JPH04500824A - Skin treatment methods to reverse the effects of photoaging - Google Patents

Abstract

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

Description

[Detailed description of the invention] Cross-reliance on applications related to skin treatment methods to reverse the effects of photoaging REFERENCE This application is filed under co-pending U.S. Patent No. 7,825/1989. This is a continuation-in-part of Application No. 384.949.

field of invention The present invention provides a method for treating skin, especially human facial skin, by topical application of a special polyene composition. This invention relates to a method for restoring the effects of aging.

Background of the invention Excessive exposure of human skin to direct sunlight causes damage and many severe skin changes. cause. These changes include wrinkle formation, leathery hardening, yellowing, sagging, These include dryness, mottling (pigmented spots), and benign and malignant skin tumors. Ru. People who exhibit these signs appear to age quickly.

Photoaging affects people with pale skin who tan easily and do not darken very much. This is the most obvious. The effects of direct sunlight are cumulative. As a result, this direct sunlight induces skin Skin damage has been referred to as photoaging.

Most signs of photoaging can be prevented by the careful use of topically applied sunscreens. Can be stopped. Sunscreens should be used at a young age, such as when children spend a considerable amount of time outdoors. It is important to use it as soon as you start spending time with it.

Many people will forget to use sunscreen, or worse, Use natural or artificial sunlight to benefit from the cosmetic properties of tanned skin Some people may deliberately expose themselves too much to the line. In later life, people often For example, some people seek medical care in the hope that cosmetic surgery will reduce skin damage. It will be.

Pharmaceutical compositions that can promote the recovery of photoaged skin can help prevent forgetting to use sunscreen. This is an alternative treatment for patients who do not prefer cosmetic surgery. Open test and Topically applied all-trans retinoic acid inhibited photoaging in both It has been reported to improve the appearance of the skin. The beneficial changes are important for both researchers and patients. clinically significant for patients. These are the elimination of fine wrinkles and the reduction of rough skin. , skin pink increase and pigmentation session (black and white) Including lightening of sun-induced freckles).

In a double-blind study, 92% of patients had mottled erythema, focal swelling, xeroderma and It was reported that the patient was experiencing dermatitis characterized by mild desquamation. 1 of the patients One required strong topical steroids for relief of dermatitis. Three patients The study was discontinued due to severe retinoid-induced dermatitis.

It is not accompanied by the adverse effects of dermatitis that are noted in the case of all-trans retinoic acid treatment. There has been a desire to provide a method of treating photoaged skin.

The use of 13-cis-retinoic acid as a treatment for the adverse effects of elastosis was reported by Hoffman Australian Patent AU-A-8302718 by Ann-La Roche 7 and European'Patent Application Public It is described in cation0253393.

In U.S. Pat. No. 4,595,696, certain polyenes are It has been described as useful in treating allergic conditions. Of course these conditions Well, far beyond photoaging, there are substances useful in treating inflammatory conditions that can treat photoaging. It is not expected that it will be useful in this case, and vice versa.

In U.S. Pat. No. 4,603,146, all-trans retinoic acid (retin A) have been disclosed to be useful in the treatment of photoaging. However, this treatment It also causes severe irritation to the skin, which severely limits its effectiveness. Ru.

Summary of the invention The present invention describes the use of special polyenes in the restoration of aging changes in the skin, especially on exposed areas of the face. Concerning business. These polyenes can be used without materially adverse effects on patients. Slows and reverses the loss of largen fibers and deterioration of small blood vessels.

The method of the present invention has a structure: R,, R,, R,, R4 and R5 are HSCl, OR@, carbon number! -10 Straight chain or branched chain alkyl, No, , C0OR@, CN, OR,, NR'@ R7,NRgC(=S)NR,R,,NR,COR,,SO□NR-Rt,C H(CH,)COOH1CONR@R? ,C0R5,0CONR@R,,NR 5C0NRJa, R-ORs, NR, SO, Rt, 5i(CHs)s and NR5 independently selected from the group consisting of C0NRJa, R2 together with R4 forming a ring or together with R1 benzo or tetrahydrobenzo form a ring, or together with R2 and R1 form a moiety, or together with R2. together form a moiety, or R2 together with R1 forms a benzo ring. or R2 together with R8 forms a part, or R2 is independently selected from a group of parts, R-1R? and R8 is a straight chain or branched alkyl having 1 to 10 carbon atoms, and R8 is a straight chain or branched alkyl having 1 to 10 carbon atoms; independently selected from the group consisting of 10 aryls and hydrogen, and R8 is alkylene having 1 to 6 carbon atoms] and its iron carbonyl The complex is applied topically to an area of the skin in an amount sufficient to repair the effects of skin elastosis. the skin damaged by direct sunlight.

The polyene may be supplemented with any non-toxic, dermatologically acceptable excipient, preferably non-toxic. Can be applied to the skin at various concentrations in volatile emollients or anti-friction vehicles; This will be explained in more detail below.

Detailed description of preferred embodiments Skin treatment with the polyene of the present invention alleviates aging changes in the dermis and epidermis of the skin. delay and delay. As we age and exposure to direct sunlight increases, skin cells split at a slower rate. The thickness of the epidermis decreases and the stratum corneum protects it from loss of moisture The cells form large groups and become desquamated, resulting in rough texture and dry cells that become smaller with age. and, along with this, the number of collagen fibers decreases. Degradation of these fibers leads to wrinkle formation and cause a decrease in elasticity.

Polyene compounds useful in the present invention have the structure: R+, R2, Rs, R4 and R6 are , H, C1, OR3, straight-chain or branched alkyl having 1 to 10 carbon atoms (examples are below) ), NO2, C0OR,, CN, OR,, NR, R7, NR, c (=S) NRJ,,NR-CORt,5O2NR@R1,CH(CHs)COOH5CO NRJt　,CORg,0CONRsRi,NR,C00NR7,R,OR,, From the group consisting of NR, SO□R7,5i(CHs)s and NR, C0NR7Rm independently selected, R2 together with R4 forms a benzo ring, or together with R2 forms a benzo ring. form a hydrobenzo or tetrahydrobenzo ring, or together with R2 and R1 together with R2 to form a part, or R7 to form a part to R1 together with R2 to form a benzo ring, or R2 together with R2 'C part form or independently selected from a group of parts, R*, R7 and R8 are straight or branched alkyl having 1 to IQ carbon atoms (examples are shown below) ), as well as aryls having 6 to 10 carbon atoms and hydrogen (examples are shown below). independently selected from the group, and R1 is alkylene having 1 to 6 carbon atoms, such as methylene, propylene, butylene , trimethylene] and The structure of its iron carbonyl complex is as follows.

For the purposes of the invention, examples of alkyl having 1 to 10 carbon atoms are methyl, butyl, pentyl. , octyl, ethyl, tert-butyl, benzyl, isopropyl, chloroethyl, Lolopropyl, 1-nitroxypropyl, carboxyethyl, carboxymethyl, phenyl, cyanoethyl and 2-ethylhexyl; Examples of reels are phenyl and naphthyl.

Methods for making these polyenes are known and generally described in U.S. Patent No. 4.595.69. No. 6 (incorporated herein by reference) ing. Generally, these compounds include polyenoic acids and acetic anhydride, boron trifluoride, and Salkylene chloride, formed by reaction with phosphorus trichloride or thionyl chloride, It is then further treated with a phenolic compound.

Useful polyenes within the scope of this invention include those having the following structures: : Engineering.

Engineering I engineering.

Engineering V.

Veeeeee.

Engineering X.

x Eh.

X Engineering II.

XVeeeeee.

XXIeeee.

xx Engineering

XXXV.

XL engineering.

XLeeeeee.

XLVeeee.

The therapeutic agents of the present invention can be administered alone or in combination with a pharmaceutically acceptable carrier. The proportion of carrier will depend on the solubility and chemical properties of the compound, the chosen route of administration. as determined by standard pharmaceutical practice. For example, these are starch, tablets or capsules containing excipients such as milk, sugar, certain clays, etc. It can be administered orally. These are liquid formulations that may contain colorants or flavoring agents. It can be administered orally. Sprinkle when applied topically for the treatment of ex-aging aqueous compositions, including agents, aerosol sprays, ointments, solutions and suspensions; It can be provided in the form of a lotion, etc. In this regard, as is known, the product Any conventional filler can be used depending on the nature of the filler.

The most appropriate dose of this treatment is for your doctor to decide; This will vary depending on the form and compound selected, and will also depend on the patient being treated. It also changes depending on the person. Physicians generally use substantially less than adequate doses of compounds. Start treatment with a small dose of One may wish to increase the dosage.

Polyenes incorporated into moisturizing bases such as creams or ointments are usually , provided in low concentrations. For example, Compound I is about 0.001 weight of base. It can be used in concentrations of 0% by weight, preferably from about 0.01% to 5% by weight.

Polyene or other non-toxic, dermatologically acceptable excipients stable therein. or carriers will be apparent to those skilled in the art. Generally an oily substance that helps hydrate the skin Emollients or anti-friction excipients such as are preferred. Terms used herein "Emollient J" refers to the non-irritating properties of the composition as a whole. Please understand that it refers to. That is, the nature of the excipients in the composition and the The amount should be selected to provide a sub-irritating dose for topical application. leather Volatile excipients that dry or irritate the skin, such as alcohol and acetic acid tons should be avoided.

Ointment bases (without water) are preferred in winter and in patients with very dry skin. Delicious. Examples of suitable ointment bases are petrolatum, petrolatum + volatile silicone, and lano. Phosphorous and water-in-oil emulsions, such as Eucerin (Beiersdorf) It is.

Oil-in-water emulsions (cream paints) are used in warmer climates and often in relatively young people. m) base is preferred. An example of a suitable cream base is N1vea Cream ( Beiersdarf), cold cream (USP), Purpos e Cream (Johnson & Johnson), hydrophilic ointment (U SP) and Lubriderm (Warner-1ambert).

The duration of human skin treatment can vary. Usually by young adulthood, or more typically in middle age, when the effects of aging begin to appear, the treatment of the present invention It is almost pointless to start. The specific program of maintenance therapy according to the invention It will vary depending on the person being treated and the conditions. Generally, the age at the start of treatment and Reduce and control the effects of aging that have already occurred, depending on the skin condition To do this, it is necessary to apply polyene once a day for a period of less than 2 months. It turned out that it would be. Once stabilized skin control is achieved, The number of applications of polyene may be, for example, 2-3 times per week, and in some cases continuously thereafter. This can be reduced to only once a week until death. i.e. the aging process Once the disease is under control, twice a week is necessary to maintain it. A maintenance dose similar to the application of is generally sufficient.

The topical compositions of the present invention may desirably include a suitable sun protection agent. . In the formulation of polyene formulations that can be used in accordance with the present invention, any conventional tanning is Inhibitors can be used.

These topical compositions may contain any of the usual excipients commonly used in the manufacture of topical compositions. It may contain excipients and additives.

Commonly used additives or excipients that can be used in the manufacture of these cosmetic compositions include preservatives. , thickeners, fragrances, etc. In addition, commonly used antioxidants such as butylated hydrogen Droxyanisole (BHA), ascorbyl palmitate, propylate gallate , citric acid, butylated hydroxytoluene (BIT), ethoxyquin, etc. It can be mixed into these compositions. These topical compositions Includes conventional carriers commonly used in compositions and acceptable for topical application. I can do it. These compositions contain commonly used thickeners, humectants, Emulsifiers and viscosity stabilizers may be included. Additionally, these compositions are suitable for cosmetic compositions. Flavoring agents, colorants and perfumes which are common in the manufacture of compositions may be included.

The invention is further illustrated by the following examples, which are merely illustrative. .

Compound ■ was tested for its effect on epidermal and dermal differentiation in hairless mice. A direct comparison was made with trans-retinoic acid.

In the first test used, vitamin A containing all-trans retinoic acid Polyene compounds form horn-like structures in the skin of hairless rhino mice. is extremely effective in reducing the size of chambers filled with Interlocular epidermal cell layer The number of cells increases as the size of the chamber decreases. The increase in the number of epidermal cell layers also increases the overall It is also significant in pre-aged human skin treated with trans-retinoic acid.

Temple Llniversity 5kin and Cancer H Hairless rhino mice (hr') from o5pital were continuously fed for 4 weeks. Compound ■, all-trans retinol was administered once daily to the dorsal skin for 5 days. 0.05 ml of phosphoric acid or ethanol:acetone (1:1) vehicle.

Three days after the last treatment, mice were killed with CO□. 7/8” skin biopsy specimen Removed and divided into thirds.

One side of the trisected material was separated so that a horizontal sheet of epidermis could be removed from each biopsy specimen. was placed in 0.5% acetic acid overnight at 4°C. The next day, peel it off using a metal spatula. The epidermal sheet was removed from the dermis by this. These sheets are placed in formalin. Fixed, dehydrated with ethanol, and stored in xylene. The other half of the biopsy material is 1 Placed in 0% buffered formalin and treated with hematoxylin and eosin (H&E ) Stained vertical section specimens.

To assess the diameter of the cell, place each epidermal sheet on a glass slide with a few drops of xylene. I put it inside. The diameters of the 40 chambers were measured using an image analyzer. ). The epidermal thickness of H&E-stained section specimens was measured by an image analyzer for each section. Measurements were taken on 15 interlocular areas of the specimen.

Table 1 Dose-related activity of compound ■ and all-trans retinoic acid on rhino mouse skin lobe diameter % concentration, average diameter % reduction Processing W/vIM:! :S, D, *vS, excipient excipient 138±160 Compound II 0.5 58±958 0, 1 62±l055 0.01 73±1047 0.001 74±1446 0.0001 110±1820 All-trans retinoic acid 0.1 54± 8 610.01 62± 9 55 0.001 70±10 49 0.0001 95±16 31 1 Group of 5 mice.

As can be seen from Table 1, compound ■, like all-trans retinoic acid, has a wide concentration range. It has remarkable activity across the spectrum.

The results of interventricular epidermal thickness are shown in Table 2 (from the same rhino mouse with data in Table 1). (for skin samples from et al.).

Table 2 Dose-related activity of compound ■ and all-trans retinoic acid on rhinomouse skin epidermal thickness Sex % concentration, epidermal thickness % control Compound ■0.5 55.4±8.9 2360, l 55.0±8.4 23 4 0.01 48.2±3.3 205 0.001 43.7±6.4 1860, 0001 35.7±2.5 15 2 All-trans retinoic acid 0,1 62.2±7.0 2650.0+, 47. 7±1.3 2030.001 37.6±7.7 1600.0001 37 ．． 6±6.2 1609 5 mice per group.

Compound ■ was as effective as all-trans retinoic acid in increasing interlocular epidermal thickness in rhino mice. It was very effective. This increase in epidermal thickness is due to an increase in the number of epidermal cell layers. It was.

Additionally, epidermal differentiation when applied to the wrinkle-free line of hairless mice (hrhr) Evaluate polyene compounds for their effect on These mice are Reno Mouse There are fewer chambers filled with horn-like structures in the skin compared to the skin. Various polyene compounds The substance causes an increase in the number of epidermal cell layers when applied once to the dorsal skin.

The dorsal skin of hairless mice obtained from Jackson Labs was measured on days 0 and 1. Twice a day, compound ■, all-trans retinoic acid or ethanol vehicle 0.05 treated with m1. Mice were killed by CO□ at the peak of acanthosis on day 4. A 7/8” needle biopsy was then removed from the treated skin and placed in 1096 buffered forma. I put it in Rin. Prepare H&E-stained vertical sections and measure the epidermal thickness in the follicular opening area. Measured by image analyzer.

The results are shown in Table 3.

Table 3 Surface in hairless mouse skin induced by compound ■ and all-trans retinoic acid Skin thickening 96 concentration, epidermal thickness % control Processing w/v -±S, D, "Vs, excipient excipient 22.2±3.4 1 00 Compound II 0.1 56.9±2.6 2550.01 53.4±3.02 39 0゜001 37.6±6.1 169 All-trans retinoic acid 0.1 49.3 ±4.2 2210.01 38.9±3.8 174 0.001　33.3±5゜3　149゜Group of 5 mice.

At all three concentrations, compound ■ has three equivalents of all-trans retinoic acid. It caused acanthosis similar to the concentration.

All-trans-retinoic acid affects cell differentiation in the dermis of hairless mouse skin It is most effective in the skin of mice that has been damaged by UV rays. It is known that Topical treatment with all-trans retinoic acid reduces aging The formation of new bands of connective tissue is promoted in the skin of hairless mice. this is This is due to an increase in the number of fibroblasts and their metabolic activity. the result , new collagen bundles and elastic fibers are formed, which connect the newly created dermal matrix. resulting in compression of old abnormal elastic fibers.

Temple [Juniversity 5kin and Cancer H 6-8 week old female hairless mice (Skh-HRI) obtained from o5pital. The dorsal skin was placed on 8 Westinghous placed 16 cm above the mouse's back. se every Monday, Wednesday and week for 10 weeks using a bank of FS-40 UV lamps. Ultraviolet B (UVB) was irradiated on Friday. During the first three weeks, the line per day The dose was increased progressively from 1 up to 5 microerythema doses (MED) up to 4 MED. Then, During the last 7 weeks, the 4 MED doses per day were continued 1'j.

At the end of the 10th week, irradiation was stopped, and starting from the 11th week, 5 consecutive doses were given for 10 weeks. Ethanol vehicle, all-trans retinoic acid or compound on the dorsal skin once daily for days. II　O,05ml treatment was performed.

At the end of treatment, mice were killed by cervical dislocation, the dorsal skin was removed, and 10% Placed in buffered formalin. Paraffin-embedded section 10I! Cut into m thickness, Lu Stained for elastic fibers with na-aldehyde fuchsin. Reveal skin repair zone The upper part of the elastotic material compressed from the epidermis-dermis interface was measured microscopically. It is defined as the area of .

The results in Table 4 show that compound It shows that it is valid as well.

Table 4 induced in previously aged hairless mouse skin caused by the following representative compounds: Depth of skin repair zone Dermal repair % control Untreated 48.1±6.9 109 Excipient 44.0±21.4 100 Compound I1.0.19 stones 98.4±14.4 224 all-trans retinoic acid, 0 ．． 05% 110.6±21.8 251-277" 12 mice per group.

Part ■ Compound XIII, 0.1% 101.3 291 Compound IX, 0.1% 98 ．． 4 282 compound ■, 0°1% 90.72 260 all-trans retinoic acid, 0 ．． 01% 96.44 277 Excipients 34.79 Part■ Compound X, 0.1% 82.33 223 Compound XI [,0,1% 77,74 210 Compound XV, 0.1% 84.68 229 All-trans retinoic acid, 0 ．． 1% 97.50 264 Excipients 36.88 Bart■ Compound XXI [93,71414 All-trans retinoic acid, 0.1% 96.16 425 Excipients, 0.1% 22 ．． 6 B.Toxicity test Using a rabbit model of skin irritation, treatment with compound ■ and all-trans retinoic acid Therefore, the resulting dermatitis was evaluated. Rabbits may be exposed to locally applied substances It is commonly used as a skin irritation model to predict local irritation.

New Ze from Beckens Farm, 5anborn, N.Y. aland At four places on the white rabbit's back, make a square part of 4 am x 4 an. I carefully trimmed the hair with an electric shearer so that it would maintain its proper shape. Each rabbit has a Compound (1) and 0.2 ml of all-trans retinoic acid were given once daily for 14 days. Day The degree of erythema, desquamation, and edema for each eye was evaluated using the Draize O to 4 grade segment. Visually evaluated. Cumulative scores were taken for each parameter over 14 days and Results were evaluated as the average daily aize score obtained by dividing by 14. .

Table 5 shows three doses of compound ■ (0,1 , 0,01 and 0.001%).

Table 5 Average daily aize score averaged over 14 days ±S,D,” treatment whole All-trans retinoic acid.

0.1 1.86±0.53 1.3±0.70 0.63±0.42 Compound ■.

0.1 1.21±0.54 0.8±0.57 0.21±0.340.01 0.83±0.57 0.47±0.48 0.11±0.540.001 0.52±0.33 0.17±0.19 0±01 10 domestic rabbits.

Part ■ All-trans retinoic acid.

0.1 6.6 Compound It 1.65 Compound XIX.

0, 1 2.5 Compound XX.

0, 1 4.5 Compound XXV.

0, 1 3.3 Table 5 (continued) Overall processing Compound xxvr.

0, 1 3.3 Compound XX■.

0, 1 6.6 Compound XX■.

0, 1 6.6 Compound XXXI.

0.17.3 ``10 domestic rabbits.

The degree of irritation caused by compound Even at 0x, it is significantly lower than all-trans retinoic acid in terms of erythema and desquamation.

Due to the variability associated with edema scores, compound ■ has a numerically relatively low edema score. There was no statistically significant difference between the treatments, even if they had a.

For the purposes of the present invention, global irritation (Global Irritation) score is defined.

Toxicity caused by systemically administered compounds ■ evaluated in white mice did. Vitamin VIII-related polyene compounds can cause weight loss, skin desquamation, hair loss and It produces multiple signs of toxicity called vitamin A hyperpruritus syndrome, which is characterized by bone fractures.

Charles River Laboratories, Wilmingt Compound ■ and all-trans were administered to arpino CD-ITM mice from Ma; Retinoic acid was injected intraperitoneally in peanut oil (8 m 1/kg).

While treating symptoms of vitamin A hyperemia by Bollag's method , mice were divided into equal lines each day. Weight loss, skin desquamation, hair loss and fracture grade Defined as having hypervitaminosis A if the sum of .

The results are shown in Table 6. 200■/k, which is twice the highest dose of all-trans retinoic acid Compound ■ of g did not cause hypervitaminosis A. In contrast, all-trans Retinoic acid is highly toxic at 100 μ/kg, so 10 out of 10 mice All mice showed hypervitaminosis A and mice treated with this dose were Died on day 00.

Table 6 All-trans retin against signs of hypervitaminosis A in CD-ITM mice Non-evaluation of the effects of acids and compounds (■) Average hypervitaminosis A grade ±S, D.

All-trans retinoic acid 100■/kg 5.4±1.6- 50■/kg 2.3±2.2 10■/kg O± 0 Peanut oil excipient 0±0 Untreated 0±0 Table 6 (continued) Compound■ 200■/kg 0.1±0.3 Peanut oil excipient 0±0 Untreated 0±0 There were 10 mice in the reciprocal and iodo-treated groups. Untreated and vehicle-treated groups There were probably five mice. Three mice died between days 7 and 10. Each retinoid were evaluated in separate studies.

0° Based on 7 mice. Three mice died between days 7 and 100.

In the comparative treatment with 13-cis-retinoic acid, compound Approximately twice as effective and also less likely to cause skin irritation than 13-cis-retinoic acid. It turned out to be little.

The invention will be described in detail with particular reference to preferred embodiments, and will also illustrate the spirit and spirit of the invention. It is to be understood that changes and modifications within the scope are possible.

international search report +mm11m ＾e−=j−−−＆　PCT/US　90104052 International search report

Claims (10)

[Claims] 1. structure: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R1, R2, R3, R4 and R5 are H, Cl, OR6, a straight chain having 1 to 10 carbon atoms or branched chain alkyl, NO2, COOR6, CN, OR6, NR6R7, NR 6C (=S) NR7R8, NR6COR7, SO2NR6R7, CH (CH3) COOH, CONR6R7, COR6, OCONR6R7, NR6COONR7 , R9OR6, NR6SO2R7, Si(CH3)3 and NR8CONR7R8 independently selected from the group consisting of, R3 together with R4 forms a benzo ring. or together with R2 to form a benzo or tetrahydrobenzo ring, Or together with R2 and R1, there are ▲mathematical formulas, chemical formulas, tables, etc.▼ Forms a part or together with R2 ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or R2 together with R1 forms a benzo ring, or R2 and R3 have ▲mathematical formulas, chemical formulas, tables, etc.▼or ▲mathematical formulas, There are chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Forming parts or R1 is ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ independently selected from a group of parts, R8, R7 and R8 are straight chain or branched alkyl having 1 to 10 carbon atoms, and 6 to 10 carbon atoms; independently selected from the group consisting of 10 aryls and hydrogen, and R8 is alkylene having 1 to 6 carbon atoms] and their iron carboxyl compounds. Bonyl complex to the area of skin in an amount sufficient to repair the effects of skin elastosis. Repairing human skin damaged by direct sunlight, comprising topical administration. Method. 2. R2 and R3 are independently NR6COR7, CONR6R7, SO2NR6 R7, OCONR6R7, NR6COONR7, NR6CONR7R8, NR6 Claims selected from the group consisting of SO2R7 and NR6C (=S)NR7R8 Method of Section 1. 3. Claims in which R2 is NHCOCH2 and R1, R2 and R4 are H Method of Section 1. 4. The above compound has the structure: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ A method according to claim 1, comprising: 5. The method according to claim 1, wherein said compound is selected from the group consisting of: ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ 6. 2. A method according to claim 1, wherein the skin is human facial skin. 7. According to claim 1, the compound is applied in an emollient vehicle. Method. 8. Claim 1, wherein said compound is applied together with a dermatologically acceptable carrier. 2. Methods pertaining to paragraphs. 9. The compound may represent from about 0.001 to about 10% by weight of the applied mixture. The method described in item 1 of the scope of the request. 10. Claims that said compound accounts for about 0.01 to about 5% by weight of the applied mixture. The method according to the first term of the scope.