KR100538417B1 - Assay for identification of compounds that promote melanin production and retinoid-like compounds identified by said assay - Google Patents

Abstract

Laboratory assays are provided for selecting compounds that alter the pigmentation of the skin. Also provided is a new class of pre-pigmentary compounds comprising substituted aromatic or heterocyclic carboxylic acids, or derivatives thereof, or pharmaceutically acceptable salts, which are free or protected phenols, naphthol, thio It does not contain a phenol or thionaphthol functional group. In a preferred embodiment, the compound exhibits activity against RXR. The compounds can be used in cosmetic or dermatological compositions for alteration of pigmentation of the skin and / or hair of humans and for the treatment of disorders and disease states that affect skin or hair pigmentation.

Description

ASSAY FOR IDENTIFICATION OF COMPOUNDS THAT PROMOTE MELANIN PRODUCTION AND RETINOID-LIKE COMPOUNDS IDENTIFIED BY SAID ASSAY}

Normal skin color is the result of the combined expression of a mixture of different pigments, the main component of which is the brown pigment melanin. Melanin is synthesized by melanocytes, which are specific cells found in the envelope. Melanocytes synthesize melanin in organelles called melanosomes. When the melanosomes are saturated with melanin, they are transported to the arms of the melanocyte dendrites and transferred to surrounding keratinocytes. The keratinocytes then migrate to the surface of the skin, causing brown pigmentation on the skin. The amount of melanin in keratinocytes determines the extent of pigmentation in the skin and hair.

Due to the effects of melanin on skin and hair pigmentation, studies aimed at identifying compounds that affect melanogenesis and / or transport of melanin to surrounding keratinocytes have been conducted. Such compounds have potential applicability to alter hair and skin pigmentation. For example, compounds such as melanocyte stimulating hormone (MSH), and theophylline are known to induce pigmentation. In addition, analogs of MSH are being tested for clinical efficacy to promote skin pigmentation. It has also been reported that alpha-lipoproteins can stimulate melanin production in the skin ( Jpn. Kokai Tokyo, Koho, JP 82-153348, GB 2124900, Empresa Cubana Importadora y Exportadora de Productos Medicos, Cuba). In contrast, some compounds for inhibiting pigmentation, such as for treating melanoma , such as hydroquinone (HQ), and monobenzene ethers (Pathak et al. , J. American Academy Dermotol. 15: 894-899 (1986); Smith et al., Pigment Cell Research, 1: 386-389 (1988)), and the use of arbutin, HQ's gluconate ( Proceeding Japan Soc. Invest. Dermotol. 12: 138-139 (1988)) is also known. .

It has also been reported that kojic acid and its derivatives and / or valeric acid inhibit melanin formation ( Japan Kokai Tokyo Koho, JP 03011010; Oyama, Yasuaki, Sansei Pharmaceutical Co., Ltd., Japan).

In addition, propionic acid, butyric acid and valeric acid and their salts, combined with or without unsaturated fatty acids, inhibit the formation of tyrosinase, which promotes the production of melanin (Mishima et al., EPA 345081, Hayashibara Biochemical Laboratories, Inc.). ., Japan).

EP 0 509 241 and WO 93/19729 disclose that hyperpigmentation or tanning the skin can be carried out by topically applying an effective amount of trans-retinic acid there for a sufficient time. Nevertheless, the compounds used in this method induce stimulation.

Suitable laboratory methods according to the report for identifying compounds that inhibit novel melanin synthesis and potential anti-melanosomes, cytotoxic compounds are reported in Dooley et al., Pharmcol., 7: 188-200 (1994). . This method utilizes cell lines from two immortalized mice of melanin cell origin, Mel-Ab (Dooley et al., Oncogene, 3: 531-535 (1988)), and other fibroblast origin. Mel-Ab cells are derived from naturally immortalized rat C57BL＼6 melanin cell lines that grow rapidly in culture and produce large amounts of melanin. Reportedly, this assay was used to select compounds with pathways similar to intermediates in melanin biosynthetic pathways unique to melanocytes. In particular, it relates to 1,3-dihydroxybenzene, 1,4-dihydroxybenzene, 1,4-dimethoxybenzene, and 1,4-benzoquinone, as well as para-substituted phenols related to tyrosine and DOPA 1,2-dihydroxybenzene was selected. Various compounds have been identified using this screening that alter the reported pigmentation. However, unlike the present invention, this laboratory selection uses immortalized mouse cells instead of normal human melanocytes.

However, it would be very advantageous if other compounds capable of performing pigmentation and melanin production and / or transport could be identified. It would also be very advantageous if a compound that was very resistant to skin and nonirritating could be identified. It would also be useful if improved laboratory screening assays were developed to provide for the identification of such compounds.

BRIEF DESCRIPTION OF THE INVENTION AND PURPOSES

It is therefore an object of the present invention to provide novel assays for the identification of compounds capable of altering (enhancing or inhibiting) the expression of melanin by melanocytes, preferably human melanocytes.

It is another object of the present invention to provide a dermatological / cosmetic / pharmaceutical composition comprising an amount of at least one compound which promotes or inhibits melanin identified by the above assay.

It is more specific of the present invention to provide a topically applicable dermatological / cosmetic / pharmaceutical composition comprising a melanin enhancing or inhibitory amount of at least one compound that alters (enhances or inhibits) melanogenesis by human melanocytes. Purpose.

It is an even more specific object of the present invention to provide a dermatological / cosmetic / pharmaceutical composition comprising a melanin-enhanced or inhibited amount of at least one substituted aromatic or heterocyclic carboxylic acid or derivative thereof. Carboxylic acids include free phenol, naphthol, thiophenol, or thionaphthol functional groups or are protected by a protecting group).

In a subject in need of treatment comprising topically applying an effective amount of a composition comprising at least one melanin affecting (increase or inhibit) retinoid compound for a time sufficient to induce pigmentation of the skin and / or hair, It is another specific object of the present invention to provide a method for altering pigmentation of skin and / or hair.

A therapeutically effective method comprising topically applying an effective amount of a composition comprising one or more substituted aromatic or heterocyclic carboxylic acids or derivatives thereof for a time sufficient to affect pigmentation of the skin and / or hair. It is a more specific object of the present invention to provide a method of altering, increasing or decreasing pigmentation of skin and / or hair in a subject, provided that the carboxylic acid is free or protective phenol, naphthol, thiophenol, or thionaphthol. Group).

1 includes structures for compounds identified according to the invention that affect melanin production;

2-4 list pigmentary diseases that can be treated using the compounds of the present invention.

In a first embodiment, the present invention provides a novel assay for identifying compounds that alter (increase or inhibit) the expression of melanin by human melanocytes, preferably compounds that increase melanogenesis by human melanocytes. to provide.

Typically, this assay standardizes melanin content based on the number (proliferation) of the cultured human melanocytes and identifies compound (s) that affect melanogenesis based on an increase or decrease in melanogenesis per cell. The effect of the specific compound or combination of compounds on the growth or proliferation of human melanocytes in the culture, and the effect of the same compound on melanogenesis by the cultured human melanocytes will be tested.

More specifically, this assay will include:

(i) contacting two or more human melanin cell cultures with one or more selected compounds for effect on melanogenesis;

(ii) measuring proliferation of melanocytes contained in one of said human melanocyte cell cultures;

(iii) measuring the amount of melanin contained in the second human melanocyte cell culture;

(iv) to determine the effect of said compound (s) on melanogenesis (increase or decrease), the data obtained in steps (ii) and (iii) are compared and the number of melanocytes contained in the culture Normalize based data;

(v) also comparing the data obtained in steps (ii) and (iii) with the proliferation and melanogenesis in control human melanin cell culture cultured under the same conditions as the previous culture, except that the compound was absent;

(vi) alters (increases or decreases) melanin expression by human melanocytes based on an increase or decrease in melanogenesis by melanocytes cultured in the presence of the compound compared to a control culture not in contact with the compound. As a result, the selected compounds were identified.

The method will preferably be carried out by obtaining human melanocytes, such as neonatal skin melanocytes, from a suitable source. These melanocytes are then seeded simultaneously into two cell culture chambers, such as 96-well plates and 24-well plates. After allowing these cells to adhere to the surface of the wells, each well is incubated with a fixed amount of specific compound (s) and its effect on melanin expression is measured. Such culturing, if present, will be performed for a sufficient time to determine the effect of the compound (s) on melanogenesis by the cultured melanocytes.

The culture will then vary from about 1 minute to about 1 month, more preferably from about 1 hour to about 2 weeks, most preferably from about 12 hours to 1 week. After incubation, the proliferation of cells in one of the cultures is evaluated. This will be done by any suitable method such as for example absorbance.

In a preferred embodiment, cells in 96-well plates are treated with 3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H- Treatment with tetrazolium (tetrazolium dye commonly used to colorimetrically measure the proliferation of cells) (MTS), and the absorbance of the plate is read at 490 nm to measure proliferation of the cells in the 96-well plate. The results are then compared to control melanocyte cell cultures, which were incubated under the same conditions and then treated with MTS solution but not with test compounds.

Thereafter, a second culture, such as a 24-well plate, containing human melanin cell cultures, incubated with the test compound under the same conditions, is tested to determine the amount of melanin expressed by the cells contained therein. . This can be done by known methods. In the present invention, this is preferably by washing the cells with, for example, phosphate buffered saline (PBS), lysing the washed cells with an alkaline solution such as 1N NaOH and measuring the absorbance of the alkaline soluble melanin at 405 nm, for example. , By measuring the amount of alkali-soluble melanin contained therein. The data is then compared to a control melanin cell culture, preferably grown under the same conditions, except that the test compound is absent.

Data obtained from both melanocyte cell cultures, if present, were normalized based on melanocyte proliferation (cell number) to determine the effect of specific compound (s) on melanogenesis and melanin accumulation by melanocytes, if present. do.

Compounds that alter melanin expression according to the invention are compounds that affect melanogenesis and accumulation in melanocytes of cultured humans. Preferably such compounds will alter melanin expression by at least 10% relative to the control melanin cell culture. More preferably, such compounds will affect at least 20% melanin production. Most preferably, the compound will affect at least about 150-250% melanin production and accumulation.

Accordingly, the present invention relates to the identification of compounds or combinations thereof which increase or decrease melanin production and accumulation by human melanocytes. Compounds that increase melanin production and accumulation can be used, for example, for the promotion of tanning or browning of the skin and for the treatment or prevention of graying of the hair. The compounds may also be used to treat diseases or conditions associated with reduced pigmentation, such as alum.

Compounds that reduce melanogenesis can be used for the treatment of subjects with diseases or conditions associated with hyperpigmentation. Such diseases or conditions include melanoma or age-related hyperpigmentation, and brown patches.

In addition, compounds that inhibit melanin production and / or accumulation can be used to treat and / or prevent aging, such as hyperpigmentation associated with “liver spots” often observed in the hands and faces of the elderly. A list of diseases and conditions associated with pigmentation disorders can be found in Dermatology in General Medicine (Fitzpatric, T.B., et al.), Incorporated herein by reference in its entirety.

Compounds of the present invention can be used to treat pigmentation problems, such as alum, treatment of post-inflammatory pigmentation or depigmentation, treatment of pigmentation reduction or depigmentation after skin transplantation, treatment of pigmentation reduction or depigmentation due to overexposure to ultraviolet light, scar It may be useful for the treatment of postpigmentation reduction or discoloration, or for the treatment of pigmentation reduction or discoloration due to aging or sunspots.

Compounds that reduce melanin production may be useful for the treatment of melanoma or age-related hyperpigmentation.

In addition, this assay can be used to identify combinations of compounds that affect (increase or decrease) melanin production or accumulation by human melanocytes, in particular combinations that have a synergistic effect on melanin production or accumulation.

As discussed above, in a second embodiment, the present invention relates to a pharmaceutical / dermatological / cosmetic compound comprising at least one melanin affecting compound according to the present invention. In this regard, a new class of compounds has been discovered using this assay method that promotes melanin production and / or accumulation by normal human melanocytes. The compound is also advantageous in that it is very resistant to skin and non-irritating. This is surprising because many other retinoid compounds selected using this assay did not affect pigmentation under similar conditions. Such compounds are assumed to affect melanin production and / or accumulation via the retinoid signaling pathway.

In a preferred embodiment, the present invention provides pharmaceutical / cosmetic / dermatological compounds, or derivatives thereof, comprising many one or more substituted aromatic or heterocyclic carboxylic acids, provided that the carboxylic acids are free or Protective phenol, naphthol, thiophenol, or thionaphthol functionality). Examples of such carboxylic acids include benzoic acid, propiolic acid, nicotinic acid, acrylic acid, butene acid and naphthoic acid.

In a preferred embodiment, the substituted aromatic or heterocyclic carboxylic acids of the present invention will exhibit activity on RXR. In the present invention, a compound that exhibits RXR activity is a compound that exhibits a binding to RXR of less than 5000 nM, preferably less than 1000 nM. Measurement of binding to RXR is well known to those skilled in the art and is reported, for example, below: (1) RETINOIDS, Progress in Research and Clinical Applications, Chapter 10 (pp 261-267), Marcel Dekker Inc, Maria A Livrea et Lester Packer, "Selective Synthetic Ligands for Nuclear Retinoic Acid Receptor Subtypes"; (2) "Synthetic Retinoids: Receptor Selectivity and Biological Activity" in Pharmacol Skin, Basel, Karger, 1993, Vol. 5, pp 117-127; (3) "Selective Synthetic Ligands for Human Nuclear Retinoic Acid Receptors" in Skin Pharmacology, 1992, Vol. 5, pp 57-65; (4) "Identification of Synthetic Retinoids with Selectivity for Human Nuclear Retinoic Acid Receptor-γ" in Biochemical and Biophysical Research Communications, Vol. 186, No. 2, July 1992, pp 977-983; And (5) [Mol. Pharmacol., Vol. 40, pp 556-562, "Selective High Affinity RAR-α or RAR-β Retinoic Acid Receptor Ligands".

Also in a more preferred embodiment, the compound exhibiting activity against RXR exhibits agonist activity against RXR. Agonist activity for such RXRs can be measured, for example, by the methods reported in USP No. 5,696,104, which is incorporated herein by reference in its entirety.

More specifically, according to the present invention, compounds surprisingly found to promote melanogenesis and / or accumulation by human melanocytes include:

4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethenyl] benzoic acid (CD No. 2771);

3- [3- (5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -phenyl] -acrylic acid (CD No. 2908);

3- [3- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -phenyl] -but-2-enoic acid (CD No. 3206 number);

6- [1- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -cyclopropyl] -nicotinic acid (CD No. 3127);

3- [3- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -phenyl] -acrylic acid (CD No. 2915);

4- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalene-2-carbonyl) -benzoic acid (CD No. 2608);

4- (3-Bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy) -benzoic acid (CD No. 2661);

5-[(E) -2- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -propenyl] -thiophen-3- Carboxylic acid (CD No. 2425);

3- [3- (5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl) -phenyl] -acrylic acid (CD No. 3132);

6- (3-Butyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl) -nicotinic acid (CD No. 3292);

4- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio) benzoic acid (CD No. 2624);

3- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl) phenyl propionic acid (CD No. 2906); And

6- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio) nicotinic acid (CD No. 2809).

As noted above, the pharmaceutical / dermatological / cosmetic composition will be in a form suitable for topical application to the skin and / or hair. In a preferred embodiment, such compositions will be in a form suitable for artificial tanning and / or browning of the skin.

Such compositions are usually formulated in compositions of this type, with other pharmaceutical, cosmetic, or dermatologically acceptable ingredients such as ionic or nonionic thickeners, emollients, antioxidants, opacifiers, stabilizers, Tackifiers, organic sunscreens, photoprotective inorganic pigments and non-pigments, humectants, vitamins, fragrances, preservatives, fillers, containment agents, dyes, and colorants active in the UV-A and / or UV-B regions. It may include.

Naturally, one of ordinary skill in the art should be careful to select the appropriate complementary compound and / or amounts thereof so that the beneficial properties inherently associated with the compositions of the present invention are not adversely affected by the envisaged addition (s).

The compositions of the present invention may comprise one or more compounds, such as synergistic combinations, that affect melanogenesis and / or accumulation by melanocytes. The compound may also include other compounds that promote or inhibit pigmentation, such as dihydroxyacetone (DHA), or derivatives thereof. Suitable compounds are disclosed in US application Ser. No. 08 / 819,084, filed March 18, 1997, by Tuuloup et al., Whose right is transferred to L'OREAL. In addition, MSH and its analogs that promote pigmentation may be included. In contrast, compounds that inhibit pigmentation, such as HQ, monobenzene ether and arbutin, can be included with compounds identified using this assay to inhibit pigmentation.

The composition is in a form suitable for topical application to human skin and / or hair. Suitable forms may be creams, milks, cream-gels, fluid lotions, oil-in-water emulsions or water-in-oil emulsions, vehicle dispersions, or any other form commonly used in the art.

The amount of one or more melanin-affecting compounds included in the composition typically ranges from about 0.0001 weight% to about 30 weight% based on the total weight of the composition, preferably from about 0.5 weight% to about the total weight of the composition It will be in a concentration range of 15% by weight, more preferably in the range of about 0.001% to 5% by weight relative to the total weight of the composition.

The present invention also encompasses cosmetic, dermatological or therapeutic treatment regimens comprising topical application of many melanin affecting compounds according to the invention. An effective amount is an amount sufficient to affect (increase or decrease) pigmentation of the skin and / or hair. Such therapy can be performed in combination with other compounds that affect pigmentation of the skin and / or hair. The therapy can be performed repeatedly until the desired effect on pigmentation is achieved. If the compound does not irritate the skin, chronic administration should be appropriate.

As discussed, the present invention includes compositions comprising at least one compound according to the invention, which is particularly suitable for promoting the coloring of hair. Such compositions typically include other ingredients included in hair formulations, such as conditioning agents, pigments and color additives, straighteners, permanents, surfactants, perfumes, alcohols, and the like.

To make the understanding of the invention easier, the following examples are provided.

Example 1

Normal human melanocytes from newborn skin were used for analysis.

For primary selection, cells were appropriately inoculated in 96-well plates and 24-well plates simultaneously along the surface of the wells and treated with test compounds for 5 days. To ensure accuracy, compounds were added to the plates using Robot (equal amounts to each well). At the end of the 5 day treatment, cells in 96-well plates were treated with MTS solution and plates were read at 490 nm to determine the effect of the compound on the growth of the cells. Cells in 24-well plates were rinsed with PBS and then lysed with 1N NaOH to measure the absorbance of alkaline soluble melanin at 405 nm.

Data from 96-well plates was analyzed to determine the effect of each compound on the proliferation of the cells, and data from 24-well plates were used to determine the effect of the compound on the melanin content of the cells. The melanin content was then normalized to the proliferation of the cells.

Using this method, the following compounds were identified which increase the melanin content of normal human melanocytes. Based on the results, it is expected that other compounds, such as retinoids, can be identified that alter (increase or decrease) melanogenesis by human melanocytes.

CD number Maximum increase in melanin content (standardized) Explanation 2771 250% at 2 μM 2908 200% at 2 μM 3206 198% at 0.5 μM 2624 181% at 2 μM 3127 179% at 0.1 μM 2906 171% at 0.1 μM 2915 165% at 0.1 μM 2608 157% at 2 μM 2661 155% at 1 μM 2425 149% at 1 μM 2809 145% at 0.5 μM 3132 142% at 2 μM 3292 121% at 1 μM Thus, using the assay of the present invention, we have identified a new class of pro-pigmentary compounds for normal human melanocytes (thus increasing melanogenesis). It is assumed that these molecules can act via retinoid signaling pathways. The discovery of a class of retinoid molecules with pre-pigmentary activity is particularly surprising since other retinoid signaling molecules do not induce pigmentation under similar conditions. This finding is also advantageous because the compound is very resistant to skin and non-irritating. Thus, the compounds have potential applicability for altering pigmentation in skin and / or hair of human subjects.

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Example 2

Formulation example

1. Oral route

(a) The following composition was prepared in the form of 0.8 g tablets:

0.005 g of compound of formula (2)

0.265 g of pregelatinized starch

0.300 g of microcrystalline cellulose

0.200 g of lactose

0.030 g of magnesium stearate

For the treatment of post-inflammatory pigmentation, one to three tablets per adult per day were administered for three to six months, depending on the severity of the case being treated.

(b) Prepared beverage suspensions designed to fill 5 ml vials.

0.050 g of compound of formula (4)

Glycerol 0.500 g

0.500 g of 70% sorbitol

0.010 g sodium saccharate

0.040 g of methyl para-hydroxybenzoate

Appropriate amount of flavor

5 ml of purified water total

For the treatment of pigmentation reduction after skin transplantation, one vial was administered per adult per day for three months, depending on the severity of the treatment.

(c) the following formulations were designed to be filled into gelatin capsules:

0.025 g of compound of formula (5)

0.060 g of corn starch

0.300 g of total lactose

Gelatin capsules used included gelatin, titanium oxide, and preservatives.

In the treatment of alum, one gelatin capsule was administered per adult per day for 30 days.

2. Local Pathway

(a) The following nonionic water-in-oil creams were prepared:

0.100 g of compound of formula (8)

Sold under the trade name "Eucerin" by BDF,

39.900 g of a mixture of emulsified lanolin alcohols, waxes, and refined oils

0.075 g of methyl para-hydroxybenzoate

0.075 g of propyl para-hydroxybenzoate

100.000 g total sterile deionized water

This cream was applied to the depigmented transplanted skin once or twice daily for 30 days.

(b) Gels were prepared by making the following formulations:

0.050 g of compound of formula (11)

4.000 g of erythromycin base

0.050 g of butylhydroxytoluene

Marketed by Hercules under the trade name "Klucel HF",

2.000 g of hydroxypropyl cellulose

100.000 g of ethanol (95 °)

The gel was applied to transplanted skin with reduced pigmentation once to three times daily for 6 to 12 weeks, depending on the severity of the case being treated.

(c) By mixing the following components together, a lotion was prepared to correct the reduction of pigmentation after inflammation:

0.030 g of compound of formula (2)

5.000 g of propylene glycol

0.100 g of butylhydroxy toluene

100.000 g of ethanol (95 °)

This lotion was applied twice daily and significant improvement was observed within a period of 2 to 6 weeks.

(d) The following components were mixed together to prepare a cosmetic composition against the harmful effects of sunlight:

1.000 g of compound of formula (4)

Benzylidene camphor 4.000 g

Fatty acid triglycerides 31.000 g

6.000 g of glyceryl monostearate

2.000 g of stearic acid

Cetyl alcohol1.200 g

4.000 g of lanolin

0.300 g of preservatives

2.000 g of propylene glycol

0.500 g of triethanolamine

Air freshener 0.400 g

100.000 g of total deionized water

This composition was applied daily to combat light induced aging where possible.

(e) The following nonionic oil-in-water creams were prepared:

0.500 g of a compound of formula (3)

0.020 g of vitamin D3

Cetyl alcohol4.000 g

2.500 g of glyceryl monostearate

2.500 g of PEG-50 stearate

9.200 g of carit butter

2.000 g of propylene glycol

0.075 g of methyl para-hydroxybenzoate

0.075 g of propyl para-hydroxybenzoate

100.000 g total sterile deionized water

This cream was applied to the skin affected by alum once or twice daily for 30 days.

(f) Topical gels were prepared by mixing the following ingredients together:

0.050 g of compound of formula (17)

Ethanol 43.000 g

α-tocopherol 0.050 g

Marketed under the trade name Carbopol 941 by "Goodrich",

0.500 g of carboxyvinyl polymers

3.800 g of triethanolamine as a 20% by weight aqueous solution

9.300 g of water

100.00 g of propylene glycol total

The gel was applied to the skin affected by alum, once to three times a day for 6 to 12 weeks, depending on the severity of the case being treated.

(g) Hair lotions for hair recoloring were prepared by mixing the following ingredients together:

0.05 g of a compound of formula (9)

1.00 g of the compound sold under the trade name Minoxidil

20.00 g of propylene glycol

Ethanol 34.92 g

Polyethylene glycol (molecular weight = 400) 40.00 g

0.01 g of butylhydroxyanisole

0.02 g of butylhydroxytoluene

100.000 g of water

This lotion was applied twice a day for 3 months to the scalp suffering from significant discoloration.

(h) A cream after scarring was prepared by mixing the following ingredients together:

0.050 g of compound of formula (13)

0.010 g of retinic acid

Glyceryl, marketed under the trade name Gelot 64 by "Gattefosse"

15.000 g of a mixture of stearate and polyethylene glycol stearate

Marketed under the trade name Labrafil M2130 CS by "Gattefosse",

8.000 g of kernel oil polyoxyethylenated with 6 moles of ethylene oxide

10.000 g of perhydrosqualene

Preservative

Polyethylene glycol (molecular weight = 400) 8.000 g

0.050 g of disodium salt of ethylenediamine tetraacetic acid

100.000 g of purified water

This cream was applied 1-3 times a day for 6-12 weeks.

(i) the following formulation was made to prepare an oil-in-water cream:

0.020 g of compound of formula (4)

Betamethasone 17-valerate 0.050 g

3.000 g of S-carboxymethylcysteine

Marketed under the trade name Myrj 52 by "Atlas",

4.000 g of polyoxyethylene stearate (40 moles of ethylene oxide)

Marketed under the trade name Tween 20 by "Atlas",

Polyoxyethylenated with 20 ml of ethylene oxide

Sorbitan monolaurate 1.800 g

Marketed under the trade name Geleol by "Gattefosse",

4.200 g of a mixture of glyceryl mono- and di-stearate

10.000 g of propylene glycol

Butylhydroxyanisole 0.010 g

0.020 g of butylhydroxytoluene

6.200 g of cetostearyl alcohol

Preservative

Perhydrosqualene 18.00 g sold under the trade name Miglyol 812 by "Dynamit Nobel",

4.000 g of a mixture of caprylic / capric triglycerides

Triethanolamine (99% by weight) 2.500 g

100.000 g of water

This cream was applied twice a day to the skin affected by pigmentation problems due to aging.

(j) The following oil-in-water creams were prepared:

5.000 g lactic acid

0.020 g of compound of formula (13)

Marketed under the trade name Myrj 52 by "Atlas",

4.000 g of polyoxyethylene stearate (40 moles of ethylene oxide)

Marketed under the trade name Tween 20 by "Atlas",

Polyoxyethylenated with 20 moles of ethylene oxide

Sorbitan monolaurate 1.800 g

Marketed under the trade name Celeol by "Gattefosse",

4.200 g of a mixture of glyceryl mono- and di-stearate

10.000 g of propylene glycol

Butylhydroxyanisole 0.010 g

0.020 g of butylhydroxytoluene

6.200 g of cetostearyl alcohol

Preservative

Perhydrosqualene 18.000 g

Marketed under the trade name Miglyol 812 by "Dynamit Nobel",

4.000 g of a mixture of caprylic / capric triglycerides

100.000 g of water

(k) Spray skin lotion:

5.000 g of compound of formula (15)

Ethanol 30.000 g

100.000 g of total deionized water

(l) Hair Lotion:

3.000 g of compound of formula (18)

Propylene Glycol 30.000 g

40.500 g of ethyl alcohol

100.000 g of water

This lotion was applied to the scalp once or twice a day at a rate of 1 ml at each application.

(m) Concentrated lotion:

5.000 g of compound of formula (1)

Kawaine 2.000 g

Hydroxypropyl cellulose

3.500 g (Hercules Klucel G ™)

100.000 g of ethyl alcohol

This concentrated lotion was applied to the scalp once or twice daily at a rate of 1 ml at each application.

(n) Niosomal lotion:

Chimexan ML ™ 0.475 g

0.475 g of cholesterol

0.050 g of monosodium stearoylglutamate

0.100 g of compound of formula (3)

Preservative

Dye

Air freshener

100.000 g of total deionized water

This lotion was applied to the scalp once or twice a day at a rate of 1 ml at each application.

(o) Lotion:

5.000 g of compound of formula (17)

Propylene Glycol Monomethyl Ether

20.000 g of Dowanol PM (trade name) of Dow Chemical

Hydroxypropylcellulose (Klucel G from Hercules) 3.000 g

40.000 g of ethyl alcohol

Minoxidil 2.000 g

100.000 g of water

This concentrated lotion was applied to the scalp once or twice daily at a rate of 1 ml at each application.

While the present invention has been described in terms of specific embodiments, it is believed that many modifications and variations can be made by those skilled in the art without departing from the spirit of the invention. Accordingly, the appended claims are intended to embrace all such modifications and variations as fall within the true spirit and scope of this invention.

Claims (28)

An effective amount of one or more compounds or pharmaceutically acceptable salts selected from the group consisting of: to prepare cosmetic, dermatological and / or therapeutic compositions that promote pigmentation of human skin and / or human hair How to use: 4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethenyl] benzoic acid; 3- [3- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -phenyl] -acrylic acid; 3- [3- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -phenyl] -but-2-enoic acid; 6- [1- (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -cyclopropyl] -nicotinic acid; 3- [3- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -phenyl] -acrylic acid; 4- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalene-2-carbonyl) -benzoic acid; 4- (3-Bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy) -benzoic acid; 5-[(E) -2- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -propenyl] -thiophen-3- Carboxylic acid; 3- [3- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl) -phenyl] -acrylic acid; 6- (3-Butyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl) -nicotinic acid; 4- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio) benzoic acid; 3- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl) phenyl propionic acid; And 6- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio) nicotinic acid. The method of claim 1, wherein the compound is a retinoid signaling molecule that promotes pigmentation of human skin and / or hair. delete The method of claim 1 used to promote browning or tanning of human skin. The method of claim 1 which is used to promote pigmentation of human hair. The method of claim 1 wherein said compound is included in a topically applicable composition comprising from 0.001 to 30% by weight of said compound relative to the weight of the composition. The method of claim 1 wherein the amount of the compound is in the range of 0.5 to 15% by weight of the composition. A pharmaceutical / cosmetic / dermatological composition which promotes pigmentation of human skin and / or hair upon topical application, the composition comprising: (i) at least one compound or pharmaceutically acceptable salt selected from the group consisting of an effective amount for promoting pigmentation of human skin and / or hair: 4- [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethenyl] benzoic acid; 3- [3- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -phenyl] -acrylic acid; 3- [3- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -phenyl] -but-2-enoic acid; 6- [1- (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -cyclopropyl] -nicotinic acid; 3- [3- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -phenyl] -acrylic acid; 4- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalene-2-carbonyl) -benzoic acid; 4- (3-Bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy) -benzoic acid; 5-[(E) -2- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -propenyl] -thiophen-3- Carboxylic acid; 3- [3- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl) -phenyl] -acrylic acid; 6- (3-Butyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl) -nicotinic acid; 4- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio) benzoic acid; 3- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl) phenyl propionic acid; And 6- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio) nicotinic acid; And (ii) Pharmaceutically, cosmetically or dermatologically acceptable carriers. delete The composition of claim 8, wherein the amount of the compound ranges from 0.001 to 30% by weight relative to the weight of the composition. 9. A composition according to claim 8 wherein the amount of said compound is in the range of from 0.5 to 15% by weight relative to the weight of the composition. The composition of claim 8 in a form suitable for topical application selected from the group consisting of creams, milks, cream-gels, fluid lotions, oil-in-water emulsions, water-in-oil emulsions, and vehicle dispersions. The composition of claim 8 comprising other compounds that affect skin and / or hair pigmentation. 9. An organic sunscreen, photoprotective inorganic pigment, according to claim 8, which is active in the ionic or nonionic thickener, softener, antioxidant, opacifying agent, stabilizer, viscous agent, UV-A and / or UV-B region. A composition further comprising at least one substitute selected from the group consisting of non-pigments, humectants, vitamins, fragrances, preservatives, fillers, containment agents, dyes, and colorants. delete delete delete delete delete delete delete delete delete delete The method of claim 1 wherein said compound exhibits activity against RXR. The composition of claim 8, wherein said compound exhibits activity against RXR. The method of claim 25, wherein said compound exhibits a binding to RXR of less than 5000 nM. 27. The composition of claim 26, wherein said compound exhibits a binding to RXR of less than 5000 nM.