of sulfhydryl antioxidant may be between 0 and 0 when the composition is cosmetic.
It should not exceed 5%, but may be used more in the case of pharmaceutical preparations than indicated in consideration of efficacy.
The composition may also include inorganic antioxidants such as sulfinates, bisulfinates, metabisulfites or other inorganic salts and acids containing sulfur in the +4 oxidation state. The preferred level of inorganic sulfur-containing antioxidants is 0.01-0.5%, with the most preferred level being between 0.1% and 0.4%.

Oxa diacids may be used in compositions containing repellents such as aliphatic, cyclic or aromatic amides, citronella oil, terpineol, cineol, indian soap oil and terephthalic acid and its esters. it can. Another suitable insect repellent is the USDepartment of Agricult
Technical Bulletin No. 1549 or its Ag
ricultural Handbook Nos. 69, 340 and 461.

Oxadiacides are described, for example, in the following: menthol, menthyl glycerol, acylmethycarbonate, thiocarbonate and urethane, N-substituted carboxamide, J. Cosmet. Chem., Vol. 29, p. 185
(1978) Suitable for use in topical compositions containing skin cooling compounds such as urea or phosphine oxide, menthyl lactate, and menthone glycerin acetal as described in (1978). is there.

The composition of the present invention is prepared as a topical solution. The base lotion contains an effective amount of oxa diacid, up to 95% water, up to 20% emollient and 10%
Up to surfactants. Such lotions are preserved with up to 5% of preservatives and additionally 2-3.
It contains up to 5% fragrance and up to 5% dye or pigment. The composition of the present invention can be formed into a cream. The base cream is conventional and contains an effective amount of oxa diacid, up to about 30% emollient, up to about 90% water and up to about 20% surfactant.

Such lotions or creams can be prepared by the usual methods of homogenization known in the art as being skilled in the art, but the size of the emulsion particles is reduced by applying a cream prepared without applying high pressure. Via a microfluidization process that results in the simultaneous mixing of the water and oil phases of such creams or lotions using a high pressure homogenizer that can be extremely small, about 400 times smaller than the size in the lotion. It is possible to produce such lotions and creams. Microfluidization allows the preparation of elegant, stable creams and lotions containing an effective amount of oxa diacid without the commonly used surfactants and emulsifiers.

Oxa diacids can also be formed in the form of a fine emulsion. Microemulsion systems generally comprise an effective amount of oxadiacid, up to 18% hydrocarbon, up to 40% oil; 2
Contains up to 5% fatty alcohol, up to 30% nonionic surfactant, up to 30% water.

Oxa diacid is US Patent No. 4,2
Water-oil- disclosed in US Pat.
As a water-based multi-layer emulsion composition, it is suitable and convenient for use in topical applications made in the form of oil-in-water or water-in-oil emulsions, gels, lotions, ointments, sticks, sprays, tapes, and bandages. is there. The compositions of the present invention are also disclosed in US Patent No. 4,960,764 and are also formed as triple-layer emulsions of the oil-in-water-silicone fluid type cited herein by reference.

The compositions of the present invention also include, for example, Mezei
Author, J. Pharmaceut, Pharmacol., Vol. 34, pp. 473-474 (198
2) or as a liposome type according to the method described in the revised version. In such compositions, the dispersed droplets of the oxa diacid aqueous solution are trapped inside the liposome vesicles and, ultimately, are phospholipids, but other suitable lipids (eg, skin lipids) Trapped in a liposome shell that can be replaced by a liposome. Later, this liposome was used, for example, by Mezei, Topics i, cited here for reference.
n Pharmaceutical Sciences, Breimer et al. Eds., pp. 345-
358, Elsevier Sciences Publishers BV, NewYork (1985)
A synthetic mode of epidermal liposomes as described in
Depending on the application and composition, or with Szoka et al. Pro
c. Nat.Acad.Science, vol. 75, pp. 4194-4198 (1978) and also Diploses et al., J. Soc. Cosmetic Chemists, vol. 43, p.
p. 93-100 (1992), which can be added to any of the above-described carrier systems according to the reverse-phase distillation method as described all herein incorporated by reference.

The aqueous solution of oxa diacid can also be incorporated into shelled polymeric vesicles of suitable polymeric materials such as gelatin, cross-linked gelatin, polyamides, polyacrylates and the like. Such vesicles can be incorporated into any composition according to the disclosure below.

The activity and mildness on skin of this oxa diacid in topical application compositions is pH 3.5-8.0, with one or more amphoteric and pseudo-amphoteric compounds selected from those listed below. Most preferably, it is also increased by neutralization to 3.7-5.6. The compounds they contain include, but are not limited to, glycerin, alamin, valine, serine,
Telonin, methionine, rosin, asparagine, histidine, glutamic acid, glutamine, lysine, cystine, cysteine, tritophan, serine, phenylalanine, citrulline, creatine, proline, 3- or 4-
Hydroxyproline, 5-hydroxylysine, ornithine and its derivatives, 3-aminopropionic acid and other aminocarboxylic acids, canavanine, canalin, homoargin, betaine, taurine, aminoaldonic acid and aminosugar, aminouronic acid, aminoalda Lilic acid, deacetylated hyaluronic acid, hyalurouronic acid, chondrosin, desulfated neuramin or sialic acid, thyroxine, diiodotyrosine, methionine, sulfone, glycerylglycine, deacetylated, chondroitin, DL-sphingosine, Sphingomyelin, L- (erythro) -sphingosine, ophidine, homocarnosine, aminopicolinic acid,
Phosphidyl serine, cocoam foglycine, phosphatidyl ethanolamine, cysteine sulfinic acid, glutathione, aluminum oxide, zinc oxide or other amphoteric inorganic oxides, polyamidoamine, polyamidoamine-base dendrimer, sodium Hydroxymethyl glycinate and polyethylene amine.

When the oxa diacid of the present invention is used as a composition for topical application, the excellent dominant and less irritating characteristic is from about 0.01% to about 25% by weight.
%, Preferably from about 1% to 5%, by incorporating certain chelating reagents into the composition. Suitable examples of chelating agents include zinc,
Those having a high affinity for calcium, iron and / or copper ions, for example, ethylene-diamine-tetra-acetic acid, (ethylenedioxy) -diethylene-dinitrilo-tetra-acetic acid, salicylaldoxime, quinolinol, diaminocyclohexane -Tetra-acetic acid, diethylene-triamino-penta-acetic acid, dimethylglyoxime, benzoin oxime, triethylene-tetramine, desferrioxamine or a mixture thereof.

* * * * The following examples illustrate the invention more specifically but do not limit the invention thereby.

The compositions of the implementation examples the invention is typically a lotion for Tsubonesho use,
Formed in a cream or gel.

Example 1 Preparation of Composition for Local Application of Oxa Diacid In a suitable container, water, glycerin, propylene glycol, Na ₂ EDTA (ethylenediaminetetraacetic acid)
And trioxaundecanoic acid are added and mixed simultaneously. Aqueous ammonia is added to the container as an increment to adjust the pH to the desired range. This phase, which has completed pH adjustment, is subsequently heated to 170-175 ° F. Next, to complete Phase A, hydroxyethyl
Add the cellulose with stirring until uniform.

For lotions and creams, add Phase B to a suitable second container and combine
Heat to a temperature of 70-175 ° F. Then, add Phase B to Phase A with sufficient agitation,
Bring to -175 ° F. The batch is then
Cool. Add Phase C to the batch and mix until uniform.

Phase Gel Lotion Cream (A) Water Q. SQ. SQ. S glycerin 5.00 3.00 5.00 Propylene glycol 3.00 3.00 3.00 Disodium-EDTA 0.10 0.10 0.10 3,6,9-Trioxaundecanoic acid 10.00 10. 00 10.00 Hydroxyethyl cellulose 0.50 0.30 0.50 Aqueous ammonia (30%) pH3.7-3.9 pH3.7-3.9 Until pH3.7-3.9 (B) Octyl palmitate-3.00 5.00 Myristyl myristate-3.00 5.00 Glyceryl monostearate-1.50 3.00 cetearyl alcohol &-3.00 5.00 ceteareth-20 methylparaben-0 .20 0.20 (C) Imidazolidylyl urea 0.30 0.30 0.30 ---------------------------------- ---------- range of pH and Q. S. With the exception of, all figures are expressed as a percentage of the total weight of the composition.

Those skilled in the art will readily recognize that excipients other than lotions, creams or gels can be used after understanding that the disclosure is beneficial.

* * * * Normalization visible by peeling off the stratum corneum of the tissue layer,
Alternatively, epidermal peeling action is an essential mode of action for alleviating the skin condition for which the oxa diacid compounds and compositions of the present invention are intended. The following examples illustrate, among other things, the oxa
It demonstrates the prominent tissue and stratum corneum stripping action provided by the composition of diacid.

Example 2 Peeling action bandage test to see the peeling action In general, the procedure of the peeling action bandage test was performed by
It consisted of occlusively applying a bandage for 4 hours. The determination of the skin is performed immediately after the bandage is applied and when the bandage is removed 24 hours later. This test focuses primarily on the effect of the product on the tissue and stratum corneum, mainly on the exfoliation.

Sampling of the effect of removing keratinocytes (“C
RAS ") was performed, and the judgment was made by visual observation 24 hours after the bandage was removed. The CRAS score was based on a quantitative measurement of the exfoliation of keratinocytes, and the calculation was based on the amount of keratinocytes removed by each sampling. It is performed based on.

A series of studies were carried out, the first of which was a 10% by weight of 3,6,9-
The composition of trioxaundecanoic acid pH 3.7 showed excellent exfoliating action compared to the composition of pH 3.8 containing 4% by weight of glycolic acid. In this study, 10% by weight of oxa diacid was p
The exfoliation properties of the composition with raised and lowered H and the 5% by weight oxa diacid composition at low pH were investigated.
4% by weight glycolic acid was included as a comparative example. Table 1 below provides a summary of all data along with material identification.

Table 1 pH CRAS value 5% by weight oxa diacid 3.7 2.58 10% by weight oxa diacid 3.7 2.93 10% by weight oxa diacid 5.4 2.684 4% by weight glycolic acid 3 .8 2.80 --------------------------------------------------------------------

No noticeable irritation was observed in any of the samples. In all of the various comparisons, the low pH sample at 10% by weight oxa diacid showed consistently good and differential release effects throughout.

The next study in this series showed that a composition of 10% by weight of 3,6,9-trioxaundecanoic acid had a better exfoliating action than that of a composition of 4% by weight of glycolic acid. Was reconfirmed. At the same time, the 3,6,9-trioxaundecandioic acid composition was also milder on the skin than with glycolic acid. It should be noted that, on a molar basis, the concentration of the "acid" in the 10 wt% 3,6,9-trioxaundecanoic acid composition is lower than the concentration in the formula of 4 wt% glycolic acid. . Recall from the clinical results presented here, this indicates that the intrinsic exfoliating effect of 3,6,9-trioxaundecandioic acid is less pronounced but higher than that of glycolic acid. ing.

The second study confirmed the results previously observed with a 10% oxa diacid, pH 3.7 composition. Table 2 below gives a summary of the data and the fact that the substances are the same for this second study.

Table 2 Previous pH PII CRAS CRAS 10% by weight oxa diacid 3.7 0.13 3.23 2.93 10% by weight oxa diacid 3.74 0.18 3.33 -4 weight % Glycolic acid 3.7 0.23 3.05 2.80 --------------------------------------------------------------------------- −

None of the extracted participants complained of significant irritation, but when oxa diacid was used, the irritation was displayed as compared to both glycolic acid and excipient alone (PII). The score showed a low value. This result confirms what was observed in the previous analysis of the stripping action.

******* Example 3 Cream for Abnormal Pigment Spots This example illustrates a cream that can be prepared and used to reduce the appearance of abnormal pigment spots on the skin of hands. It is a thing. W / W% Isopropyl myristate 3.0 Polyethylene glycol (1000) monostearate 5.0 Palmitic acid 10.0 3,6,9,12-Tetraoxatetradecandioic acid 10.0 Glycerin 3.0 Polyethylene -Glycol (300) monostearate 5.0 Methyl paraben 0.2 Magnesium ascorbyl phosphate 2.0 Water 60.0 Flavors and colorants Triethanolamine Until the pH reaches 100 Triethanolamine pH 4.0-- All figures, except those relating to pH, refer to the total weight of the composition. Expressed as a percentage of

Example 4 Cream for Dry Skin, Ichthyosis and Abnormal Keratinous Fibers In this example, a silicone formulation that can be prepared and used to cure dry skin, ichthyosis and abnormal keratinous fibers
The cream will be described according to the present invention. w / w% Phase A 2.0 Lauryl methicone copolyol 2.0 Mineral oil 1.0 Lanolin 1.5 Sunflower oil or soybean oil 10.0 Cyclomethicone 6.0 Rosemary extract soluble in oil 2.0 Phase B Sodium iodide 2.0 3,6,9-Trioxaundecandioic acid 9.0 3,6,9,12,15-Pentaoxaheptadecandioic acid 1.0 Sodium hydroxymethyl・ Glycinate 0.5 Demineralized water Until it becomes 100 Sodium biphosphite Until the pH becomes 3.8 −−−−−−−−−−−−−−−−−−−−−−−−−−− All figures, except those relating to pH, are expressed as a percentage of the total weight of the composition.

Example 5 Silicon Gel This example describes a water-in-silicon gel composition. w / w% Phase A Dimethiconol 10.0 Dimethicone copolyol 10.0 Cyclomethicone 5.0 Phase B 3,6,9-Trioxaundecandioic acid 8.0 Glycerin 20.0 Demineralized water 100 Until the pH of triethanol reaches 4.0, a section related to pH is given. With the exception of all figures, all figures are expressed as a percentage of the total weight of the composition.

Example 6 Cream for Acne, Skin Wounds and Senile Purpura This example describes a facial cream that can be used to treat acne, skin scars and senile purpura. w / w% Phase A Oleic acid 1.0 Stearic acid 17.0 Polyoxyethylene (20 propylene glycol monostearate) 10.0 Retinol 0.1 Phase B Glycerin 5.0 2-Pyrrolidone-5-carboxylic acid 5.0 3,6,9-Trioxaundecandioic acid 7.5 3,6,9,12-Tetraoxatetradecandioic acid 2.5 Lactic acid 3.0 Demineralized water Up to 100 Ammonia water Up to pH 4.2 Except for those relating to pH, all figures are of the composition. Expressed as a percentage of total weight.

* * * * Reading this disclosure may be beneficial to improvements and modifications to the present invention. These modifications and additions are intended to be within the scope and spirit of the invention as defined in the following claims.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI A61K 7/48 A61K 7/48 31/165 31/165 31/20 31/20 31/23 31/23 (72) Inventor Nail Scancarrera, United States 07481, New Jersey, High View Drive 781, Wykov, inventor Robert Karafsky, United States 07439, New Jersey, United States Owensberg, Willow Glove Court 24

Claims (33)

[Claims] A suitable topical excipient and a compound of formula (I) Wherein R ₄ is (CR ₅ R ₆ -CR ₇ R ₈ X ₁ ) _n -C
R ₉ R ₁₀ —C (＝ X ₂ ) X ₃ R ₁₁ , where n is an integer from 1 to 18, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R
₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are independently
A substituent of a hydrogen atom or a non-hydrogen atom; X, X ₁ ,
X ₂ , X ₃ , Y and Z are each independently O, NH or S. A topical coating composition comprising the compound of (1). 2. The composition of claim 1 wherein said compound of structural formula (I) comprises from about 0.1 to about 95% by weight of said composition, and said composition comprises A composition wherein n is an integer from 2 to 12. 3. The composition according to claim 1, further comprising:
A composition comprising a mixture of two or more different such compounds of structural formula (I). 4. The composition according to claim 2, wherein said composition is mild and non-irritating. 5. The composition according to claim 1, wherein the non-hydrogen atom substituent of the compound is selected from the group consisting of alkyl, alkenyl, oxa-alkyl, aralkyl and allyl. 6. The composition according to claim 5, wherein said non-hydrogen atom substituent is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, hexyl, heptyl, octyl, nonyl, dodecanyl, methoxy, A composition selected from the group consisting of ethoxy, propoxy, butoxy, cyclohexenyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclobutyl and cyclohexanyl groups. 7. The composition according to claim 1, wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R
_8. A composition characterized in that each of R ₉ , R ₁₀ and R ₁₁ is a hydrogen atom. 8. The composition according to claim 1, wherein each of X, X ₁ , X ₂ , X ₃ , Y and Z of the compound is an oxygen atom. 9. The composition according to claim 1, wherein X, X ₁ , X ₂ , X ₃ , Y and Z of the compound are each an amino group. 10. The composition according to claim 1, wherein each of X, X ₁ , X ₂ , X ₃ , Y and Z of the compound is a sulfur atom. 11. The composition according to claim 1, wherein said compound is 3,6-dioxaoctadioic acid;
9-trioxaundecandioic acid; 3,6,9,12-tetraoxatetradecandioic acid; 3,6,9,12,15-pentaoxaheptadecandioic acid; 2-methyl-3,6,
9-trioxaundecandioic acid; 2-ethyl-3,3
6,9-12-tetraoxatetradecandioic acid; 2-phenyl-3,6,9-trioxaundecandioic acid;
6,9-trioxaundecandioic acid diethyl ester; 3,6,9-triaminoundecandioic acid; 3,
6,9,12-tetraaminotetradecandioic acid; 3-amino-6,9-dioxaundecandioic acid; 3,6-diamino 9-oxaoundecanedioic acid; 3,6,9-trithioundecane 3,6-dithio-9,12-dioxatetradecandioic acid; 3-amino 6,9-dioxaundecandioic acid monoamide; 3-amino
6,9-dioxaundecandioic acid diamide; 3,
6,9-trioxaundecandioic acid monoamide;
3,6,9-trioxaundecandioic acid diamide;
2,10-dimethyl-3,6,9-trioxaundecandioic acid; 2,10-dimethyl-3,9-dithio-6-oxaundecandioic acid; and a mixture thereof. A composition comprising: 12. The composition according to claim 1, further comprising an antibacterial agent, a vitamin agent, a sunscreen agent, a retinoid,
Antiallergic agent, depigmenting agent, anti-inflammatory agent, anesthetic, emulsifier, wetting agent, release agent, surfactant, stabilizer, preservative,
A composition in combination with at least one active ingredient selected from the group consisting of an antiseptic, an emollient, a thickener, a lubricant, a wetting agent, a chelating agent, a fragrance, a coloring agent, and a skin penetration enhancer. 13. The composition according to claim 2, wherein said compound of formula (I) comprises up to about 60% by weight and has a pH of less than 7.0. 14. The composition of claim 13, wherein said topical excipient comprises up to about 90% by weight of water; up to about 30% by weight of an emollient; and 20% by weight. Compositions comprising up to a surfactant. 15. The composition according to claim 14, wherein said compound is 3,6-dioxaoctadioic acid;
6,9-trioxaundecandioic acid; 3,6,9,12-tetraoxatetradecandioic acid and 3,6,9,12,1
Selected from the group consisting of 5-pentaoxaheptadecandioic acid; wherein the emollient is mineral oil, petroleum wax, paraffin, ceresin, ozokerite, microcrystalline wax, perhydrosqualene, dimethyl polysiloxane, methyl Phenyl polysiloxane,
Silicon-glycol copolymer, triglyceride
Esters, acetylate monoglycerides, ethoxylate glycerides, alkyl fatty acid esters, fatty acids and alcohols, lanolin and lanolin derivatives, polyhydric alcohol esters, sterols, beeswax derivatives, polyhydric alcohol and polyesters And surfactants selected from the group consisting of sorbitans, alkoxylate / aliphatic alcohols, alkyl / polyglycosides, soaps, alkyl sulfates, monoalkyl and dialkyl phosphates, alkyl sulfones. And acyl
A composition selected from the group consisting of isothionates. 16. The composition according to claim 2, wherein said topically applied excipient is selected from the group consisting of gels, lotions and creams. 17. The composition according to claim 16, wherein said topically applied excipient comprises aqueous ammonia, cetearyl alcohol / ceteareth-20, EDTA, glycerin, glyceryl monostearate, hydroxy A composition selected from the group consisting of ethyl cellulose, imidazolidyl urea, methyl paraben, myristyl myristate, octyl palmitate, and propylene glycol. 18. The composition according to claim 16, wherein said composition comprises from about 0.1% to about 20% by weight of 3,3%.
Consisting of 6,9-trioxaundecandioic acid and the excipient, the composition comprising: (a) glycerin from about 2% to about 10% by weight; (b) about 1% to about 10% by weight. Propylene up to
Glycol (c) from about 0.1% to about 2% by weight of hydroxyethyl cellulose; (d) from about 0.1% to about 1% by weight of imidazolidyl urea; (e) about 0.01% by weight % To about 2% by weight Na ₂ E
DTA; and having a pH of about 7.0 or less. 19. The composition according to claim 16, wherein said composition comprises from about 0.1% to about 20% by weight of 3,3%.
Consisting of 6,9-trioxaundecandioic acid and the excipient, the composition comprising: (a) about 1% to about 10% by weight glycerin; (b) about 1% to about 10% by weight. Propylene up to
Glycol; (c) from about 1% to about 10% by weight of octyl palmitate; (d) from about 1% to about 10% by weight of myristyl.
(E) about 1% to about 6% by weight cetearyl alcohol / ceteareth-20; (f) about 0.5% to about 6% by weight glyceryl monostearate; From about 0.1% to about 2% by weight of hydroxyethyl cellulose; (h) from about 0.1% to about 1% by weight of imidazolidylyl urea; (i) from about 0.05% to about 0% by weight. Up to about 0.5% by weight methyl paraben; (j) from about 0.01% to about 2% by weight of Na ₂ E;
DTA; and having a pH of about 7.0 or less. 20. The composition of claim 16, wherein the composition comprises from about 0.1% to about 20% by weight of 3,3%.
Consisting of 6,9-trioxaundecandioic acid and the excipient, the composition comprising: (a) glycerin from about 2% to about 10% by weight; (b) about 1% to about 10% by weight. (C) from about 1% to about 10% by weight of myristyl palmitate;
(D) about 1% to about 7% by weight of cetearyl alcohol / ceteareth-20; (e) about 1% to about 10% by weight of propylene.
Glycol; (f) from about 1% to about 6% by weight of glyceryl monostearate; (g) from about 0.1% to about 2% by weight of hydroxyethyl cellulose; From about 0.05% to about 1% by weight imidazolidylyl urea; (i) from about 0.05% to about 0.5% by weight methyl paraben; (j) from about 0.01% to about 2% by weight; Na ₂ E
DTA; and having a pH of about 7.0 or less. 21. caused by Uroko剥means not normal, there is provided a method of cure state of progress, or worse skin following chemical formula in its said skin (I) ## STR1 ## (wherein, R ₄ is _{(CR 5 R 6 -CR 7 R} 8 X
_{1) n -CR 9 R 10 -C} (= X 2) represented by X ₃ R _11,
n is an integer from 1 to 18, and R ₁ , R ₂ , R ₃ ,
R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁
Is independently a substituent of a hydrogen atom or a non-hydrogen atom; X, X ₁ , X ₂ , X ₃ , Y and Z are each independently O, NH or S. A method for incorporating and applying an effective amount of a compound with 22. The method of claim 21, wherein said compound is in combination with a suitable topical excipient in a topical composition. 23. The method according to claim 21, further comprising an effective amount of a mixture of two or more different compounds of formula (I) and applying to the skin. 24. The method of claim 22, wherein said compound of formula (I) comprises from about 0.1 to about 95% by weight of said composition, wherein n of said compound is A method that is an integer from 2 to 12. 25. The method according to claim 21, wherein the non-hydrogen atom substituent of the compound is an alkyl, alkenyl, oxa-alkyl, aralkyl and allyl group. 26. The method according to claim 25, wherein the non-hydrogen atom substituent of the compound is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, hexyl, heptyl, octyl, nonyl, dodecanyl, methoxy. , Ethoxy, propoxy, butoxy, cyclohexenyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclobutyl and cyclohexanyl groups. 27. The method according to claim 21, wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ ,
The method wherein each of R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ is a hydrogen atom. 28. The method according to claim 21, wherein each of X, X ₁ , X ₂ , X ₃ , Y and Z of the compound is an oxygen atom. 29. The method according to claim 21, wherein each of X, X ₁ , X ₂ , X ₃ , Y and Z of said compound is an amino group. 30. The method according to claim 21, wherein each of X, X ₁ , X ₂ , X ₃ , Y and Z of the compound is a sulfur atom. 31. The method according to claim 21, wherein the compound is 3,6-dioxaoctadioic acid;
9-trioxaundecandioic acid; 3,6,9,12-tetraoxatetradecandioic acid; 3,6,9,12,15-pentaoxaheptadecandioic acid; 2-methyl-3,6,
9-trioxaundecandioic acid; 2-ethyl-3,3
6,9-12-tetraoxatetradecandioic acid; 2-phenyl-3,6,9-trioxaundecandioic acid;
6,9-trioxaundecandioic acid diethyl ester; 3,6,9-triaminoundecandioic acid; 3,
6,9,12-tetraaminotetradecandioic acid; 3-amino-6,9-dioxaundecandioic acid; 3,6-diamino9-oxaoundecanedioic acid; 3,6,9-trithioundecane 3,6-dithio-9,12-dioxatetradecandioic acid; 3-amino 6,9-dioxaundecandioic acid monoamide; 3-amino 6,9-
Dioxaundecandioic acid / diamide; 3,6,9-trioxaundecandioic acid / monoamide; 3,6,9-
Trioxaundecandioic acid diamide; 2,10-
Dimethyl-3,6,9-trioxaundecandioic acid;
A method selected from the group consisting of 2,10-dimethyl-3,9-dithio-6-oxaundecandioic acid; and mixtures thereof. 32. The method according to claim 21, further comprising an antibacterial agent, a vitamin agent, a sunscreen agent, a retinoid, an allergy inhibitor, a depigmenting agent, an inflammation inhibitor, an anesthetic, an emulsifier, a wetting agent, and a peeling agent. Agents, surfactants, stabilizers, preservatives, antiseptic agents, emollients, thickeners, lubricants, wetting agents, chelating agents, fragrances, coloring agents, and at least one selected from the group consisting of skin penetration enhancers. A method that encompasses one active thing. 33. The method according to claim 21, wherein the skin condition to be treated is dry skin, ichthyosis, palm, abnormal stratum corneum of farmers, dandruff, simple chronic disease of lichen, Dariel's disease, keratinous fiber, mole, senile purpura, melasmas, wounded skin, acne, psoriasis, eczema,
Pruritus, inflammatory dermatosis, bulging streaks, warts, induration of skin,
Signs of dermatological growth, wrinkles of the skin, fine wrinkles around the mouth, abnormal pigmentation, ruddy skin, loss of skin resilience and elasticity, gathering on nails, pericarp and ingrown hair A method selected from the group consisting of irregular, follicular and follicular whiskers.