CN1247192C - Assay for identification of compound that promote meianin prodn. and retinoid-like compounds identified by said assay - Google Patents
Assay for identification of compound that promote meianin prodn. and retinoid-like compounds identified by said assay Download PDFInfo
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- CN1247192C CN1247192C CNB998058858A CN99805885A CN1247192C CN 1247192 C CN1247192 C CN 1247192C CN B998058858 A CNB998058858 A CN B998058858A CN 99805885 A CN99805885 A CN 99805885A CN 1247192 C CN1247192 C CN 1247192C
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Abstract
An in vitro assay for selecting compounds that alter pigmentation of skin is provided. Also, a novel class of pro-pigmentatory compounds is provided which comprise substituted aromatic or heterocyclic carboxylic acids, or derivatives thereof, or pharmaceutically acceptable salts, which do not contain a pheno, naphthol, thiophenol, or a thionaphthol function in free or protected form. In a preferred embodiment, thess compounds will display activity for RXRs. These compounds may be used for altering pigmentation of human skin and/or hair in cosmetic or dermatological compositions, and for the treatment of disorders and disease conditions that affect skin or hair pigmentation.
Description
Background of invention
The normal skin color is to be united the result of expression by the mixture of different pigments, melanin wherein, and a kind of brown pigment is its main component.Melanin is synthetic by melanocyte special, that can find in epidermis.Melanocyte is synthesis of melanin in being called as the organelle of melanosome.When melanosome was saturated by melanin, they were transported on the arborizations of melanosome and are converted into outer keratinocyte.These keratinocytes are moved to skin surface subsequently, cause skin to present the brown pigment calmness.Melanic amount in the keratinocyte has determined skin and the Pigmented degree of hair.
Because melanin to skin and the Pigmented effect of hair, has carried out being intended to differentiate the research that influences the melanin generation and/or melanin is transported to the chemical compound of outer keratinocyte.These chemical compounds are having potential using value aspect change hair and the cutaneous pigmentation.For example, as you know, melanotropin (MSH) and can induce pigmentation such as the chemical compound of theophylline.In addition, also tested the clinical usefulness of MSH analog promotion cutaneous pigmentation.Report is also arranged simultaneously, and alpha-lipoprotein can the interior melanic generation of chafe.(Jpn.kokai Tokyo, Koho, JP 82-153348, GB 2124900, by the Empresa Cubana Importadora y Exportadora deProductos MedicoS company application of Cuba).On the contrary, also known and used some chemical compounds to suppress pigmentation, for example treated melasma, as using hydroquinone (HQ) and monophenyl ether (people such as Pathak, " U.S. dermatological association will " 15:849-899 (1986); People such as Smith, " pigment cell's research " 1:386-389 (1988)) and a kind of glucose conjugate-arbutin of HQ (" Japanese IDS paper compilation " 12:138-139 (1998)).
And, report that in addition kojic acid and derivant thereof and/or valeric acid can suppress melanin and form that (JP 03011010 for Jpn.kokai Tokyo, Koho; Japan Oyama, Yasuaki, Sansei medicine company limited).
In addition, report in addition, propanoic acid, butanoic acid and valeric acid and salt thereof, with or do not combine with unsaturated fatty acid, can suppress formation people such as (, EPA345081, Japanese Hayashibara biochemical laboratory) Mishima of the tryrosinase that catalysis melanin generates.
EP 0 509 241 and WO 93/19729 have described that trans retinoic acid by local application effective dose in one sufficiently long period can carry out hyperpigmentation or skin tanning.In any case employed chemical compound can cause stimulation in these ways.
People such as Dooley in " pharmacology " 7:188-200 (1994), reported a kind of be intended to be suitable for differentiating can suppress the synthetic again and in vitro method potential anti-melanosome, cytotoxic compound of melanin.This method has been utilized the mouse cell line in the melanocyte source of two kinds of immortalizations, the mouse cell line in Mel-Ab people such as (, " oncogene " 3:531-535 (1988)) Dooley and other fibroblasts sources.The Mel-Ab cell derives from the Mus C57BL/6 melanocyte system of spontaneous immortalization, the ramp and produce a large amount of melanin in culture of this cell line.It is reported that this checking method is used for screening and the chemical compound that has similar structures at the intermediate of melanin biosynthesis pathway, they are unique for melanocyte.Particularly screened the phenol of the para-orientation relevant and relevant 1 with DOPA with tyrosine, the 2-dihydroxy benzenes, and 1,3-dihydroxy benzenes, 1,4-dihydroxy benzenes, 1,4-dimethoxy benzene and 1,4-benzoquinone.Utilize this screening technique to differentiate several Pigmented chemical compounds that are intended to change.But, different with the present invention, this in-vitro screening method utilization be the mouse cell line of immortalization, rather than normal people's melanocyte.
But, will be useful if can identify other chemical compounds that influence pigmentation and melanin generation and/or transhipment.Can be well tolerable and also will be useful if can identify to the non-irritating chemical compound of skin.In addition, a kind ofly be used to differentiate that the improved in-vitro screening checking method of these chemical compounds will be useful if develop.
Purpose of the present invention and concise and to the point the description
Finally, an object of the present invention is to provide a kind of new being used for and differentiate and can change that (strengthen or suppress) is by melanocyte, preferred checking method of the melanic chemical compound of people's melanocyte expression.
Another object of the present invention provides dermatological/cosmetics/pharmaceutical composition, and said composition comprises at least a promotion of being determined by this checking method or the chemical compound that suppresses the melanin amount.
The present invention more particularly purpose provide can local application dermatological/cosmetics/pharmaceutical composition, said composition comprises at least a can the change that strengthen or suppress the melanin amount (strengthen or suppress) people's melanocyte generate melanic chemical compound.
Of the present invention in addition more particularly a purpose provide dermatological/cosmetics/pharmaceutical composition; said composition comprises aromatics or the heterocyclic carboxylic acid or derivatives thereof that strengthens or suppress at least a replacement of melanin amount, and condition is phenol, naphthols, phenylmercaptan. or the thionaphthol functional group that described carboxylic acid does not comprise free or protected base protection.
Another special purpose of the present invention provides a kind of skin and/or Pigmented method of hair that changes the curee who needs this treatment, what this method was included in a kind of effective dose of local application in one sufficiently long period contains the melanic retinoid sample compound compositions of at least a influence (strengthen or suppress), to induce skin and/or hair pigmentation.
More particularly purpose of the present invention provides the curee's of a kind of change-increase or this treatment of minimizing-needs skin and/or the Pigmented method of hair; this method is included in the aromatics that contains at least a replacement of a kind of effective dose of local application in one sufficiently long period or the compositions of heterocyclic carboxylic acid or derivatives thereof; to influence the pigmentation of skin and/or hair,, condition do not comprise free or protected phenol, naphthols, phenylmercaptan. or thionaphthol base but being described carboxylic acid.
Brief description of the drawings
Fig. 1 contains the structure of the chemical compound of determining according to the present invention that can influence the melanin generation;
Fig. 2 to 4 has listed the pigment disorders that can use compounds for treating of the present invention.
Detailed Description Of The Invention
In first embodiment, the invention provides a kind of new being used for and differentiate that can change (increasing or inhibition) human melanocytes expresses the checking method of melanic compound, preferably can increase human melanocytes and generate melanic compound.
In general, this checking method will check the composition of specific compound or compound to the effect of human melanocytes growth or propagation in the culture, and described same compound generates melanic effect to the human melanocytes of described cultivation, melanin content is calibrated on basis in human melanocytes (propagation) quantity of described cultivation, and the compound of melanin generation is determined affect in the basis that melanic generation increases or reduces in each cell.
More particularly, this checking method will comprise:
(i) at least two kinds of human melanocytes cultures to be contacted with regard to the compound that its effect that melanin is generated is screened with at least a;
(ii) measure the melanocytic propagation situation that contains in certain described human melanocytes culture;
(iii) measure the melanic amount that contains in second human melanocytes culture;
(iv) with step (ii) and the data that obtain (iii) compare, purpose is the effects (increase or reduce) of determining that these chemical compounds generate melanin, and calibration data on the basis of the melanocytic amount that contains in described culture;
But (v) further with step (ii) with (iii) in the data that obtain with generate data at the identical propagation that does not add the contrast people melanocyte culture of cultivating under the condition of described chemical compound with aforementioned culture and melanin and compare;
(vi) the melanin that produces of the melanocyte of in the presence of described chemical compound is arranged, cultivating with respect to not with control cultures that described chemical compound contact on the melanic amount that the produces basis that increases or reduce, identify in the chemical compound that is screened and can change (increase or minimizing) people's melanocyte and express melanic chemical compound.
This method will be preferably by finishing from suitable source acquisition people melanocyte, for example newborn skin melanocyte.Then these melanocytes are planted simultaneously two cell culture chambers, for example one 96 hole is dull and stereotyped and one 24 hole flat board in.After having been allowed on the surface of being attached to the hole when these cells, cultivate each hole, thereby determine the effect that they are expressed melanin with the specific compound of fixed amount.This cultivation will continue one section to be enough to regard to these chemical compounds the melanocyte by these cultivations be generated melanic effect, if any, and the time of assessing.
Cultivate then will continue from about 1 minute to about time of waiting in 1 month, more preferably from about 1 hour to about two weeks, first-selected from about 12 hours about 1 week extremely.After cultivating end, assess the propagation situation of cell in one of them described culture.This can utilize suitable method, for example utilize absorbance to finish.
In a preferred embodiment, cell in 96 hole flat boards 3-(4,5-dimethylthiazole 2-yl)-5-(3-carboxyl methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (a kind of be usually used in the tetrazolium dye that colorimetric is determined the cell proliferation situation) (MTS) handles, and under 490nm, read this dull and stereotyped absorbance, to determine the propagation situation of cell in described 96 hole flat boards.Then with these results with cultivate under the same conditions, subsequently with MTS solution handle, but do not compare with the result of the contrast melanocyte culture of test compounds processing.
Check is under the same conditions with test compounds second kind of culture that cultivate, that contain people's melanocyte culture then, and 24 hole flat boards for example are to determine the melanic amount by the cellular expression that wherein contains.This can finish with known method.In the present invention, this will preferably finish with following method: (PBS) cleans these cells with for example phosphate-buffered saline, with the alkaline solution cell of the described cleaning of 1N NaOH cracking for example, and by for example under 405nm, measuring the melanic amount of alkali solubility that the melanic absorbance of alkali solubility is measured wherein to be contained.Then these data preferably with at the same terms but do not exist the contrast melanocyte culture of growing under the condition of described test compounds to compare.
On the basis of melanocyte propagation (cell number), calibrate afterwards, in order that determine that specific compound is to being generated melanin and accumulated melanic effect by melanocyte, if any from these two kinds of data that the melanocyte culture obtains.
The chemical compound that changes the melanin expression according to the present invention is to influence the generation of melanin in people's melanocyte of being cultivated and those chemical compounds of accumulating.Preferred this compounds will change with respect to contrast melanocyte culture at least 10% melanin expression.More preferably this compounds will influence at least 20% melanin generation.First-selected this chemical compound will influence melanic generation and accumulate and reach about 150% to 250%, or higher.
Therefore, the present invention relates to increase or to reduce the discriminating that generates and accumulate melanic chemical compound or its compositions by people's melanocyte.The chemical compound that increases the melanin generation and accumulate can be used for, for example: promote skin tanning or overstrike, treatment or prevention hair graying.These chemical compounds also can be used for the treatment of and hypopigmentation diseases associated and state, for example white macula.
The chemical compound that reduces the melanin generation can be used for the treatment of the patient who suffers from hyperpigmentation diseases associated or state.This class disease comprises melasma or the hyperpigmentation relevant with the age with state, and moth patch.
Suppress that melanin generates and/or the chemical compound accumulated also can be used for the treatment of and/or prevent the hyperpigmentation relevant with aging, for example through the old people that is everlasting on hand and " freckle " seen on the face.Can find the list with disorderly diseases associated of pigmentation and state in " dermatological in the general medical science " (Fitzpatric, people such as T.B.), the document quotes in full at this as a reference.
Chemical compound of the present invention can be used for the treatment of the worries of hypopigmentation, such as white macula, postinflammatory hypopigmentation or the depigmentation, be used for the treatment of the hypopigmentation or the depigmentation after the skin transplantation, be used for the treatment of the hypopigmentation or the depigmentation that cause because of the excessive contact ultraviolet, be used for the treatment of the hypopigmentation or the depigmentation behind the cicatrization, perhaps be used for the treatment of the hypopigmentation or the depigmentation that cause because of aging or lentigo.
The chemical compound that reduces the melanin generation can be used for the treatment of melasma or the hyperpigmentation relevant with the age.
In addition, checking method of the present invention can be used for differentiating influence (increasing or minimizing) by the generation of people's melanocyte or accumulate melanic compound compositions, particularly to melanic generation or accumulate synergistic compositions is arranged.
As mentioned above, in second embodiment, the present invention relates to contain the medicine/dermatological/cosmetic compounds of the melanic chemical compound of at least a influence of the present invention.In this, use calibration method of the present invention to find that the new promotion of a class is generated by normal person's melanocyte and/or accumulates melanic chemical compound.These chemical compounds are in well tolerable property and also be not favourable aspect the chafe.This is wonderful, because use many other retinoid sample chemical compounds of checking method screening of the present invention not influence pigmentation under similar condition.Infer that these chemical compounds influence melanic generation and/or accumulate through retinoid sample signal pathway.
In a preferred embodiment; the invention provides the aromatics that comprises an amount of at least a replacement or the medicine/cosmetics/dermatological chemical compound of heterocyclic carboxylic acid or derivatives thereof, do not contain phenol, naphthols, phenylmercaptan. or the thionaphthol functional group of free or protected form but condition is described carboxylic acid.For instance, this class carboxylic acid comprises benzoic acid, acetylenecarboxylic acid, nicotinic acid, acrylic acid, butenoic acid and naphthoic acid.
In a preferred embodiment, the aromatics of replacement of the present invention or heterocyclic carboxylic acid will demonstrate the activity to RXR.According to the present invention, show that the active chemical compound of RXR is to present the combination of RXR less than 5000nM, preferably less than the chemical compound of 1000nM.The bonded of RXR determined it is well known to those skilled in the art, in following document, report is arranged, for example: (1) " is used to examine the synthetic part of selectivity of retinoic acid receptors hypotype ", be stated from " retinoid-research and Clinical advances ", the 10th chapter (261-267 page or leaf), Marcel Dekker company is published by Maria A.Livrea et Lester Packer; (2) " synthetic retinoid: receptor-selective and biological activity " is stated from " PharmacolSkin, Basel, Karger,, the 5th volume, 117-127 page or leaf in 1993; (3) " the synthetic part of selectivity that is used for people's nucleoid retinoic acid receptors " was stated from " dermatopharmacology " 1992, the 5th volume, 57-65 page or leaf; (4) " people's nucleoid retinoic acid receptors-γ is had the optionally discriminating of synthetic retinoid ", be stated from " biochemistry and biophysical studies communication " the 186th volume, the 2nd phase, in July, 1992,977-983 page or leaf; (5) " optionally high affinity RAR-α or RAR-β retinoic acid receptors part " is stated from " molecular pharmacology " the 40th volume, the 556-562 page or leaf.
In addition, in a preferred embodiment, RXR is shown that active chemical compound presents the stimulant activity to RXR.For example can utilize in No. the 5th, 696,104, the United States Patent (USP) reported method to measure to this stimulant activity of RXR, this full patent texts is quoted at this as a reference.
More particularly, be surprisingly found out that according to the present invention and can promote to generate and/or accumulate melanic chemical compound to comprise by people's melanocyte:
4-[1-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl-2-naphthyl) vinyl] benzoic acid (CDNo.2771);
3-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydrochysene-naphthalene-2-yl)-phenyl]-acrylic acid (CDNo.2908);
3-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrochysene-naphthalene-2-yl)-phenyl]-but-2-ene acid (CDNo.3206);
6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrochysene-naphthalene-2-yl)-cyclopropyl]-nicotinic acid (CDNo.3127);
3-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrochysene-naphthalene-2-yl)-phenyl]-acrylic acid (CDNo.2915);
4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrochysene-naphthalene-2-carbonyl)-benzoic acid (CD No.2608);
4-(3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydrochysene-naphthalene-2-base oxygen)-benzoic acid (CDNo.2661);
5-[(E)-2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrochysene-naphthalene-2-yl)-acrylic]-thiophene-3-carboxylic acid (CD No.2425);
3-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydrochysene-naphthalene-2-base sulfane base)-phenyl]-acrylic acid (CDNo.3132);
6-(3-butyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydrochysene-naphthalene-2-base sulfane base)-nicotinic acid (CDNo.3292);
4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrochysene-2-naphthyl sulfo-)-benzoic acid (CD No.2624);
3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrochysene-2-naphthyl) phenyl acetylenecarboxylic acid (CD No.2906); With
6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrochysene-2-naphthyl sulfo-) nicotinic acid (CD No.2809).
As mentioned above, these medicine/dermatological/cosmetic composition will be the form that is suitable for being locally applied to skin and/or hair.In a preferred embodiment, these compositionss will be the forms that is suitable for artificial tanning and/or makes the skin overstrike.
These compositionss can comprise that other drug in the compositions that generally is formulated into these types is learned, acceptable component on cosmetic conduct and learning or the dermatological, such as the inorganic pigment of ion or non-ionic thickening agent, softening agent, antioxidant, opacifying agent, stabilizing agent, emollient, effectively organic sunscreen agent in UV-A and/or UV-B zone, illumination protection and non-pigment, wetting agent, vitamin, spice, antiseptic, filler, chelating agen, dyes and dyestuffs.
Nature, those skilled in the art should carefully select additional chemical compound and/or its consumption of these the bests, so that can not be subjected to envisioning the adverse effect of additive with the advantageous property of this qualitative correlation of compositions of the present invention.
Compositions of the present invention can comprise one or more to be influenced the melanocyte generation and/or accumulates melanic chemical compound, for example cooperative compositions.And these compositionss can comprise other promotions or suppress Pigmented chemical compound, for example dihydroxy acetone (DHA) or derivatives thereof.People such as Tuloup on March 18th, 1997 application and be presented in the United States Patent (USP) 08/819,084 of L'OREAL (FR) and disclose suitable compound.In addition, also can comprise Pigmented MSH of promotion and analog thereof.On the contrary, suppress Pigmented chemical compound,, can be included in the Pigmented chemical compound of inhibition that uses checking method of the present invention to determine such as HQ, monophenyl ether and arbutin.
Compositions of the present invention will be the form that is suitable for being locally applied to people's skin and/or hair.Suitable dosage form comprises any other form commonly used in cream frost, milk, cream gel, liquid emulsion, oil-in-water emulsion or water-in-oil emulsion, vesicle dispersion or this area.
The amount of the melanic chemical compound of at least a influence that contains in the compositions of the present invention generally will with respect to the said composition gross weight about 0.0001% to the scope of about 30% (weight), preferably will with respect to the said composition gross weight about 0.5% to the concentration range of about 15% (weight), more preferably will with respect to the said composition gross weight about 0.001% to the concentration range of about 5% (weight).
The present invention also comprises a kind of processing, beauty treatment, dermatological or therapeutic scheme, and this scheme comprises an amount of melanic chemical compound of influence of the present invention of local application.Effective dose is to be enough to influence (increase or reduce) skin and/or the Pigmented amount of hair.This scheme can with other influence skin and or the Pigmented chemical compound of hair unite and finish.This scheme can be carried out repeatedly, until pigmentation has been reached Expected Results.Long term administration should be suitable, because chemical compound of the present invention does not have stimulation to skin.
As mentioned above, the present invention includes, particularly, be suitable for promoting compositions hair coloring, that contain at least a The compounds of this invention.This based composition can comprise in the hair preparation other components commonly used, for example conditioner, pigment and colored component, hair straightening agent, agent for permanent hair waving, surfactant, essence, alcohol and following or the like.
In order to promote the understanding of the present invention better, now provide the following example.
Embodiment 1
To be used for calibrating from normal person's melanocyte that newborn skin obtains.For first screening, suitably cell is planted simultaneously in 96 holes flat board and the 24 hole flat boards according to the surface area in each hole, handled 5 days with test compounds.Utilize robot that chemical compound is joined in the flat board to guarantee degree of accuracy (amount in each hole is identical).Processing phase of 5 days is when finishing, with the cell in the MTS solution-treated 96 hole flat boards and read dull and stereotyped data under 490nm, with the effect of definite chemical compound cell growth.Cell in the 24 hole flat boards washes with PBS, uses 1N NaOH cracking then, measures the melanic absorbance of alkali solubility under 405nm.
The data that analysis obtains from 96 hole flat boards, determining the effect of every kind of chemical compound on cell proliferation, the data that obtain from 24 hole flat boards are used for determining the effect of melanin content the chemical compound pair cell.Then melanin content is calibrated to the propagation of cell.
Utilize the method, the inventor has identified the chemical compound of the melanocytic melanin content of following increase normal person.According to these results, expectation can identify and can change (increase or reduce) by the generation of people's melanocyte melanic other chemical compounds, for example retinoid.
| CD No. | The maximum recruitment (calibration) of melanin content | Estimate |
| 2771 | Under 2 μ M, be 250% | |
| 2908 | Under 2 μ M, be 200% | |
| 3206 | Under 0.5 μ M, be 198% | |
| 2624 | Under 2 μ M, be 181% | |
| 3127 | Under 0.1 μ M, be 179% | |
| 2906 | Under 0.1 μ M, be 171% | |
| 2915 | Under 0.1 μ M, be 165% | |
| 2608 | Under 2 μ M, be 157% | |
| 2661 | Under 1 μ M, be 155% | |
| 2425 | Under 1 μ M, be 149% | |
| 2809 | Under 0.5 μ M, be 145% | |
| 3132 | Under 2 μ M, be 142% | |
| 3292 | Under 1 μ M, be 121% |
Therefore, use checking method of the present invention, the inventor identified a class new be used for the melanocytic chromogen chemical compound of normal person (increasing melanic generation thus).Suppose that these molecules can work by the retinoid signal pathway.Discovery with the active class retinoid sample molecule of chromogen is very wonderful, because other retinoid sample signaling molecules are not induced pigmentation under conditions of similarity.It is very good that this finds that further benefit is that these chemical compounds tolerate, and skin is not had zest.Therefore, they have potential using value aspect the pigmentation of skin that changes the people and/or hair.
Embodiment 2
Example of formulations
1, oral route
(a) the following compositions of preparation 0.8g tablet form:
Formula (2) chemical compound 0.005g
Starch,pregelatinized 0.265g
Microcrystalline Cellulose 0.300g
Lactose 0.200g
Magnesium stearate 0.030g
In order to treat postinflammatory hypopigmentation, according to the order of severity of the treatment state of an illness, the adult is individual
Body administration every day 1-3 sheet, administration 3-6 month.
(b) the preparation plan is with the suspension of drinking of 5ml bottle packing:
Formula (4) chemical compound 0.050g
Glycerol 0.500g
70% Sorbitol 0.500g
Sodium saccharinate 0.010g
Methyl parahydroxybenzoate 0.040g
Flavoring agent adds to capacity
An amount of 5ml purifies waste water
In order to treat hypopigmentation after the skin transplantation,, become individual human administration every day 1 bottle, administration 3 months according to the order of severity of the treatment state of an illness.
(c) the following series preparation packed with gelatine capsule is planned in preparation:
Formula (5) chemical compound 0.025g
Corn starch 0.060g
An amount of 0.300g of lactose
Used gelatine capsule is made up of gelatin, titanium dioxide and antiseptic.
During the treatment white macula, become individual human administration every day 1 capsules, administration 30 days.
2, local approach
(a) the following non-ionic oil water-in type cream frost of preparation:
Formula (8) chemical compound 0.100g
Emulsifying lanolin alcohol, wax and refined oil
Mixture, by BDF company with "
Anhydrous eucerin " title sell 39.900g
Methyl parahydroxybenzoate 0.075g
Propyl p-hydroxybenzoate 0.075g
An amount of 100.000g of sterile demineralized water
This cream frost is applied to the insufficient cutify of pigment, every day 1-2 time, continues 30 days.
(b) prepare following gel preparation:
Formula (11) chemical compound 0.050g
Erythromycin substrate 4.000g
Butylated hydroxytoluene 0.050g
By Hercules company with " Klucel HF "
The hydroxypropyl cellulose 2.000g that title is sold
An amount of 100.000g of ethanol (95 °)
According to the order of severity of the treatment state of an illness, this gel is applied to the insufficient cutify of pigment, every day 1-3 time, continue 6-12 week.
(c) by being mixed, following ingredients prepares the emulsion that is used to correct postinflammatory hypopigmentation:
Formula (2) chemical compound 0.030g
Propylene glycol 5.000g
Butylated hydroxytoluene 0.100g
An amount of 100.000g of ethanol (95 °)
This emulsion is used 2 times every day, can observe tangible improvement at 2-6 in week.
(d) by being mixed, following ingredients prepares the cosmetic composition that is used for the antisum injury effect:
Formula (4) chemical compound 1.000g
Benzylidene camphor 4.000g
Fatty acid glyceryl ester 31.000g
Glyceryl monostearate 6.000g
Stearic acid 2.000g
Spermol 1.200g
Lanoline 4.000g
Antiseptic 0.300g
Propylene glycol 2.000g
Triethanolamine 0.500g
Spice 0.400g
An amount of 100.000g of demineralized water
Use said composition every day, make its might to antisum cause aging.
(e) the following nonionic oil-in-water type cream frost of preparation:
Formula (3) chemical compound 0.500g
Vitamin D3 0.020g
Spermol 4.000g
Glyceryl monostearate 2.500g
PEG-50 stearate 2.500g
Shea oil 9.200g
Propylene glycol 2.000g
Methyl parahydroxybenzoate 0.075g
Propyl p-hydroxybenzoate 0.075g
An amount of 100.000g of sterile demineralized water
This cream frost is applied to the skin that influenced by white macula, and every day 1 or 2 times continue 30 days.
(f) by being mixed, following ingredients prepares topical gels:
Formula (17) chemical compound 0.050g
Ethanol 43.000g
Alpha-tocopherol 0.050g
By " Goodrich " with Carbopo1941_
Run after fame and weigh up the carboxy vinyl polymer 0.500g that sells
20 weight % aqueous solution 3.800g of triethanolamine
Water 9.300g
An amount of 100.00g of propylene glycol
According to the order of severity of the treatment state of an illness, this gel is applied to the skin that influenced by white macula, every day 1-3 time, continue 6-12 week.
(g) by being mixed, following ingredients prepares the hair emulsion that is used for making again hair coloring:
Formula (9) chemical compound 0.05g
Chemical compound 1.00g with title Minoxidil_ sale
Propylene glycol 20.00g
Ethanol 34.92g
Polyethylene Glycol (molecular weight=400) 40.00g
Butylated hydroxyanisole 0.01g
Butylated hydroxytoluene 0.02g
An amount of 100.000g of water
This emulsion is applied to the seriously scalp of the depigmentation, every day 2 times, continues 3 months.
(h) by being mixed, following ingredients prepares the cream frost of using behind the cicatrization:
Formula (13) chemical compound 0.050g
Tretinoin 0.010g
Tristerin and polyglycol distearate
Mixture (70mol) is by " Gattefosse "
Sell 15.000g with title Gelot64_
With the seed kernel oil of 6mol oxirane polyoxyethyleneization,
By " Gattefosse " with title Labrafil M2130
CS_ sells 8.000g
Perhydro-squalene 10.000g
Antiseptic is an amount of
Polyethylene Glycol (molecular weight=400) 8.000g
The disodium salt 0.050g of ethylenediaminetetraacetic acid
An amount of 100.000g purifies waste water
This cream frost uses 1-3 time every day, continues 6-12 week.
(i) the following oil-in-water type cream frost of preparation preparation:
Formula (4) chemical compound 0.020g
Betamethasone 17-valerate 0.050g
S-Carbocisteine 3.000g
Myrj 45 (40mol oxirane),
Sell 4.000g by " Atlas " with title Myrj52_
Sorbitan one lauric acid ester is used the 20ml epoxy
The ethane polyoxyethyleneization, by " Atlas " with title
Tween 20_ sells 1.800g
Glyceryl monostearate and distearin
Mixture, by " Gattefosse " with title
Geleol_ sells 4.200g
Propylene glycol 10.000g
BHA 0.010g
Fourth hydroxy-methylbenzene 0.020g
Cetearyl alcohol 6.200g
Antiseptic is an amount of
Perhydro-squalene 18.000g
The mixture of caprylic/capric triglyceride, by
" Dynamit Nobel " is with title Miglyol 812_
Sell 4.000g
Triethanolamine (99% weight) 2.500g
An amount of 100.000g of water
This cream frost is applied to the skin that is subjected to the puzzlement of pigmentation problem because of old and feeble, every day 2 times.
(j) the following oil-in-water type cream frost of preparation:
Lactic acid 5.000g
Formula (13) chemical compound 0.020g
Myrj 45 (40mol oxirane),
Sell 4.000g by " Atlas " with title Myrj52_
Sorbitan one lauric acid ester is used the 20mol epoxy
The ethane polyoxyethyleneization, by " Atlas " with title
Tween 20_ sells 1.800g
Glyceryl monostearate and distearin
Mixture, by " Gattefosse " with title
Geleol_ sells 4.200g
Propylene glycol 10.000g
BHA 0.010g
Fourth hydroxy-methylbenzene 0.020g
Cetearyl alcohol 6.200g
Antiseptic is an amount of
Perhydro-squalene 18.000g
The mixture of caprylic/capric triglyceride, by
" Dynamit Nobel " is with title Miglyol 812_
Sell 4.000g
An amount of 100.000g of water
(k) be used to the skin emulsion of spraying:
Formula (15) chemical compound 5.000g
Ethanol 30.000g
An amount of 100.000g of demineralized water
(I) hair emulsion:
Formula (18) chemical compound 3.000g
Propylene glycol 30.000g
Ethanol 40.500g
An amount of 100.000g of water
This emulsion is applied to scalp with the ratio of each 1ml, every day 1 or 2 times.
(m) thickening emulsion:
Formula (1) chemical compound 5.000g
Kawine 2.000g
Hydroxypropyl cellulose
(from the Klucel G_ of Hercules) 3.500g
An amount of 100.000g of ethanol
This thickening emulsion is applied to scalp with the ratio of each 1ml, every day 1 or 2 times.
(n) Niosomal emulsion:
Chimexane ML_ 0.475g
Cholesterol 0.475g
Stearoyl-glutamic acid one sodium 0.050g
Formula (3) chemical compound 0.100g
Antiseptic is an amount of
Dyestuff is an amount of
Spice is an amount of
An amount of 100.000g of demineralized water
This emulsion is applied to scalp with the ratio of each 1ml, every day 1 or 2 times.
(o) emulsion:
Formula (17) chemical compound 5.000g
Glycol Monomethyl ether
(from the Dowanol PM_ of Dow Chemical) 20.000g
Hydroxypropyl cellulose
(from the Klucel G_ of Hercules) 3.000g
Ethanol 40.000g
Minoxidil 2.000g
An amount of 100.000g of water
This thickening emulsion is applied to scalp with the ratio of each 1ml, every day 1 or 2 times.
Although the present invention is described with some specific embodiment, should be appreciated that those skilled in the art can carry out many modifications and change to the present invention under the situation that does not deviate from essence of the present invention.Therefore, appending claims will cover all modifications and the change in essence of the present invention and the scope.
Claims (16)
1. the aromatics of the replacement with tetrahydric naphthalene ring or heterocyclic carboxylic acid are used for changing, promote or suppress the purposes of medicine of Pigmented beauty treatment, dermatological and/or the treatment of people's skin and/or hair in preparation; condition is phenol, naphthols, phenylmercaptan. or the thionaphthol functional group that described carboxylic acid does not contain free or protected base protection, and described carboxylic acid is selected from:
4-[1-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl-2-naphthyl) vinyl] benzoic acid;
3-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydrochysene-naphthalene-2-yl)-phenyl]-acrylic acid;
3-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrochysene-naphthalene-2-yl)-phenyl]-but-2-ene acid;
6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrochysene-naphthalene-2-yl)-cyclopropyl]-nicotinic acid;
3-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrochysene-naphthalene-2-yl)-phenyl]-acrylic acid;
4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrochysene-naphthalene-2-carbonyl)-benzoic acid;
4-(3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydrochysene-naphthalene-2-base oxygen)-benzoic acid;
5-[(E)-2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrochysene-naphthalene-2-yl)-acrylic]-thiophene-3-carboxylic acid;
3-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydrochysene-naphthalene-2-base sulfane base)-phenyl]-acrylic acid;
6-(3-butyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydrochysene-naphthalene-2-base sulfane base)-nicotinic acid;
4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrochysene-2-naphthyl sulfo-)-benzoic acid;
3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrochysene-2-naphthyl) phenyl acetylenecarboxylic acid; With
6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrochysene-2-naphthyl sulfo-) nicotinic acid.
2. purposes as claimed in claim 1, wherein said chemical compound are a kind ofly can promote application on human skin and/or the Pigmented retinoid signaling molecule of hair.
3. purposes as claimed in claim 1, it is used to promote application on human skin overstrike or tanned.
4. purposes as claimed in claim 1, it is used to promote that the human hair is painted.
5. purposes as claimed in claim 1, but wherein said chemical compound be included in the topical application of compositions, described compositions contains the described chemical compound of 0.001-30 weight % with respect to the said composition gross weight.
6. purposes as claimed in claim 1, the amount of wherein said chemical compound are the 0.5-15 weight % of compositions.
7. purposes as claimed in claim 1, wherein said compound exhibits goes out the activity to RXR.
8. purposes as claimed in claim 7, wherein said compound exhibits go out combination to RXR less than 5000nM.
9. one kind can change application on human skin and/or the Pigmented medicine of hair, cosmetics or dermatological compositions after local application, and it comprises:
(i) aromatics or the heterocyclic carboxylic acid carboxylic acid compound of the replacement described in an amount of at least a claim 1 with tetrahydric naphthalene ring;
Acceptable carrier on (ii) a kind of materia medica, cosmetic conduct and learning or the dermatological; With
(iii) one or more chemical compounds that influence melanocytic melanic generation and/or accumulate are selected from dihydroxy acetone, melanotropin, hydroquinone, monophenyl ether or arbutin.
10. compositions as claimed in claim 9, the amount of wherein said chemical compound are the 0.001-30 weight % with respect to said composition weight.
11. compositions as claimed in claim 9, the amount of wherein said chemical compound are the 0.5-15 weight % with respect to said composition weight.
12. compositions as claimed in claim 9, it is the form that is suitable for local application, and described form is selected from: cream frost, milk, cream gel, liquid emulsion, oil-in-water emulsion, water-in-oil emulsion and vesicle dispersion.
13. compositions as claimed in claim 9, it further comprises at least a following member's of being selected from sub: inorganic and millimicro pigment, wetting agent, vitamin, spice, antiseptic, filler, chelating agen, the dyes and dyestuffs of ion or non-ionic thickening agent, softening agent, antioxidant, opacifying agent, stabilizing agent, emollient, effectively organic sunscreen agent in UV-A and/or UV-B zone, illumination protection.
14. compositions as claimed in claim 9, wherein said compound exhibits goes out the activity to RXR.
15. as the compositions of claim 14, wherein said compound exhibits goes out combination to RXR less than 5000nM.
16. the chemical compound in the cosmetic composition of claim 9 is used to change application on human skin and/or the Pigmented non-therapeutic use of hair.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8447898P | 1998-05-06 | 1998-05-06 | |
| US60/084,478 | 1998-05-06 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1299274A CN1299274A (en) | 2001-06-13 |
| CN1247192C true CN1247192C (en) | 2006-03-29 |
Family
ID=22185213
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB998058858A Expired - Fee Related CN1247192C (en) | 1998-05-06 | 1999-05-06 | Assay for identification of compound that promote meianin prodn. and retinoid-like compounds identified by said assay |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP1082111A4 (en) |
| JP (1) | JP3669925B2 (en) |
| KR (1) | KR100538417B1 (en) |
| CN (1) | CN1247192C (en) |
| AR (1) | AR018340A1 (en) |
| AU (1) | AU762364B2 (en) |
| BR (1) | BR9909599A (en) |
| CA (1) | CA2324001C (en) |
| ID (1) | ID26632A (en) |
| IL (1) | IL138772A0 (en) |
| NO (1) | NO20004723L (en) |
| WO (1) | WO1999056740A1 (en) |
| ZA (1) | ZA200005026B (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19926779A1 (en) * | 1999-06-11 | 2000-12-14 | Basf Ag | Use of substituted vinyl tetrahydronaphthalenes and vinyl benzotetrahydropyrans as light stabilizers |
| US20020034772A1 (en) | 1999-06-29 | 2002-03-21 | Orlow Seth J. | Methods and compositions that affect melanogenesis |
| FR2831439A1 (en) * | 2002-02-14 | 2003-05-02 | Oreal | Cosmetic composition used for coloring or repigmenting skin or hair contains self tanning agent and melanogenesis activator |
| JP4303616B2 (en) * | 2004-03-01 | 2009-07-29 | 花王株式会社 | Detection method of melanosome transfer |
| KR100798853B1 (en) * | 2005-02-15 | 2008-01-28 | (주)한국스티펠 | A pharmaceutical composition comprising retinoid for prevention and treatment of vitiligo |
| WO2008025965A2 (en) * | 2006-08-29 | 2008-03-06 | Reinnervate Limited | Retinoid compounds and their use |
| US9162984B2 (en) | 2007-03-30 | 2015-10-20 | University Of Rochester | Small-molecule modulators of melanin expression |
| EP2755942A2 (en) * | 2011-09-15 | 2014-07-23 | Arizona Board of Regents, a Body Corporate of the State of Arizona acting for and on behalf of Arizona State University | Therapeutic compounds |
| US10328040B2 (en) | 2014-01-17 | 2019-06-25 | Arizona Board Of Regents On Behalf Of Arizona State University | Therapeutic methods |
| WO2018048358A1 (en) * | 2016-09-08 | 2018-03-15 | Agency For Science, Technology And Research | Use of polyamines in compositions and methods for inducing or promoting skin darkening and regulating melanogenesis |
| US10231947B2 (en) | 2017-01-23 | 2019-03-19 | Arizona Board Of Regents On Behalf Of Arizona State University | Isochroman compounds and methods of use thereof |
| US10238626B2 (en) | 2017-01-23 | 2019-03-26 | Arizona Board Of Regents On Behalf Of Arizona State University | Therapeutic compounds |
| US10238655B2 (en) | 2017-01-23 | 2019-03-26 | Arizona Board Of Regents On Behalf Of Arizona State University | Dihydroindene and tetrahydronaphthalene compounds |
| WO2019096546A1 (en) | 2017-11-14 | 2019-05-23 | Unilever N.V. | Peptides for increasing melanin in melanocytes |
| US11419803B2 (en) | 2017-12-06 | 2022-08-23 | Conopco, Inc. | Skin darkening composition |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE195716T1 (en) * | 1992-04-22 | 2000-09-15 | Ligand Pharm Inc | RETINOID-X RECEPTOR SELECTIVE COMPOUNDS |
| US5455265A (en) * | 1993-02-11 | 1995-10-03 | Allergan, Inc. | Method of treatment with compounds having selective agonist-like activity on RXR retinoid receptors |
| US5470577A (en) * | 1993-07-07 | 1995-11-28 | Trustees Of Boston University | Stimulation of tanning by DNA fragments or single-stranded DNA |
| US5824685A (en) * | 1995-02-01 | 1998-10-20 | The Johns Hopkins University School Of Medicine | Method of preventing proliferation of retinal pigment epithelium by retinoic acid receptor agonists |
| FR2735367B1 (en) * | 1995-06-19 | 1997-07-18 | Cird Galderma | USE OF LIGANDS SPECIFIC TO RXRS RECEPTORS |
| FR2735370B1 (en) * | 1995-06-19 | 1997-07-18 | Cird Galderma | METHOD FOR IDENTIFYING AGONIST COMPOUNDS OF RXRS RECEPTORS |
| ES2169804T3 (en) * | 1995-06-23 | 2002-07-16 | Us Gov Health & Human Serv | DEPIGMENTING ACTIVITY OF THE AGUTI SIGNAL PROTEIN AND PEPTIDES OF THE SAME. |
| FR2746101B1 (en) * | 1996-03-14 | 1998-04-30 | BICYCLIC-AROMATIC COMPOUNDS | |
| JP2000509251A (en) * | 1996-03-28 | 2000-07-25 | トラスティーズ オブ ボストン ユニバーシティー | How to regulate melanin synthesis |
| FR2755965B1 (en) * | 1996-11-19 | 1998-12-18 | Cird Galderma | BIAROMATIC COMPOUNDS, PHARMACEUTICAL AND COSMETIC COMPOSITIONS CONTAINING THEM AND USES |
-
1999
- 1999-05-06 CA CA002324001A patent/CA2324001C/en not_active Expired - Fee Related
- 1999-05-06 AU AU38829/99A patent/AU762364B2/en not_active Ceased
- 1999-05-06 CN CNB998058858A patent/CN1247192C/en not_active Expired - Fee Related
- 1999-05-06 EP EP99921689A patent/EP1082111A4/en not_active Withdrawn
- 1999-05-06 KR KR10-2000-7012047A patent/KR100538417B1/en not_active IP Right Cessation
- 1999-05-06 JP JP2000546767A patent/JP3669925B2/en not_active Expired - Fee Related
- 1999-05-06 BR BR9909599-8A patent/BR9909599A/en not_active Application Discontinuation
- 1999-05-06 IL IL13877299A patent/IL138772A0/en unknown
- 1999-05-06 AR ARP990102143A patent/AR018340A1/en unknown
- 1999-05-06 ID IDW20002069A patent/ID26632A/en unknown
- 1999-05-06 WO PCT/US1999/009845 patent/WO1999056740A1/en active IP Right Grant
-
2000
- 2000-09-20 ZA ZA200005026A patent/ZA200005026B/en unknown
- 2000-09-21 NO NO20004723A patent/NO20004723L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| IL138772A0 (en) | 2001-10-31 |
| JP3669925B2 (en) | 2005-07-13 |
| NO20004723L (en) | 2000-11-06 |
| KR20010043147A (en) | 2001-05-25 |
| EP1082111A4 (en) | 2004-03-10 |
| ZA200005026B (en) | 2001-05-22 |
| AU3882999A (en) | 1999-11-23 |
| NO20004723D0 (en) | 2000-09-21 |
| CN1299274A (en) | 2001-06-13 |
| ID26632A (en) | 2001-01-25 |
| EP1082111A1 (en) | 2001-03-14 |
| WO1999056740A1 (en) | 1999-11-11 |
| CA2324001A1 (en) | 1999-11-11 |
| KR100538417B1 (en) | 2005-12-22 |
| CA2324001C (en) | 2007-08-07 |
| AR018340A1 (en) | 2001-11-14 |
| AU762364B2 (en) | 2003-06-26 |
| BR9909599A (en) | 2001-09-25 |
| JP2002513756A (en) | 2002-05-14 |
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