COSMETIC COMPOSITION, NON-THERAPEUTIC METHODS TO REDUCE OR TREAT SKIN AGING SIGNS AND TO PREVENT, LI

专利摘要:
abstract “cosmetic or dermatological composition, methods for the regulation or prevention of a skin condition, for the reduction or treatment of the signs of skin aging, for the prevention, whitening or reduction of the appearance of visible discontinuities of the skin and use of a composition ”The present invention relates to methods and compositions comprising resorcinol derivatives for the use of treating, regulating or preventing a skin condition characterized by oxidative stress, or a degenerative process. the present invention also relates to methods of preventing, lightening or reducing the appearance of visible discontinuities of the skin resulting from skin pigmentation, skin aging, or other disorders.
公开号:BR112015021033B1
申请号:R112015021033-3
申请日:2014-03-06
公开日:2020-08-04
发明作者:Andrew W. Hinman；Dana Davis；Viktoria Kheifets
申请人:Unilever N.V；
IPC主号:

专利说明:

CROSS REFERENCE TO RELATED PATENT APPLICATION
[001] The present patent application claims the priority benefit of the provisional patent application US 1961 / 775,384, filed on March 8, 2013. The total contents of this patent application are incorporated herein by reference. FIELD OF THE INVENTION
[002] The present invention relates to cosmetic and dermatological compositions, such as resorcinol derivatives, with anti-aging properties, uniform skin toning and other properties useful for skin treatment. BACKGROUND OF THE INVENTION
[003] The natural appearance of the skin is influenced by a number of physiological and genetic factors. Standard definitions of beautiful skin include skin that has a transparent quality with uniform tones of color and without visible or tactile discontinuities. The basis for this natural appearance is the structure of the skin itself. The outer layer of human skin is a semitransparent layer known as the stratum corneum. The transparency of the stratum corneum allows for glimpses of the deeper layers of the skin, in which the blood vessels and pigments meet. The pale reddish hue of blood vessel hemoglobin, and the brown / black hue of melanin, which is the skin's primary pigment, combine to produce skin color. The ideal skin should also be smooth and uniform, with no visible surface defects, in addition to having a transparent appearance with uniform color distribution.
[004] The skin is composed of an upper layer, the epidermis, which is from about 20 layers of cells or about 0.1 mm thick, and a lower layer, the dermis, which is from about 1 to about 4 mm thick and contains small vessels of blood, collagen, elastin and fibroblasts. The dermis provides structural support and nutrients for the epidermis. Aging has been shown to increase cell heterogeneity in the epidermal layer. Aging does not affect the number of cell layers in the epidermis, but the total thickness is reduced. The supporting dermis is known to thin with age and exposure to the sun and environmental contaminants. The dermal layer provides support and blood supply to the epidermis, therefore, the dermal layer is important in maintaining the skin's elasticity and appearance.
[005] Considerable effort is spent to find ways to prevent adverse skin changes caused by exposure to ultraviolet (UV) radiation and other causes. Preventive approaches include blocking or physically absorbing UV radiation before it can enter the skin using UV-absorbing compounds. Skin problems in aging individuals can result from a variety of extrinsic or intrinsic factors, such as harmful UV radiation from the sun, exposure to the environment, stress, fatigue, illness, or one of its combinations.
[006] Many people at different stages of their lives are concerned with the degree of pigmentation of their skin and may want to reduce skin darkening, or may want to lighten or even tone their natural skin color. The mechanism by which skin pigmentation is formed, melanogenesis, is especially complex and schematically involves the following main steps: Tyrosine L-Dopa Dopaquinona -> Dopachromo -> Melaninas. The first two reactions in this series are catalyzed by the enzyme's tyrosinase. Tyrosinase activity is promoted by the action of α-melanocyte stimulating hormone or UV rays. It is well established that a substance has a depigmentation effect if it acts directly on the vitality of melanocytes in the epidermis in which melanogenesis normally occurs and / or interferes with one of the stages of melanin biosynthesis. Pigmentation disorders can take a variety of forms, such as hyperpigmentation, hypopigmentation, and irregular pigmentation, and include, but are not limited to melasma (pregnancy mask or chloasma), liver spots (which often develop with age ) and leucoderma such as vitiligo. Some of the pigmentations occur as a side effect of birth control pills, as a result of a skin lesion, as a persistent result of acne, burns, stings and other skin lesions, such as post-burn scars, such as scar blemishes, such as as the scars of stretch marks and, such as dark circles and puffiness under and around the eyes. The degree of skin pigmentation disorders in many cases increases with the age of individuals. Because of tyrosinase involvement in melanogenesis, tyrosinase inhibition analyzes are often used to screen for potential skin lightening agents. Some mushroom tyrosinases (such as from Agaricus bisporus) are homologous with mammalian tyrosinase, and mushroom tyrosinase is often used in inhibition analyzes due to its ready commercial availability. However, enzyme inhibition analyzes may not be a good indicator of activity like analyzes that are more similar to the intended clinical or cosmetic use, such as the MatTek Corporation's MelanoDerm ™ Skin Model (a system consisting of keratinocytes in the epidermis derived from normal human and melanocytes formed in a multilayer model of human epidermis).
[007] In the United States, the most widely used treatment for hyperpigmentation is 1,4-benzenediol, which is known as hydroquinone. Treatment with hydroquinone interferes with the action of tyrosinase, which is an enzyme used in the synthesis of melanin, and the compositions are sold over the counter in about 2% hydroquinone and by prescription in higher concentrations. Hydroquinone compositions are effective, but have some undesirable side effects. These can be burning, redness, irritation and sensitization in some patients. US patent 4,526,179 refers to certain hydroquinone fatty esters that have good activity and are less irritating and more stable than hydroquinone. Japanese patent application 27909/86 (JP 1961-27,909) relates to other hydroquinone derivatives which do not have the drawbacks of hydroquinone, but which have relatively little effectiveness. Other compounds with a hydroquinone core structure have been described in the patent literature, for example, US patent 5,449,518 refers to 2,5-dihydroxyphenyl carboxylic acid derivatives, and European patent application EP 341,664A1 and international publication PCT WO 1999/15148 refer to certain resorcinol derivatives as tyrosinase inhibitors.
[008] A variety of additional agents are applied to the skin to lighten the skin. Such agents include, but are not limited to, cojic acid, licorice and its derivatives, ascorbic acid and its derivatives, arbutin, bearberry, Glycyrrhiza glabrae its derivatives, Chlorella vulgaris extract, Peril la extract, and coconut fruit extract. Perilla extract is described as a bleaching agent in US patent 5,980,904 and Japanese publications 07-025742, 07-187989, 10-265322, 2001 -163759 and 2001 -181173. The coconut fruit extract is described as a bleaching agent in Japanese patent 2,896,815 B2.
[009] Resorcinol derivatives (1,3-benzenediol) are used to provide cosmetic benefits for skin and hair. The 4-substituted resorcinol derivatives are used for skin lightening; see, for example, US patent 4,959,393, US patent 6,132,740, US patent 6,504,037, US patent application publication 2008 / 0.131,382, and Japanese patent applications published JP 2001 / 010.925 and JP 2,000 / 327,557. Resorcinol-derived dimers, which are tyrosinase inhibitors, are described in US patent 5,399,785. Resorcinol-type skin whitening agents, which can be synthesized using coumarin as a starting material, are described in US patent application publication 2004 / 0.042,983. However, some of these compounds can be difficult to formulate, or can cause skin irritation.
[010] It would be desirable to have a safe and non-toxic composition for the treatment or prevention of pigmentation disorders. The compounds and compositions described herein comprise resorcinols to meet this need. BRIEF DESCRIPTION OF THE INVENTION
[011] The present invention relates to methods for reducing or enhancing the appearance of visible discontinuities in the skin, associated with damage associated with age, or damage resulting from ultraviolet radiation, such as those contained in sunlight, pollution and other aggressions environmental stress or fatigue. In addition, methods for reducing the appearance of color due to pigmentation disorders are also provided at present. Compositions and methods for improving the appearance of the skin are also provided by mitigating the skin discoloration associated with age and simultaneously reducing the appearance of color due to pigmentation disorders. Also provided are resorcinol derivatives for reducing or preventing the appearance of skin pigmentation and the resulting skin problems that arise with age, and compositions comprising such resorcinol derivatives, such pharmaceutically acceptable compositions, including pharmaceutically acceptable compositions topical.
[012] Methods for reducing or enhancing the appearance of pigmentation or discoloration on the skin are also provided. Also provided are methods for reducing age spots, liver spots, and other pigmentation disorders associated with age, and methods for treating pigmentation disorders, such as vitiligo and melasma. The methods include applying a therapeutically or cosmetically effective amount of the compounds to the skin in an amount sufficient to reduce or enhance the appearance of pigmentation or discoloration on the skin, or in an amount sufficient to reduce age spots, age spots. liver, or other associated pigmentation disorders, or in an amount sufficient to treat a pigmentation disorder, such as melasma and vitiligo. Also provided are compounds for use in reducing or enhancing the appearance of pigmentation or discoloration on the skin, or for use in reducing age spots, liver spots, or other pigmentation disorders associated with age, or for use in the treatment of pigmentation diseases, such as vitiligo and melasma.
[013] The resorcinol derivatives provided herein, which are defined below and are used in the various methods provided herein, are useful in the treatment or prevention of one or more dermatological conditions, as desired by the individual to be treated, as for medicinal or cosmetic purposes, such as for the prevention, whitening, reduction or treatment of signs or undesirable appearance of skin pigmentation affected by one or more conditions.
[014] A cosmetic or dermatological composition comprising one or more Formula I resorcinols is provided here:
where R1 and R2, independently, are alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or halogen, each of alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with -OH, -OR3, - NR3R4, -C (O) OR3, -C (O) NR3R4, or halogen; and R3 and R4, independently, are hydrogen, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, aryl, or heteroaryl; or a pharmaceutically acceptable salt thereof. Mixtures of two or more compounds of Formula I are also provided. In some variations, R1 is alkyl or halogen, and R2 is alkyl or cycloalkyl. In some variations, R1 is alkyl, just like methyl. In some variations, R1 is haloalkyl, perhaloalkyl, fluoroalkyl or perfluoroalkyl, such as trifluoromethyl. In some variations, R1 is halogen, such as fluorine, chlorine, bromine, or iodine. In some variations, R1 is fluoro or chloro. In some variations, R2 is alkyl, such as ethyl or hexyl. In some variations, R2 is cycloalkyl, as is cyclohexyl.
[015] In some variations, R1 is alkyl (CI-CΘ), alkenyl (C2-C6), cycloalkyl (Ca-Ce), heterocycloalkyl (Ca-Cs), aryl (C6-C12), heteroaryl (C3-C12) ), or halogen, each of alkyl (C1-Cβ), alkenyl (C2-C6), cycloalkyl (Ca-Ce), heterocycloalkyl (Ca-Ce), aryl (C6-C12), or heteroaryl (C3-C12) is optionally substituted with one, two, or three substituents selected from the group consisting of -OH, -OR3, -NR3R4, -C (O) OR3, -C (O) NR3R4, or halogen; and R2 is alkyl (Ci-Ce), alkenyl (C2-C6), cycloalkyl (Cs-Cs), heterocycloalkyl (Cs-Ce), aryl (CΘ-C12), heteroaryl (C3-C12), or halogen, each one of alkyl (CI-CΘ), alkenyl (C2-C6), cycloalkyl (Cs-Cs), heterocycloalkyl (Cs-Cβ), aryl (CΘ-C12), or heteroaryl (C3-C12) is optionally substituted with one, two, or three substituents selected from the group consisting of -OH, -OR3, -NR3R4, -C (O) OR3, C (O) NR3R4, or halogen.
[016] In some variations, R1 is alkyl (CI-CΘ), alkenyl (C2-CΘ), cycloalkyl (Cs-Cs), heterocycloalkyl (Cs-Cs), aryl (C6-C12), heteroaryl (C3-C12) ), or halogen, each of alkyl (CI-CΘ), alkenyl (C2-C6), cycloalkyl (C3-C8), heterocycloalkyl (Cs-Cs), aryl (C6-C12), or heteroaryl (C3-C12) it is optionally substituted with one, two, or three substituents selected from the group consisting of -OH, -OR3, -NR3R4, -C (O) OR3, -C (O) NR3R4, or halogen; and R2 is cycloalkyl, such as cycloalkyl (Cs-Cs), such as cyclohexyl.
[017] In some variations, R3 and R4, independently, are hydrogen, alkyl (CI-CΘ), alkenyl (C2-C6), cycloalkyl (Ca-Cs), heterocycloalkyl (Cs-Cs), cycloalkyl (C3-Cs) ) -alkyl (CI-CΘ), heterocycloalkyl (C3-Cs) -alkyl (CI-CΘ), aryl (Cθ-Ci2) -alkyl (CI-CΘ), heteroaryl (C3-Ci2) -alkyl (CI-CΘ) , aryl (C6-C12), or heteroaryl (C3-C12).
[018] In some variations, R1 is alkyl (CI-CΘ), alkenyl (C2-CΘ), cycloalkyl (Cs-Cβ), or halogen, and R2 is alkyl (CI-CΘ), alkenyl (C2-C6), or cycloalkyl (Cs-Cs).
[019] In some variations, R1is alkyl (CI-CΘ) OUhalogen, and R2is alkyl (CI-CΘ) OR cycloalkyl (Cs-Cs).
[020] In some variations, R1is methyl, fluoro, or trifluoromethyl, and R2is ethyl, hexyl, or cyclohexyl.
[021] According to the invention, the cosmetic or dermatological composition contains one or more of the following compounds:
or a pharmaceutically acceptable salt thereof.
[022] In some variations, cosmetic and dermatological compositions comprising one or more compounds of Formula I can be used for the prophylaxis and treatment of cosmetic and dermatological changes in the skin in an individual in need thereof, such as skin pigmentation undesirable or changes in skin pigmentation or skin tone, which is achieved by administering an effective amount of one or more of the compositions to the individual. In some variations, changes in the skin are produced through degenerative or oxidative processes.
[023] In some variations, cosmetic compositions that comprise one or more compounds of Formula I can be used to prevent, clear or reduce the visible signs of aging in an individual, which is achieved by administering an effective amount of one or more of the compositions for the individual. In some variations, cosmetic and dermatological compositions comprising one or more compounds of Formula I can be used in an individual to reduce the appearance of visible and / or tactile discontinuities of skin coloring associated with aging, age-related damage , or damage resulting from harmful factors, such as those contained in sunlight, ultraviolet radiation, pollution and other environmental aggressions, stress, or fatigue, which is achieved by administering an effective amount of one or more of the compositions to the individual .
[024] In some variations, cosmetic and dermatological compositions comprising one or more compounds of Formula I can be used on an individual, for the prophylaxis or treatment of dermatological conditions including skin irregularity or pigmentation, which is achieved by administering an effective amount of one or more of the compositions to the individual.
[025] In some variations, cosmetic and dermatological compositions comprising one or more compounds of Formula I can be used in a patient, for the prevention, whitening or reduction of the appearance of visible and / or tactile discontinuities of the skin, such as stains, which is achieved by administering an effective amount of one or more of the compositions to the individual.
[026] In some variations, cosmetic and dermatological compositions comprising one or more compounds of Formula I can be used on a patient, for the prevention, whitening or reduction of the appearance of visible discontinuities of the skin resulting from the aging processes, which it is achieved by administering an effective amount of one or more of the compositions to the individual.
[027] In some variations, cosmetic and dermatological compositions comprising one or more compounds of Formula I can be used on an individual to prevent, lighten or reduce the appearance of visible discontinuities of the skin, such as pigmentation, age spots , vitiligo and melasma, which is achieved by administering an effective amount of one or more of the compositions to the individual.
[028] In some variations, cosmetic and dermatological compositions comprising one or more compounds of Formula I can be used in an individual to prevent, lighten or reduce the appearance of visible discontinuities of the skin, such as coloring, discoloration, or pigmentation resulting from stress, fatigue, or extrinsic aggressions such as harmful factors contained in sunlight, ultraviolet radiation, pollution and other environmental aggressions, which is achieved by administering an effective amount of one or more of the compositions to the individual.
[029] In some variations, cosmetic and dermatological compositions comprising one or more compounds of Formula I can be used to prevent, lighten or reduce the appearance of dark circles, dark spots and uneven skin tone, which is achieved through administering an effective amount of one or more of the compositions to the individual.
[030] In another variation, cosmetic and dermatological compositions comprising one or more compounds of Formula I can be used to reduce the appearance of visible discontinuities in the skin associated with inflammation, which is achieved by administering a quantity effectiveness of one or more of the compositions for the individual. Visible discontinuities can be caused by hypopigmentation or post-inflammatory hyperpigmentation. The inflammation can be due to several causes. Inflammation can be caused by rosacea. Inflammation can be caused by diaper rash. Inflammation can be caused by acne. Inflammation can be caused by dermatitis such as atopic dermatitis, contact dermatitis, or seborrheic dermatitis. Inflammation can be caused by poison ivy or poison oak. Inflammation can be caused by erythema. Inflammation can be caused by psoriasis.
[031] Also provided herein is a cosmetic composition comprising a cosmetically acceptable or dermatologically acceptable carrier, in combination with any one or more of the compounds of Formula I. The carrier can be formulated for topical use.
[032] Also provided herein is a cosmetic composition that comprises a pharmaceutically acceptable carrier in combination with any one or more of the compounds of Formula I.
[033] In a variation, non-therapeutic methods for reducing the appearance of visible discontinuities in the skin, such as coloring, discoloration, or pigment discontinuities, are also provided in the present with a composition comprising one or more compounds of Formula I, wherein the composition is included in a topical formulation, which comprises administering an effective amount of the composition to an individual.
[034] In a variation, non-therapeutic methods for reducing the appearance of visible discontinuities in the skin such as coloring, discoloration, or pigment discontinuities are also provided in the present, with a composition comprising one or more compounds of Formula I, wherein the composition is included in a topical pharmaceutical formulation, which comprises administering an effective amount of one or more compounds of Formula I to an individual. In other embodiments, administration is topical or dermatological administration. The composition can comprise pharmaceutically and / or dermatologically acceptable vehicles and vehicles.
[035] In a variation, non-therapeutic methods for reducing the appearance of visible discontinuities in the skin such as coloring, discoloration, or pigment discontinuities are also provided in the present, with a composition comprising one or more compounds of Formula I, wherein the composition is formulated for transdermal administration, which comprises administering an effective amount of one or more compounds of General Formula I to the skin of an individual. The composition can comprise pharmaceutically and / or dermatologically acceptable vehicles and vehicles.
[036] A non-therapeutic method for whitening an individual's skin is also provided herein, providing the reduction or treatment or prevention of signs of skin aging, which comprises administering to said individual an amount of one or more Formula I compounds effective for uniform toning, skin lightening or pigmentation reduction. In other embodiments, administration is topical or dermatological administration. In a special variation, a non-therapeutic method is provided in the present to lighten the skin of an individual in need of said treatment, providing the reduction or treatment or prevention of the signs of aging of the skin, which comprises the administration to said individual of an amount of a composition comprising a compound of Formula I effective for uniform toning, lightening the skin or reducing pigmentation in the skin. In other embodiments, administration is topical or dermatological administration. The composition can comprise pharmaceutically and / or dermatologically acceptable vehicles and vehicles.
[037] In addition, a non-therapeutic method for enhancing the appearance of an individual's skin is provided, which comprises administering to that individual an amount of a composition comprising a Formula I compound effective in reducing pigmentation . In other embodiments, administration is topical or dermatological administration. In a special variation, a non-therapeutic method for reducing or preventing the appearance of pigmentation in an individual in need of said treatment is provided herein, which comprises administering to said individual an amount of a composition comprising a compound of Formula I effective for reducing the appearance of pigmentation in an individual, or for preventing the appearance of pigmentation in an individual. The composition can comprise pharmaceutically and / or dermatologically acceptable vehicles and vehicles. In some variations, a non-therapeutic method is provided for treating pigmentation or reducing the appearance of pigmentation or prophylaxis against the appearance of pigmentation, by administering an effective amount of a composition comprising a Formula I compound. variations the individual a pigmentation disorder selected from age spots, vitiligo and melasma.
[038] In another variation, a non-therapeutic method is provided for the treatment or regulation of a skin condition characterized by oxidative stress which comprises administering to an individual who exhibits said skin condition, a composition comprising one or more compounds of Formula I. The composition may comprise pharmaceutically and / or dermatologically acceptable vehicles and vehicles. In other embodiments, administration is topical or dermatological administration.
[039] In another variation, a non-therapeutic method for regulating and / or preventing visible signs of skin aging is provided at present, comprising administration to an individual, who exhibits skin damage due to aging, from a composition comprising one or more compounds of Formula I. The composition may comprise pharmaceutically and / or dermatologically acceptable vehicles and vehicles. In other embodiments, administration is topical or dermatological administration.
[040] In another variation, a non-therapeutic method for regulating and / or preventing visible skin damage due to extrinsic factors is presently provided, which includes administering to an individual, who exhibits skin damage, a composition comprising an effective amount of one or more compounds of Formula I. The composition may comprise pharmaceutically and / or dermatologically acceptable vehicles and vehicles. In other embodiments, administration is topical or dermatological administration. Extrinsic factors may include, but are not limited to, diaper rash, erythema, UV radiation damage, sunburn, photoaging, contact dermatitis, and combinations thereof.
[041] A non-therapeutic method for reducing the appearance of pigmentation and aging processes on the skin of an individual is also provided herein, which comprises administering to said individual an amount of a composition comprising one or more compounds of Formula I effective for reducing the appearance of pigmentation, or for preventing the appearance of pigmentation, in combination with another therapeutic agent. In a variation, a non-therapeutic method for reducing the appearance of pigmentation, or for preventing the appearance of pigmentation, is provided in the skin of an individual, which comprises administering to said individual an effective amount of a composition which comprises one or more compounds of Formula I in combination with an antioxidant. In a variation, a method is presently provided for reducing the appearance of pigmentation and aging processes, or for preventing the appearance of pigmentation and aging processes, in an individual in need of said treatment, which comprises administering said individual of an effective amount of a composition comprising one or more compounds of Formula I in combination with ascorbic acid or its derivatives. In another variation, a non-therapeutic method for reducing the appearance of pigmentation and aging processes, or for preventing the appearance of pigmentation and aging processes, is provided in an individual in need of said treatment, which comprises administering to said individual an effective amount of a composition comprising one or more compounds of Formula I in combination with alpha-tocopherol or any mixture of tocopherols or their derivatives. In another variation, a non-therapeutic method for reducing the appearance of pigmentation and aging processes, or for preventing the appearance of pigmentation and aging processes, is provided in an individual in need of said treatment, which comprises administering to said individual an effective amount of a composition comprising one or more compounds of Formula I in combination with alpha-tocotrienol or any mixture of tocotrienols or their derivatives. In another variation, a non-therapeutic method is provided in the present to reduce the appearance of pigmentation and aging processes, or to prevent the appearance of pigmentation and aging processes, in an individual in need of said treatment, which comprises administering to said individual an effective amount of a composition comprising one or more compounds of Formula I in combination with any mixture of tocopherols and tocotrienols or their derivatives. In yet another variation, a non-therapeutic method is provided in the present to reduce the appearance of pigmentation and aging processes, or to prevent the appearance of pigmentation and aging processes, in an individual in need of said treatment, which includes administration said individual of an effective amount of a composition comprising one or more compounds of Formula I in combination with ascorbic acid and alpha-tocopherol or derivatives thereof. In other variations, a non-therapeutic method is presently provided for reducing the appearance of pigmentation and aging processes, or for preventing the appearance of pigmentation and aging processes, in an individual in need of said treatment, which includes administration to said individual of an effective amount of a composition comprising one or more compounds of Formula I in combination with retinoids or an exfoliating agent. When administered in combination, the therapeutic agents can be formulated as separate compositions that are delivered at the same time or at different times, or the therapeutic agents can be delivered as a single composition. The composition may also comprise pharmaceutically and / or dermatologically acceptable vehicles and vehicles. In any of the foregoing embodiments, the administration can be topical or dermatological administration.
[042] Also provided herein is a product that comprises instructions that direct a user to apply a composition that includes a composition for treating the skin that comprises one or more compounds of Formula I. The composition may comprise vehicles and vehicles pharmaceutically and / or dermatologically acceptable.
[043] A kit is also provided in the present, comprising a container comprising one or more specific compounds or dermatological compositions described herein that lighten the skin pigmentation. The set can also comprise the instructions as a label or an information leaflet guiding the use of the included compound or composition to lighten skin pigmentation.
[044] The use of a composition of any of the previous variations in the production of a cosmetic or dermatological composition for the treatment of a mammalian individual, such as a human, who presents a dermatological condition, in which the Treatment is for the prevention, reduction or treatment of signs of skin aging or skin pigmentation, or for reducing the appearance of skin aging or skin pigmentation.
[045] For all the compositions described herein, and all methods using a composition described herein, the compositions may include the components or steps mentioned, or they may "consist essentially" of the indicated components or steps. When a composition is described as “essentially consists” of the listed components, the composition contains the listed components, and may contain other components, which do not substantially affect the skin or skin condition to be treated, but do not contain any other component than substantially affects the skin or skin condition to be treated, with the exception of the components expressly listed; or, if the composition contains additional components other than those listed that substantially affect the skin or skin condition being treated, the composition does not contain a sufficient concentration or quantity of the additional components to substantially affect the skin or skin condition that is being treated. being treated. When a method is described as “essentially consists” of the steps mentioned, the method includes the steps indicated, and may contain other steps that do not substantially affect the skin or skin condition to be treated, but the method does not contain any other steps that substantially affects the skin or skin condition to be treated, with the exception of the steps expressly listed. DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS
[046] As used herein, the term "individual" or "patient" is a mammal, especially a human. It should be understood that the use of "in" an individual or patient may also comprise the use of "in" an individual or patient; that is, the use of “in” an individual or patient can comprise internal use, external use, or both, according to the context of use.
[047] As used herein, the terms "uniform toning", "bleaching", "bleaching" and "depigmentation" are used interchangeably throughout the present invention. For skin whitening purposes, the topical application of the skin whitening agent should have a whitening effect only on the area to be treated, preferably it does not produce any or minimal irritation, preferably it does not produce any or minimal pigmentation secondary post-inflammatory and preferably does not cause an allergic reaction. In addition, skin lightening should be effective for normal skin pigmentation and its excesses, including, but not limited to, senile lentigo, chloasma, brown scar spots, and hyperpigmentation after using photosensitization products. Preferably, skin whitening should be effective, simultaneously, providing the anti-aging benefits of the skin.
[048] As used herein, the term amount "for skin lightening or pigmentation reduction of a Formula I compound", means a quantity or concentration of the compound capable of detectably lightening or reducing skin pigmentation in a individual, such as a human, as determined by any standard analysis. The active compound is usually administered in a pharmaceutical or dermatological composition for a standard course of treatment that produces the desired skin depigmentation result.
[049] As used herein, the term “administration to the skin in need of such treatment” means that contact (for example, through the use of hands or an applicator, such as, but not limited to, a cloth, tube, roller , spray or adhesive) of the area of the skin in need of such treatment or of an area of skin in the vicinity of the area of the skin in need of such treatment.
[050] As used herein, the term "composition" means a composition suitable for topical administration to the skin.
[051] As used in the present, the term "cosmetic" includes makeup, foundation, and skin care products. The term "makeup" refers to products that leave color on the face, including foundations, blacks and browns, for example, mascara, concealers, eyeliner, eyebrow pencil, eye shadows, blushers, lipsticks, and so on. The term “foundation” refers to products of the liquid, cream, mousse, pancake, compact, or concealer type, which uniform the overall color of the skin. The foundation is usually produced to work better on hydrated and / or oiled skin. The term "skin care products" refers to products used for treatment or also for skin care, hydration, enhancement or cleansing. Products covered by the term “skin care products” include, but are not limited to, adhesives, bandages, anhydrous occlusive moisturizers, antiperspirants, facial wash products, cold cream, deodorants, soaps, occlusive drug release dressings, powders, scarves, cleaning cloths, solid compact emulsion, anhydrous hair conditioners, medicinal shampoos, scalp treatments and the like.
[052] As used herein, the term "cosmetically acceptable" or "dermatologically acceptable" means that its compositions or the components described in this way are suitable for use in contact with the skin, especially human skin, without toxicity, incompatibility , instability, irritation, or undue allergic response.
[053] As used herein, the term "cosmetically acceptable carrier", "cosmetically acceptable carrier", "dermatologically acceptable carrier" or "dermatologically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents , and isotonic and similar absorption delay agents, which are cosmetically acceptable or dermatologically acceptable. The use of such means and agents for cosmetically active substances is well known in the art. Except to the extent that any conventional medium or agent is incompatible with the active ingredient, its use in cosmetic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. Dermatologically acceptable vehicles that are suitable for topical application to the skin, have good aesthetic properties, are compatible with the active agents described herein and any other components, and cause minimal or no safety or toxicity concerns. A safe and effective amount of the vehicle is from about 50% to about 99.99% or from about 50% to about 99%, preferably from about 80% to about 99.9 % or from about 75% to about 99%, more preferably from about 90% to about 98% and most preferably from about 90% to about 95% or about 85% to about 95% of the composition. The percentages are preferably percentages by weight.
[054] As used herein, the term "effective amount" refers to that amount of a compound described herein that is sufficient to effect treatment, as defined below, when administered to an individual in need of such treatment. The effective amount will vary depending on the individual and the condition of the skin or condition of the disease being treated and the like, all of which can be readily determined by a person skilled in the art.
[055] As used herein, the term "regulating a skin condition" includes regulating the appearance of a skin condition, including discontinuities visible on the skin such as, but not limited to, discoloration, discoloration, and unwanted pigmentation. The regulation of a skin condition still includes uniform skin toning and reduced pigmentation.
[056] As used herein, the term "signs of skin aging" includes, but is not limited to, all external manifestations of skin aging, which are visibly perceptible due to changes in skin pigmentation, skin color, or discoloration of the skin. These signals can be induced or caused by intrinsic or extrinsic factors, for example, chronological aging and / or environmental damage (for example, sunlight; UV; smoke, including cigarettes, cigars or other tobacco products; ozone; pollutants stress and the like). These signs include, but are not limited to, the spot (eg, uneven red color due to, for example, rosacea), pallor (pale color), discoloration caused by telangiectasia or arachnid vessels; hyperpigmented (or unevenly pigmented) skin regions related to melanin, such as age spots (liver spots, brown spots) and freckles; post-inflammatory hyperpigmentation or hypopigmentation, such as that occurring after an inflammatory event (for example, as an acne lesion, growing hair, insect / spider bite or bite, scratch, cut, sore, abrasion, and the like) ; and tissue responses to attacks such as itching or itching.
[057] As used herein, the terms "skin condition", "dermatological condition" and "dermal condition" are used interchangeably.
[058] As used herein, the term "sunscreen" may include, but is not limited to, organic or inorganic sunscreens, such as methoxycinnamate, oxybenzone, avobenzone and the like; sun blockers, such as titanium oxide and zinc oxide; and skin protectors; or their mixtures.
[059] As used herein, the term "topical application" means to apply or spread the compositions described herein on the surface of the skin.
[060] As used herein, the terms "treat" and "treatment" and the like refer to the reversal, mitigation, or inhibition of the progress of the disorder or condition to which that term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, refers to the act of treatment, just as the term "treatment" is defined immediately above. The term "treatment" or "treating" includes reducing the appearance of skin imperfections irrelevant to the mechanism of action. A common practitioner will consider that the final stage of treatment selected in a special case will vary according to the disease, condition or disorder being treated, the outcome desired by the patient, individual, or physician responsible for the treatment and other factors . When the composition is used to lighten the skin color, such as, for example, to reverse the hyperpigmentation caused, for example, by diseases such as melasma or age spots, any of a series of final stages can be selected. For example, the final stages can be subjectively defined such as, for example, when the individual is simply "satisfied" with the results of the treatment. For pharmacological compositions, the final stage can be determined by the satisfaction of the individual, the patient, or the physician responsible for the treatment, with the results of the treatment. Alternatively, the final stages can be defined objectively. For example, the skin of the individual or the patient in the treated area can be compared to a color scale. Treatment is terminated when the skin color in the treated area is similar in appearance to a color on the scale. Alternatively, the reflectance of the treated skin can be measured, and the treatment can be terminated when the treated skin reaches a specified reflectance. Alternatively, the melanin content of the treated skin can be measured. The treatment can be terminated when the melanin content of the treated skin reaches a specified value. The melanin content can be determined in any way known in the art, including through histological methods, with or without melanin patch intensification.
[061] As used herein, the term "alkyl" is intended to encompass a straight or branched hydrocarbon chain containing the specified number of carbon atoms. In one embodiment, the alkyl groups can contain from 1 to 12 carbon atoms. The term "alkylene" is intended to encompass a straight or branched divalent hydrocarbon chain containing the specified number of carbon atoms. In one embodiment, alkylene groups can contain from 1 to 12 carbon atoms.
[062] As used herein, the term "cycloalkyl" is intended to include a saturated cyclic hydrocarbon chain containing the specified number of carbon atoms. In one embodiment, the cycloalkyl groups can contain 3 to 12 carbon atoms.
[063] As used herein, the term "alkenyl" is intended to encompass a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond. In one embodiment, alkenyl groups can contain 2 to 12 carbon atoms. The term "alkenylene" is intended to encompass a straight or branched divalent hydrocarbon chain with at least one carbon-carbon double bond, and containing the specified number of carbon atoms. In one embodiment, alkenylene groups can contain from 2 to 12 carbon atoms.
[064] As used herein, the term “haloalkyl” indicates an alkyl group in which at least one hydrogen atom in the alkyl group has been replaced by a halogen substituent, which is a fluorine (F) substituent, chlorine ( Cl), bromine (Br), or iodine (I). The term "perhaloalkyl" indicates an alkyl group in which all available valences have been replaced by halogen. For example, the term "perhaloethyl" can refer to CCI2CF3, CF2CBrs or CCI2CCI3.
[065] As used herein, the term "fluoroalkyl" means an alkyl group in which at least one hydrogen atom in the alkyl group has been replaced by a fluorine substituent. The term "perfluoroalkyl" means an alkyl group in which all available valences have been replaced by fluorine. For example, the term "perfluoroethyl" refers to CF2CF3.
[066] As used herein, the term "chloroalkyl" indicates an alkyl group in which at least one hydrogen atom in the alkyl group has been replaced by a chlorine substituent. The term "perchloralkyl" indicates an alkyl group in which all available valences have been replaced by chlorine. For example, the term "perchlorethyl" refers to CCI2CCI3.
[067] As used herein, the term "aryl" is defined as an optionally substituted aromatic ring system, such as phenyl or naphthyl. Aryl groups include monocyclic aromatic rings and polycyclic aromatic ring systems containing the specified number of carbon atoms. In one embodiment, aryl groups can contain six to twenty carbon atoms. In other embodiments, aryl groups can contain six to twelve carbon atoms, or six to ten carbon atoms. In other embodiments, aryl groups may be unsubstituted. In other embodiments, aryl groups can be replaced.
[068] As used herein, the term "heterocycloalkyl" is intended to encompass an optionally substituted cyclic hydrocarbon chain containing the specified number of carbon atoms and one or more hetero atoms (such as one to three hetero atoms, such as 0 oxygen, nitrogen , sulfur and phosphorus). In one embodiment, heterocycloalkyl groups can contain from 3 to 12 carbon atoms and from 1 to 3 hetero atoms. Examples of heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, piperidinyl and piperazinyl. In some embodiments, heterocycloalkyl groups may be unsubstituted. In other embodiments, heterocycloalkyl groups can be substituted.
[069] As used herein, the term "heteroaryl" is defined as an optionally substituted aromatic ring system, containing the specified number of carbon atoms, and one or more heteroatoms (such as one to three heteroatoms), in that heteroatoms include, but are not limited to oxygen, nitrogen, sulfur and phosphorus. In some embodiments, the hetero ring groups may contain 3 to 12 carbon atoms and one to three hetero atoms, or six to ten carbon atoms and one to three hetero atoms. In some embodiments, heteroanla groups may be unsubstituted. In other embodiments, heteroanla groups can be substituted. Examples of heteroanla groups include, but are not limited to, imidazolyl, pyrrolyl and pyridinyl.
[070] As used herein, the term “tocopherols or tocotrienols” includes a family of molecules characterized by a 6-chromanol ring structure and a secondary chain in position 2. Tocopherols have a secondary chain of phytol 4 ', 8 ', 12'-trimethylatridecyl, while tocotrienols have an unsaturated phytol secondary chain. As used herein, the term “tocopherol or tocotrienols” means alpha, beta, gamma or delta, 27 sulfoni- and zeta-tocopherol or tocotrienols (see, The Merck Index (1996), Merck & Co., Whitehouse Station, NJ 1.620-1.621 and 1,712, and their references cited), as well as vitamin E. The term “tocopherol” also includes esters of cosmetically acceptable, for example, tocopherol acetate, tocopherol outlined, or tocopherol stearate. The term "tocopherol" also includes mixtures of tocopherols, tocotrienols and / or stereoisomers, as well as enriched compositions that comprise at least 50% of any tocopherol or tocotrienol. Tocopherols and tocotrienols can be of natural or synthetic origin.
[071] As used herein, the term “retinoids” means retinol, retinyl, retinol esters, retinyl palmitate, retinyl linoleate, retinoic acid, or retinoic acid esters, as well as that of synthetic or natural vitamin A. The term "retinol" includes the following retinol isomers: all-trans-retinol, 13-cis-retinol, 11-cis-retinol, 9-cis-retinol, 3,4-didehydro-retinol. A retinyl ester is a retinol ester. Suitable retinyl esters are C1-C30 esters of retinol, preferably C2-C20 esters and, most preferably, C2, C3 and C16 esters. Some esters can be selected from retinyl palmitate, retinyl acetate, retinyl propionate, and retinyl linoleate. The retinyl ester is an ester of retinoic acid with an alcohol. Suitable retinyl esters include C1-C30 alcohol esters of retinoic acid, preferably C2-C20 esters and, more preferably, C2-C3 and C16 esters. Some retinoyl esters comprise the retinoic acid linoleyl alcohol ester, retinoic acid hexanedecanol ester, retinoic acid alcohol oleic ester, retinoyl ascorbate, and the retinoic acid linolenic alcohol ester.
[072] While the compounds described herein can occur and can be used as the neutral (non-saline) compound, the description is intended to cover all salts of the compounds described herein, as well as the methods of using such salts of the compounds. In one embodiment, the salts of the compounds include the pharmaceutically acceptable salts and / or their dermatologically acceptable salts. Pharmaceutically acceptable salts are those salts that can be administered as drugs or pharmaceutical products to humans and / or animals and that, after administration, retain at least some of the biological activity of the free compound (neutral compound or non-salt compound) . Dermatologically acceptable salts are those salts that can be applied as drugs or pharmaceutical products to the skin of human beings and / or animals and that, after application, retain at least some of the biological activity of the free compound (neutral compound or compound not salt). The desired salt of a basic compound can be prepared using methods known to those skilled in the art, by treating the compound with an acid. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, sulfonic acid , cinnamic acid, mandelic acid, sulfonic acids, and salicylic acid. Salts of basic compounds with amino acids, such as aspartate salts and glutamate salts, can also be prepared. The desired salt of an acidic compound can be prepared using methods known to those skilled in the art, by treating the compound with a base. Examples of inorganic salts of acid compounds include, but are not limited to, alkali and alkaline earth metal salts, such as sodium salts, potassium salts, magnesium salts and calcium salts; ammonium salts; and aluminum salts. Examples of organic salts of acidic compounds include, but are not limited to, the salts of procaine, dibenzylamine, N-ethylpiperidine, N, N-dibenzylethylenediamine, and triethylamine. Salts of acidic compounds with amino acids, such as lysine salts, can also be prepared. Other pharmaceutically acceptable salts are described in Bighley, “Salt Forms of Drugs”, Encyclopedia of Pharmaceutical Technology, volume 13 pages 453-499 (1996) (Swarbrick, Boylan, eds.), And Berge, “Pharmaceutical Salts”, J. Pharm . Sci. 66: 1 (1977).
[073] The present invention also includes, if chemically possible, all stereoisomers of the compounds, including diastereomers and enantiomers. The present invention also includes mixtures of possible stereoisomers in any proportion, including, but not limited to, racemic mixtures. Unless stereochemistry is explicitly stated in a structure, the structure is intended to encompass all possible stereoisomers of the represented compound. If stereochemistry is explicitly indicated by a portion or portions of a molecule, but not for the other portion or portions of a molecule, the structure is intended to cover all possible stereoisomers for the portion or portions in which the stereochemistry is not explicitly indicated.
[074] The compounds can be administered in the form of prodrugs. Prodrugs are derived from compounds, which are relatively inactive, but convert to the active compound, when introduced into the individual in which they are used through a biological or chemical process, in vivo, such as an enzymatic conversion. Suitable prodrug formulations include, but are not limited to, the peptide conjugates of the compounds of the present invention and their esters of compounds of the present invention. A more detailed discussion of suitable pro-drugs is provided in H. Bundgaard, Design of Prodrugs, New York: Elsevier, 1985; in R. Silverman, The Organic Chemistry of Drug Design and Drug Action, Boston: Elsevier, 2004; (ed.) in R.L.Juliano, Biological Approaches to the Controlled Delivery of Drugs {Annals of the New York Academy of Sciences, volume 507), New York: New York Academy of Sciences, 1987; eem E.B. Roche (ed.), Design of Biopharmaceutical Properties Through Prodrugs and Analogs {Symposium sponsored by Medicinal Chemistry Section, AphA Academy of Pharmaceutical Sciences, November 1976 national meeting, Orlando, Florida), Washington: The Academy 1977.
[075] The description of the compounds in the present also includes all isotopologists, for example, partially deuterated perduterate analogs or all compounds in the present. METHODS
[076] Any of the compounds described herein can be mixed as cosmetics, cosmeceuticals, quasi-drugs (if appropriate), or pharmaceutical drugs. The compounds can be suitably mixed with other components. Examples of such components include oily components, such as hydrocarbons, fats and oils such as liquid paraffin, squalene, vaseline, such as Vaseline® (a registered trademark of Conopco Corp., Englewood Cliffs, New Jersey), cetyl alcohol, isostearyl alcohol, cetyl-2-ethylhexanoate, 2-octyldodecyl alcohol, glycerin, glycerin triisostearate, nut oils, and lanolin, wax, as well as silicone, surfactants, thickeners, neutralizers, antiseptics, germicides , antioxidants, powder components, pigments, perfumes, ultraviolet light absorbers, drugs, metal sealant, and pH modifiers.
[077] Occurrences in the skin of perceptible but undesirable pigmentation as a result of overproduction or insufficient production of melanin or of irregular texture perceptible as a result of aging can be reduced, treated or prevented using the methods described herein. Cosmetic applications for the methods described herein include topical application of compositions containing one or more of the compounds described herein for enhancing or otherwise altering the visual appearance of the skin. The cosmetic compositions described herein are also useful to provide a smoother and more delicate appearance of the skin.
[078] The active compounds described herein can also be used in combination with skin exfoliating agents (including glycolic acid or trichloroacetic acid face scrubs) or skin exfoliating agents (including retinoids such as retinoic acid or retinoi) to lighten skin tone and prevent repigmentation. The appropriate dosage regimen, the amount of each dose administered, and the specific intervals between doses of the active compound will depend on the special active compound used, the condition of the patient or individual being treated, and the nature and severity of the disorder or condition. being treated. Preferably, the active compound is administered in an amount and at an interval that results in the desired treatment or amelioration of the disorder or condition to be treated.
[079] An active compound described herein can also be used in combination with sunscreens (UVA or UVB blockers) to prevent repigmentation; for protection against sun or UV-induced skin darkening, or for intensifying its skin lightening or whitening action or for intensifying its skin melanin reduction capacity. An active compound described herein can also be used in combination with any of the compounds that interact with retinoic acid receptors and accelerate or intensify the skin's melanin-reducing ability, accelerate or intensify the skin's whitening or whitening action , or accelerate or intensify its ability to prevent the accumulation of melanin in the skin. An active compound described herein can also be used in combination with 4-hydroxyanisole. An active compound described herein can also be used in combination with ascorbic acid, its derivatives and products based on ascorbic acid (such as magnesium ascorbate) or other products with an antioxidant mechanism (such as resveratrol, tocopherols, tocotrienols and derivatives) that accelerate or intensify its ability to reduce skin melanin, or accelerate or intensify its skin whitening action.
[080] In some variations, the composition still comprises a soy extract which is a mixture of compounds isolated from soy. The soy extract can only contain a portion of the soy (for example, a soy extract such as filtered soy milk or low-lipid soy powder) or it can contain all of the soy (for example, a ground soy powder). The soy extract can be in the form of a fluid (for example, soy milk) or a solid (for example, a soy powder or powdered soy milk).
[081] One or more active compounds used in the methods described herein can be used alone or in combination with one or more other compounds known in the art. For example, any of the compounds described herein can be used in combination with a tyrosinase inhibitor or other skin lightener, pigmentation modifier, or a skin bleaching agent, including any one or more of these agents, including the compounds or extracts, described in the following patent publications: US patent 4,278,656 to Nagai et al.;, US patent 4,959,393 to Torihara et al .; US patent 5,164,182; US patent 5,580,549 to Fukuda et al .; US patent 5,723,109'de L'Oreal; US patent 6,123,959 to Jones et al .; US patent 6,132,740 to Hu; US patent 6,159,482 to Tuloup et al .; US patent 6,365,135'de L'Oreal; US patent 6,514,538 to Shiseido Co. Ltd .; publication of US patent application 2006 / 188,559 to Neis; WO 1999/64025 to Fytokem Prod. Inc .; US patent 6,348,204'de LOreal, publication WO 2000/56702 by Pfizer Inc .; JP 5,221,846 to Kunimasa Tomoji; JP 7,242,687 to Shiseido Co. Ltd .; JP patent 7,324,023 to Itogawa H, JP patent 8,012,552 to Shiseido Co. Ltd .; JP 8,012,554 to Shiseido Co. Ltd .; JP 8,012,557 to Shiseido Co. Ltd .; JP 8,012,560 to Shiseido Co. Ltd .; JP patent 8,012,561 to Shiseido Co. Ltd .; JP 8,134,090 to Fujisawa; JP 8,277,225 to Kansai Koso KK; JP patent 9,002,967 to Sanki Shoji KK; JP patent 9,295,927 to Yagi Akir, JP patent 10,072,330 to Kansai Kouso; JP 1,0081,626 to Kamiyama KK; JP 10,101,543 to Kansai Kouso KK; JP 11 071,231 to Maruzen Pharm, JP 11,079,934 to Kyodo Nyugyo; JP 11,246,347 to Shiseido Co. Ltd .; JP 11,246,344 to Shiseido Co. Ltd, JP 2000 / 080,023 to Kanebo Ltd, JP 2000 / 095,663 to Kose KK; JP 2000 / 159,681 to Hai Tai Confeitaria Co. Ltd, JP 7,206 ^ 753 to Nlkken Food KK; patent Jp 5g, 5 JP 2001/019 618, from Shiseido; JP patent 2002 / 029,959 to Shiseido patent Jp 2004 / 315,534 by Access Business Group Int LIc; JP 2005 / 041,821 to Shiseido; JP 2007 / 063,224 to Kobayashi Pharma; JP 2007 / 091,635 to Maruzen Pharma; JP patent 2008 / 013,481 by Univ, Tokushima; patent KR 2004 / 0.078,449 to Enbioeng Co Ltd .; TW 281,863 patent to Taiyen Biotech Co Ltd; and CN 101,102,746 to Young Chung Se; among others. These patent publications are hereby incorporated by reference in their entirety.
[082] Non-therapeutic methods are provided in the present for whitening or reducing skin pigmentation and / or reducing the irregular texture in which an active compound described herein, and one or more of the other active ingredients, such as those referred to above, they are administered together as part of the same pharmaceutical composition, as well as the methods in which they are administered separately as part of an appropriate dosage regimen designed to achieve the benefits of combination therapy. The appropriate dosage regimen, the amount of each dose administered, and the specific intervals between doses of each active agent will depend on the specific combination of active agents employed, the condition of the patient or individual being treated, and the nature and severity of the treatment. disorder or condition to be treated. Such additional active ingredients can be administered in amounts less than or equal to those for which they are effective as unique topical therapeutic agents.
[083] An active compound, in general, will be administered in the form of a dermatological or cosmetic composition comprising the compound of Formula I, together with a dermatologically acceptable carrier or solvent. Alternatively, an active compound can be administered in the form of a pharmaceutical composition comprising the compound of Formula I, together with a pharmaceutically acceptable carrier or solvent.
[084] In the depigmentation compositions provided at present, the concentration of the active compound, in general, is between 0.01% and 10%, or between about 0.01% and about 10%, for example, between 0, 1% and 5% or between about 0.1% and about 5%, or between 0.1% and 2%, or between about 0.1% and about 2%, or between 0.1% and 1%, or between about 0.1% and about 1%, based on the total weight of the composition.
[085] The compositions described in the present can be applied directly to the skin. Alternatively, they can be delivered by various transdermal drug delivery systems, such as transdermal patches, as known in the prior art. For example, for topical administration, the active ingredient can be formulated into a solution, gel, lotion, ointment, cream, suspension, paste, liniment, powder, tincture, aerosol, adhesive or the like, in a pharmaceutically or cosmetically acceptable way. methods known in the art. The composition can be any of a variety of forms common in the pharmaceutical or cosmetic arts for topical application to animals or humans, including solutions, lotions, sprayers, creams, ointments, balms, gels, and the like, as described below. Exemplary agents are those that are sufficiently viscous to remain on the treated area, those that do not evaporate easily, and / or those that are easily removed by washing with water, optionally with the aid of soaps, cleaning products and / or shampoos. Current methods for preparing topical formulations are known to those skilled in the art, such as those described in Remington's Pharmaceutical Sciences, (1990); and Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed., Williams & Wilkins (1995).
[086] Compositions can be produced in a wide variety of product types, which include, but are not limited to, solutions, suspensions, lotions, creams, gels, toners, sticks, sprayers, ointments, washes and bar cleaners solids, hair shampoos and conditioners, pastes, foams, powders, mousses, shaving creams, scarves, tapes, dressings, electrically powered dressings, dressings and adhesive bandages, hydrogels, film-forming products, facial and skin masks, makeup , such as foundations, eyeliners, and eye shadows, and the like. These types of products can contain a variety of cosmetically acceptable vehicles, including, but not limited to solutions, suspensions, emulsions, such as microemulsions and nanoemulsions, gels, solids and liposomes.
[087] Compositions can be formulated as solutions. Solutions typically include an aqueous or organic solvent, for example, from about 50% to about 99.99% or about 90% to about 99% of a cosmetically acceptable aqueous or organic solvent. Examples of suitable organic solvents include: propylene glycol, polyethylene glycol (from 200 to 600), polypropylene glycol (from 425 to 2,025), glycerol, 1,2,4-butanotriol, sorbitol esters, 1,2,6- hexanotriol, ethanol, and mixtures thereof. An example of such a solvent is an ethanol / polyethylene glycol (80/20) mixture.
[088] A lotion can be produced from such a solution. Lotions typically contain from about 1% to about 20% (for example, from about 5% to about 10%) of emollient (s) and from about 50% to about 90 % (for example, from about 60% to about 80%) of water.
[089] Another type of product that can be formulated from a solution is a cream. A cream usually contains from about 5% to about 50% (for example, from about 10% to about 20%) of emollient (s) and from about 45% to about 85 % (for example, from about 50% to about 75%) of water.
[090] Yet another type of product that can be formulated from a solution is an ointment. An ointment can contain a simple base of animal, vegetable or synthetic oils or semi-solid hydrocarbons. An ointment can contain from about 2% to about 10% of emollient (s) plus from about 0.1% to about 2% of a thickening agent (s). Examples of thickeners include, but are not limited to, those presented in ICI Handbook {International Cosmetic Ingredient Dictionary and Handbook) pages 1,693-1,697.
[091] The compositions described herein can also be formulated as emulsions. If the vehicle is an emulsion, from about 1% to about 10% (for example, from about 2% to about 5%) the vehicle contains emulsifier (s). Emulsifiers can be non-ionic, anionic or cationic. Examples of emulsifiers include, but are not limited to, those presented in the ICI Handbook, pages 1,673-1,686.
[092] Lotions and creams can be formulated as emulsions. Typically, such lotions contain from 0.5% to about 5% emulsifier (s), while such creams typically contain from about 1% to about 20% (for example, from about 5% to about 10%) of an emollient (s); from about 20% to about 80% (for example, from 30% to about 70%) of water; and from about 1% to about 10% (e.g., from about 2% to about 5%) of an emulsifier (s).
[093] Individual skin care preparations, such as lotions and creams, of the oil in water type and water in oil type are well known in the art and are useful in the compositions and methods described herein. Multiphase emulsion compositions, such as water in oil in water or oil in water in oil type, are also useful in the compositions and methods described herein. In general, such individual or multiphase emulsions contain water, emollients, and emulsifiers as essential ingredients.
[094] The compositions described herein can also be formulated as a gel (for example, an aqueous, alcoholic, alcoholic / aqueous, oily or gel solution, using suitable gelling agent (s)). Suitable gelling agents for aqueous and / or alcoholic gels include, but are not limited to, gums, acrylic acid and acrylate polymers and cellulose copolymers and derivatives (e.g., hydroxymethylcellulose and hydroxypropylcellulose). Suitable gelling agents for oils (such as mineral oil) include, but are not limited to, the hydrogenated butylene / ethylene / styrene copolymer and hydrogenated ethylene / propylene / styrene copolymer. Such gels normally contain between about 0.1% and 5%, by weight, of such gelling agents.
[095] One or more additional agents can be added to topical formulations, to enhance percutaneous absorption of active ingredients, including, but not limited to dimethyl sulfoxide, dimethylacetamide, dimethylformamide, surfactants, azone (laurocaprama), alcohol, acetone, propylene glycol and polyethylene glycol. Physical methods can also be used to enhance transdermal penetration, such as iontophoresis, or sonophoresis. Alternatively, or in addition, administration via liposomes can be used.
[096] A topically applied composition provided in the present contains a pharmaceutically effective agent, which has the desired effect on the skin, as described in the present, and those ingredients which are necessary for use as a carrier, such as an emulsion, cream, ointment, aqueous solution, lotion or aerosol. Non-limiting examples of such vehicles can be found in US patent 5,691,380 to Mason et al., Filed November 25, 1997; and US patent 5,968,528 to Deckner et al., filed October 19, 1999 .; which are hereby incorporated by reference. Suitable pharmaceutical carriers are further described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa. (1990).
[097] The vehicle used in the compositions described herein can be in a variety of forms. These include emulsion vehicles, including, but not limited to, oil in water, water in oil, water in oil in water emulsions, and silicone oil in water emulsions, a cream, an ointment, an aqueous solution, a lotion or an aerosol. As will be understood by the person skilled in the art, a certain component, mainly to distribute the water phase or the oil / silicone phase, depending on the component's water solubility / dispersibility in the composition.
[098] The dermatological formulations provided in the present, normally, can comprise a derivative of any compound or composition described in the present, optionally, a polar solvent. Solvents suitable for use in the formulations described herein include any polar solvent capable of dissolving the derivative. Suitable polar solvents include: water; alcohols (such as ethanol, propyl alcohol, isopropyl alcohol, hexanol and benzyl alcohol); polyols (such as propylene glycol, polypropylene glycol, butylene glycol, hexylene glycol, maltitol, sorbitol and glycerin); and panthenol dissolved in glycerin, flavoring oils and their mixtures. Mixtures of these solvents can also be used. Exemplary polar solvents can be polyhydric alcohols and water. Examples of solvents may include glycerin, panthenol in glycerin, glycols such as propylene glycol and butylene glycol, polyethylene glycols, water and mixtures thereof. Additional polar solvents for use can be alcohols, glycerin, panthenol, propylene glycol, butylene glycol, hexylene glycol and mixtures thereof.
[099] An emollient can also be added to the cosmetic / dermatological compositions described herein. The emollient component can comprise fats, oils, fatty alcohols, fatty acids and esters that aid application and adhesion, shine performance and provide occlusive hydration. Emollients suitable for use can be derived from isostearic acid, isopropyl palmitate, lanolin oil, diisopropyl dimerate, maleatated soybean oil, octyl palmitate, isopropyl isostearate, cetyl lactate, cetyl ricinoleate, tocopherol acetate, acetylated lanolin alcohol, cetyl acetate, phenyl trimethicone, glyceryl oleate, tocopherol linoleate, wheat germ glycerides, arachidyl propionate, minstyl lactate, decyl oleate, propylene glycol ricinoleate, isopropyl linoleate, tetra-estyltolate, tetrahydrate , Dicaprilat / Neopentylglycol Dicaprato, Hydrogenated Coconut Glycides, Isononyl Isononanoate, Isotridecyl Isononanoate, Myristyl Myristate, Triisocetyl Citrate, Cetyl Alcohol, Octyl Dodecanol, Oleyl Alcohol, Panthenol, Lanolin Alcohol, Linenic Acid , sucrose esters of fatty acids, octyl hydroxystearate and mixtures thereof. Examples of other suitable emollients can be found in the Cosmetic Bench Reference, pages 1.19-1.22 (1996), or in the International Cosmetic Ingredient Dictionary and Handbook, eds. Wenninger and McEwen, pages 1,656-1,661, 1,626, and 1,654-1655 (The Cosmetic, Toiletry, and Fragrance Assoc., Washington, DC, 7th Edition, 1997) (hereinafter “ICI Handbook”), incorporated herein as reference. Suitable emollients may include polar emollient emulsifiers (such as polyglycerol esters, straight or branched chain) and non-polar emollients. The emollient component can usually comprise from about 1% to about 90%, preferably from about 10% to about 80%, more preferably, from about 20% to about 70% %, and even more preferably, from about 40% to about 60% of the cosmetic composition.
[0100] The term "polar emollient", as used herein, means any emollient emulsifier that has at least one polar group, and where the solubility (at 30 ° C) of the cytoprotective compound in the polar emollient is greater about 1.5%, preferably greater than about 2%, most preferably greater than about 3%. Suitable polar emollients may include, but are not limited to, the polyol ester and polyols, such as straight or branched chain polyglycerol esters, and polyglycerol ethers. Examples of such non-limiting emollients may include PG3 diisoestearate, polyglyceryl-2-sesquiisostearate, polyglyceryl-5-distestate, polyglyceride 1-10-distestate, polyglyceride 1-10-diisoestearate, acetylated monoglycerides, glycerol esters, glycerol esters glycerol tricaprilate / caprate, glyceryl ricinoleate, glyceryl isostearate, glyceryl myristate, glyceryl linoleate, polyalkylene glycols such as PEG 600, monoglycerides, 2-monolaurine, sorbitan esters and mixtures thereof.
[0101] The term "non-polar emollient", as used herein, means any emollient emulsifier that has no or minimal permanent electrical moments. Suitable non-polar emollients may include, but are not limited to, esters and hydrocarbons in straight or branched chain. Non-limiting examples of such emollients may include isononyl isononanoate, isopropyl isostearate, octyl hydroxystearate, diisopropyl dimerate, lanolin oil, octyl palmitate, isopropyl palmitate, paraffins, isoparaffins, acetylated lanolin esters, acid esters sucrose, isopropyl myristate, isopropyl stearate, mineral oil, silicone oils, dimethicone, allantoin, isoexadecane, isododecane, petroleum jelly, and mixtures thereof. The solubility of the compound in polar or non-polar emollients can be determined according to methods known in the art.
[0102] Suitable oils include esters, triglycerides, hydrocarbons and silicones. These can be a single material or a mixture of one or more materials. They can normally comprise from 0.1% to about 100%, preferably from about 5% to about 90%, and most preferably, from about 70% to about 90% of the emollient component.
[0103] Oils that act as emollients also impart viscosity, stickiness and drag properties to cosmetic compositions, such as lipstick. Examples of suitable oils can include acrylic triglycerides; capricious triglycerides; isostearyl triglycerides; atopic triglycerides; propylene glycol myristyl acetate; lanolin; lanolin oil; polybutene; isopropyl palmitate; isopropyl myristate; isopropyl isostearate; diethyl sebacate; diisopropyl adipate; tocopherol acetate; tocopheryl linoleate; hexadecyl stearate; ethyl lactate; cetyl oleate; cetyl ricinoleate; oleyl alcohol; hexadecyl alcohol; octyl hyoxoxearearate; octyl dodecanol; wheat germ oil; hydrogenated vegetable oils; castor oil; petroleum jelly; modified lanolines; branched chain hydrocarbons; alcohols and esters; corn oil; cotton oil; olive oil; palm seed oil; rapeseed oil; safflower oil; jojoba oil; oil of Primula; avocado oil, mineral oil, shea butter, octylpalmitate, maleatated soybean oil, glycerol trioctanoate, diisopropyl dimerate, and volatile and non-volatile silicone oils, including phenyl trimethicone.
[0104] Oils suitable for use in the present invention can be acetylglycerides, octanoates, alcohol and polyalcohol decanoates, such as glycol and glycerol, alcohol and polyalcoholic ricinoleates such as cetyl ricinoleate, PG-diiso stearate 3, polyglycerol ethers, polyglycerol esters, caprylic triglycerides, capric triglycerides, isosteric triglycerides, adipic triglycerides, phenyl trimethicone, lanolin oil, polybutene, isopropyl palmitate, isopropyl isohydrate, keto alcohol, ricinoleate , hydrogenated vegetable oils, castor oil, modified lanolines, octyl palmitate, lanolin oil, maleatated soy oil, cetyl ricinoleate, glyceryl trioctanoate, diisopropyl dimerate, synthetic lanolin derivatives and branched chain alcohols, sucrose esters of fatty acids, octyl hydroxystearate and their mixtures.
[0105] Preferably, the oils used can be selected in such a way that the majority (at least about 75%, preferably at least about 80% and most preferably at least about 99% ) of the types of oils used have solubility parameters that do not differ from more than about 1 to about 0.1, preferably from about 0.8 to about 0.1.
[0106] A surfactant can also be added to the compositions described herein, to confer cosmetic or beneficial application properties. Surfactants suitable for use can be those that can form the emulsion and / or combination structures. The emulsifying surfactant can be from 0% to about 20% of the formulation, preferably from 0% to about 15% and, most preferably, from about 1% to about 10%. Examples of suitable emulsifiers can be found in US patent 5,085,856 to Dunphy et al., And US patent 5,688,831 to El-Nokaly et al. Examples of other suitable emulsifiers can be found in Cosmetic Bench Reference, pages 1.22, 1.24-1.26 (1996), all of which are incorporated herein by reference.
[0107] Examples of surfactants that can be used in the compositions described herein include sodium alkyl sulfates, for example, sodium lauryl sulfate and sodium minstyl sulfate, sodium N-acyl sarcosinates, for example , sodium N-lauroyl sarcosinate and sodium N-myristoyl sarcosinate, sodium dodecylbeπzeπosulfonate, sodium hydrogenated fatty acid monoglyceride coconut sulfate, sodium lauryl sulfoacetate and N-acyl-glutamate, for example, glutamate glutamate N-palmitoyl, sodium N-methylacyltaurine salt, sodium N-methylacylalanine salt, sodium alpha-olefin sulfonate and sodium dioctylsulfosucciπate; N-alkylaminoglycerols, for example, N-lauryl-diamino-ethylglycerol and N-myristyldiaminoethylaglycerol, N-alkyl-N-carboxymethylammonium betaine and 2-alkyl-1-hydroxyethylimidazoline betaine; polyoxyethylenealkyl ether, polyoxyethylalkylethyl ether, polyoxyethylenelanoline alcohol, polyoxyethyleneglyceryl monoaliphatic acid ester, polyoxyethyleptesorbitol aliphatic acid ester, polyoxyethylenate aliphatic acid ester, aliphatic acid ester, aliphatic acid ester, glyphyl ester pluronic acid, and esters of aliphatic acids, such as polyoxyethylene sorbitan monooleate and polyoxyethylene sorbitan monolaurate. Emulsifying surfactants known to those skilled in the art can be used in the compositions described herein.
[0108] Also useful in the present may be the surfactants that form the association structures, preferably lamellar or hexagonal liquid crystals, at room temperature, when mixed with a polar solvent. In preparing a sample combination of surfactant and polar solvent to demonstrate the ability to form the pooling structures, the surfactant must be sufficiently soluble in the polar solvent, such that a pooling structure can be formed at room temperature. An ordinary subject matter technician is able to determine the compatible interactions.
[0109] Any surfactant that forms the association structures at room temperature and is suitable for use in cosmetics can be suitable for use in the present invention. Surfactants suitable for use in cosmetics have no or minimal dermatological or toxicological problems. Anionic surfactants, non-ionic surfactants, cationic surfactants, amphoteric surfactants and their mixtures may be suitable for use. Preferably, anionic surfactants, nonionic surfactants, cationic surfactants, amphoteric surfactants and mixtures that have a Krafft point at or below about room temperature are used. Most preferably, non-ionic surfactants, cationic surfactants, amphoteric surfactants and mixtures that have a Krafft point at or below about room temperature are used.
[0110] Surfactants can be used at levels from about 4% to about 97%, preferably from about 5% to about 95%, more preferably, from about 20% about 90% and, even more preferably, from about 30% to about 70% of the association structure.
[0111] The cosmetic compositions described herein may contain one or more materials, individually or collectively referred to herein as a "solidifying agent", which are effective in solidifying the special liquid-based material, for use in a cosmetic composition. (As used herein, the term "solidification" refers to the physical and / or chemical modification of the liquid-based material, to form a solid or semi-solid under ambient conditions, that is, to form a final composition that has a physical structure stability and can be deposited on the skin under normal conditions of use.) As is considered by those skilled in the art, the selection of the special solidifying agent for use in cosmetic compositions will depend on the special type of composition desired, that is, the base gel or wax, the desired rheology, the liquid base material used and the other materials to be used in the composition. The solidifying agent may preferably be present in a concentration from about 0.1% to about 90%, more preferably from about 1% to about 50%, most preferably , from about 5% to about 40%, even more preferably, from about 3% to about 20%.
[0112] The variations of cosmetic stick wax provided herein may preferably contain from about 5% to about 50% (by weight) of a waxy solidifying agent. The term "waxy solidifying agent", as used herein, means a solidifying material that has characteristics similar to wax. Such waxy materials can also serve as emollients. Among the waxy materials useful in the present invention are high melting point waxes, that is, which have a melting point from about 65 ° C to about 125 ° C, such as beeswax, spermacide, carnauba, laurel berry, candelilla, montana, ozocerite, ceresin, paraffin, synthetic waxes such as Fisher-Tropsch waxes, microcrystalline waxes and their mixtures. Ceresine, ozokerite, white beeswax, synthetic waxes and their mixtures, are among those that are useful at present; additional useful waxes are described in U.S. Patent 4,049,792, Elsnau, filed September 20, 1977, hereby incorporated by reference in their entirety. Low melting waxes, which have a melting point from about 37 ° C to about 75 ° C, may be preferred for use in the wax stick variations described herein. Wax stick variations, which contain volatile silicone oils as a liquid based material, preferably contain from about 10% to about 35%, more preferably, from about 10% to about 20% (by weight) of a low melting wax. Such materials include fatty acids, fatty alcohols, fatty acid esters and fatty acid amides, which have fatty chains from about 8 to about 30 carbon atoms, and mixtures thereof. Wax-like materials include cetyl alcohol, palmitic acid, stearyl alcohol, behenamide, sucrose esters of tallow fatty acids, mono and diesters of polyethylene glycol fatty acids, and mixtures thereof. Stearyl alcohol, cetyl alcohol, and mixtures thereof, are mainly used. Additional fatty acids, fatty alcohols, and other wax-like materials are also well known in the art.
[0113] In addition, these compositions can include other medicinal agents, therapeutic agents, vehicles, adjuvants and the like. Some specific additional agents may include sunscreens; retinoids; antioxidants; hydroxy acids; fatty acids, acceptable non-toxic metal salts of naturally occurring amino acids or hydroxyalkyl acids; botanical extracts, salicylic acid, benzoyl peroxide, antibiotics, antiandrogens, anti-inflammatory agents, antioxidants, ascorbic acid, B vitamins, tocopherols or tocotrienols, corticosteroids, humidifiers, surfactants, keratolytic agents, complexing agents, dyes, fragrances, and their mixtures. SKIN PIGMENTATION AND COLOR MEASUREMENT
[0114] Measurements of pigmentation and skin color can be quantified using a chromameter, colorimeter, or skin reflectance instrument (see, for example, Clarys et al., SkiNRes. Technol. 6 (4): 230-238 ( 2000)). Chromameters are commercially available from vendors such as Konica Minolta (CR-400 or CFM10 Chroma Meter) or Gigahertz-Optik (HCT-99D color meter). Baseline readings before treatment are taken, and readings during treatment can be taken at one or more wavelengths. Skin color can be measured and compared to assess treatment. Measurements can be collected at several points, such as an area affected by discoloration and a surrounding affected area. SYNTHETIC METHODS
[0115] The resorcinol compounds described herein can be synthesized by an appropriate combination of the generally well-known methods of synthesis. The techniques useful for the synthesis of the compounds in the present are both easily evident and accessible to those skilled in the art in the relevant state of the art in light of the teachings described in the present. The discussion below is offered to illustrate some of the various methods available for use in assembling the compounds at present. However, the discussion is not intended to limit the scope of reactions or reaction sequences that are useful in the preparation of the compounds at present.
[0116] The resorcinol compounds described herein can be synthesized according to Scheme 1. Reagent C (O) R2 indicates a reagent having a carbonyl group; that is, the group C = O is a part of R2, and not an additional part added to R2. Suitable protecting groups (PG in the scheme below), such as alkyl groups, can be used to protect certain functional groups from reaction conditions, and such protecting groups are removed under standard conditions, if appropriate.

[0117] Scheme 2 shows an example of synthesis of a 5-methyl resorcinol compound described herein, according to Scheme 1. Each Ra and Rb are a substituted or unsubstituted hydrogen or alkyl, where the alkyl groups substituted or unsubstituted may be the same or different, or Ra and Rb, together with the carbon to which they are attached, form a substituted or unsubstituted cycloalkyl group. Compound (1) (commercially available from Sigma-Aldrich, St. Louis, Missouri) is brominated, for example, with N-bromosuccinimide, to provide compound (2), which reacts with magnesium to form the reagent of Grignard (3). The compound (3) reacts with an alkyl ketone in the presence of lanthanum salts, followed by reduction with hydrogen over Pd / C to form the compound (4). The alkoxy groups are then converted to hydroxyl groups, to provide the resorcinol compound (5). SCHEME 2

[0118] Scheme 3 illustrates an exemplary synthesis of a 5-fluoro resorcinol compound described herein, according to Scheme 1. Each Rc and Rd are a substituted or unsubstituted hydrogen or alkyl, in which the substituted alkyl groups or unsubstituted may be the same or different, or Rc and Rd, together with the carbon to which they are attached, form a substituted or unsubstituted cycloalkyl group. Compound (6) (commercially available from Sigma-Aldrich, St. Louis, Missouri) is brominated to provide compound (7), which reacts with magnesium to form Grignard's reagent (8). The compound (8) reacts with an alkyl ketone in the presence of lanthanum salts to form the compound (9), followed by reduction with hydrogen over Pd / C to form the compound (10). The alkoxy groups are then converted to hydroxy groups to provide the compound (11). Similar resorcinol methods can be used to synthesize other 4-halogen resorcinols. SCHEME 3

[0119] Scheme 4 shows an exemplary synthesis of a 4-alkyl-5-trifluoromethyl resorcinol compound described herein, according to Scheme 1. Re is substituted or unsubstituted alkyl. The bromide compound (12) is converted to the corresponding iodide (13), which reacts with an acyl chloride to form the ketone (14). The compound (14) reacts with the difluoro-fluoro-acetic acid methyl ester (15) to form the compound (16), followed by reduction by zinc in the presence of acid (or another suitable reducing agent) to form the compound (17). The alkoxy groups are then converted to hydroxy groups to provide the resorcinol compound (18). Similar methods can be used to synthesize other 4-alkyl-5-trifluoromethyl resorcinols. SCHEME 4

[0120] Scheme 5 shows an exemplary synthesis of a 4-cycloalkyl-5-trifluoromethyl resorcinol compound described herein, according to Scheme 1. (A) represents a substituted or unsubstituted cycloalkenyl ring, and (B ) represents the corresponding substituted or unsubstituted cycloalkyl ring. The bromide compound (19) is converted to the corresponding iodide (20). The compound (20) reacts with the methyl ester of difluoro-fluoro-acetic acid to form the compound (21), followed by bromination with NBS to form the compound (22). Cycloalkenyl (A) is installed using a suitable dioxaborolane to form the compound (23), which is reduced in the presence of Pd / C (or another suitable reducing agent) to form the compound (24). The alkoxy groups are then converted to hydroxy groups to provide the compound (25). Similar resorcinol methods can be used to synthesize other 4-cycloalkyl-5-trifluoromethyl resorcinols. EXAMPLES
EXAMPLES EXAMPLE 1: 4-CYCLEEXYL-5-METHYL-BENZENE-1,3-DIOL (4,5CHMR)
4-BROMO-1,5-BIS (METOXIMETOXI) -3-METHYLBENZENE
[0121] 26.10 g of orcinol and 19.10 g of ammonium bromide were weighed in a 2-mL 3-neck round bottom flask equipped with a stir bar, thermometer and nitrogen bubbler. The nitrogen atmosphere was established and maintained. 1,000 ml of acetonitrile was added, and the mixture was stirred rapidly to suspend the solids. The suspension was cooled to 10 ° C in an ice bath and 67.88 g of Oxone ™ (OXONE is a registered trademark of Du Pont for a monopersulfate oxidizing compound) was added in one portion. The ice bath was removed, and the mixture was stirred at 20 ° for 30 h. The solids were removed by filtration. The solvent was removed from the filtrate to provide a dark orange solid. The solid was partitioned between 200 ml of 1.0 M hydrochloric acid and 400 ml of tert-butyl methyl ether. The phases were separated, and the aqueous phase was extracted with 200 ml of tert-butyl methyl ether. The combined organic phases were washed with 5 x 200 ml of phosphate buffer at pH 5.5 to 1.0 M and 200 ml of brine. 1.0 g of activated carbon was added to the solution, and the solution was dried over sodium sulfate. The solution was filtered through a 10 cm diameter Buchner funnel containing a 2 cm 5 cm silica gel filter pad on the top 2 cm of Celite (Celite ™ is a registered trademark of Imerys Minerals California , Inc. for a diatomaceous earth containing a filter aid). The filter pad was washed with 2 x 300 ml of tert-butyl methyl ether. The solvent was removed from the filtrate to provide 38.78 g of an orange-brown solid. The solid was recrystallized from 1,2-dichloroethane and dried under vacuum to provide 35.30 g of a 7: 88: 4 mixture of non-brominated orcinols: monobrominated: dibromated as brown crystals. 32.95 g of crystals were dissolved in 100 ml of anhydrous ethyl acetate, and the solution was added dropwise to a prepared methyl chloromethyl ether solution, as described below.
[0122] A 1,000 mL flask with three mouths was equipped with a magnetic stir bar, thermometer, addition funnel, efficient reflux condenser, with a nitrogen inlet, and a gas outlet bubbler which was briskly cooled to 1.0 M of aqueous sodium hydroxide. The nitrogen atmosphere was established and maintained. The flask was charged with 46.65 g of dimethoxymethane and 180 ml of anhydrous toluene. 16 mg of zinc bromide was added. 47.2 g of acetyl chloride were added dropwise over 10 minutes. The addition funnel was rinsed with 20 ml of toluene directly into the reaction mixture. The reaction mixture was stirred at 20 ° for 4.5 h. The resulting methyl chloromethyl ether solution was cooled with an ice bath, and 100 ml of N, N-diisopropylethylamine was added dropwise over 20 min. The solution of 32.95 g of brominated orcinols in 100 ml of ethyl acetate prepared above was added dropwise at a rate to maintain the reaction temperature below 10 °. A white precipitate formed during the addition. The ice bath was removed, and the mixture was stirred at 20 ° for 68 h. The reaction was quenched with 100 ml of saturated aqueous ammonium chloride. 50 mL of water was added to bring all salts into solution. The biphasic mixture was vigorously stirred for 3 hours to ensure that all residual methyl chloromethyl ether was decomposed. The phases were separated, and the aqueous phase was extracted with 250 ml of ethyl acetate. The combined organic phases were washed with 2 x 200 ml of 1.0 M aqueous citric acid, 3 x 200 ml of 1.0 M aqueous sodium hydroxide, and 250 ml of brine. The solution was dried over sodium sulfate and the solvent was removed to provide 47.87 g of a red liquid. 45.34 g of the crude product was purified by vacuum distillation to provide 35.91 g [86% yield calculated from orcinol] of the title compound as a pale yellow liquid, boiling point 92 to 94 ° / 0.046 Torr . NMR 1H (400 MHz, CDCh) δ 6.69 (d, J = 2.7 Hz), 6.64 (d, J = 2.7 Hz), 5.20 (s, 2H), 5.11 ( s, 2H), 3.50 (s, 3H), 3.45 (s, 3H), 2.37 (s, 3H). 4-CYCLEEXYL-1,5-BIS (METOXIMETOXI) -3-METHYLENZENE
[0123] 1.12 g of 2-dicyclohexylphosphine-2 ', 6'-bis (N, N-dimethylamino) biphenyl, 0.28 g of palladium (II) acetate, and 18.50 g of 4-bromo- 1,5-bis (methoxymethoxy) -3-methylbenzene (1) were weighed into a 1,000 mL round-bottom flask dried in a 3-burner oven equipped with a stir bar, thermometer, addition funnel and a nitrogen bubbler. The nitrogen atmosphere was established and maintained. 200 ml of anhydrous THF was added, and the mixture was stirred to provide a clear ruby solution. The solution was cooled with an ice bath, 150 mL of a 0.5 M cyclohexylzinc bromide solution in THF was added over 60 min, keeping the reaction temperature below 5 ° C. The cooling bath was removed , when the addition was complete, and the mixture was stirred at room temperature for 4 h. The solution was cooled in an ice bath and abruptly cooled with 350 ml of saturated aqueous ammonium chloride. The phases were separated, and the aqueous phase was extracted with 350 ml of cyclopentyl methyl ether. The combined organic phases were filtered through Celite ™ to remove fine particles. The filtrate was washed with 2 x 300 ml of 1.0 M citric acid, 300 ml of saturated aqueous sodium bicarbonate solution, and 300 ml of brine, and dried over sodium sulfate and the solvent was removed to provide a liquid dark red. The liquid was diluted with 100mL of heptane and filtered through a 5 cm thick x 9.5 cm diameter silica gel pad. The product was washed with 1,000 ml of 25% EtOAc / heptane. The solvent was removed from the filtrate. The amber liquid was purified by vacuum distillation to obtain 15.83 g [85% yield] of the title compound as a clear colorless oil, 114 to 116 ° C / 0.056 Torr Bp. NMR 1H (400 MHz, CDCh) δ 6.63 (d, J = 2.5 Hz), 6.49 (d, J = 2.5 Hz), 5.13 (s, 2H), 5.10 ( s, 2H), 3.47 (s, 3H), 3.45 (s, 3H), 2.77 (br s, 1H), 2.29 (s, 3H), from 2.10 to 1.95 (m, 2H), from 1.83 to 1.75 (m, 2H), from 1.73 to 1.66 (m, 1H), from 1.59 to 1.52 (m, 2H), from 1 , 37 to 1.18 (m, 3H). 4-CICLOEXIL-5-METHYL-BENZENE-1,3-DIOL (4.5CHMR)
[0124] 15.78 g of 4-cyclohexyl-1,5-bis (methoxymethoxy) -3-methylbenzene (2) were weighed in a 1,000 ml oven-dried flask equipped with a stir bar, septum and a bubbler. nitrogen. The nitrogen atmosphere was established and maintained. 400 ml of anhydrous methanol was added. The bottom solution was cooled to 5 ° C. 7.7 ml of acetyl chloride was added over 30 min, keeping the reaction temperature below 5 ° C. The cooling bath was removed when the addition was complete and stirred at 20 ° C. ° C for 42 h. The volatiles were removed on a rotary evaporator to provide a yellow resin. The resin was dissolved in 75 ml of MTBE and diluted with 75 ml of heptane. Impurities were removed from the baseline by passing the solution through 220 g of silica gel, washing the product through 800 mL of 50% MTBE / heptane. The solvent was removed on a rotary evaporator to provide a pale yellow solid. The solid was recrystallized twice from 50 ml of 1,2-dichloroethane. Vacuum-dried at 85 ° / 0.05 Torr to provide 9.33 g [84% yield] of the title compound as fine white needles. 300 mg of this material was purified by sublimation at 130 ° / 0.03 Torr to provide an analytical standard. NMR 1H (400 MHz, DMSO-dθ) δ 8.74 (overlapping singlet, 2H), 6.07 (d, J = 2.5 Hz), 5.98 (d, J = 2.4 Hz), 2 64 (s wide, 1H), from 2.17 to 1.98 (methyl singlet at 2.12 overlaps the multiplet, 5H), from 1.77 to 1.68 (m, 2H), from 1.68 at 1.60 (m, 1H), from 1.46 to 1.34 (m, 2H), from 1.34 to 1.10 (m, 3H). COMPARATIVE EXAMPLE 2: 4-CYCLOEXYL-5-FLUOROBENZENE-1, 3-DIOL (4.5CHFR)
3,5-DIMETOXYBENZENE 2-BROMO-1-FLUORO
[0125] 28.22 g of 3,5-dimethoxy-5-fluorobenzene were weighed in a 1,000 mL round bottom flask equipped with a stir bar, reflux condenser, nitrogen inlet, and buffer. The nitrogen atmosphere was established and maintained throughout the reaction. 200 ml of anhydrous CCk was added, followed by 32.61 g of N-bromosuccinimide (NBS). The remaining powdered residue of NBS was washed into the flask with 100 ml of CCk. The reaction mixture was stirred at reflux under an N atmosphere for 4 h, during which time the suspended yellow solids changed color to white. At the conclusion, the succinimide solids were precipitated through filtration and carefully washed with 200 ml of heptane. The CCk was removed from the filtrate by rotary evaporation at 50 ° C. More succinimide precipitated from the heptane solution and was removed through filtration while the solution was still hot. The remaining heptane was removed in vacuo to provide a clear solution, amber colored oil (40.67 g), which solidified on standing. The purification of the raw material was carried out by distillation. The condenser was kept at 50 ° C to prevent the product from solidifying before reaching the collection bottle. Then, a small impurity fraction was collected at 78 ° C / 8 Torr, the product distilled at 123 to 125 ° C / 8 Torr. The pale pale yellow liquid solidified as an off-white solid at rest (37.88 g, 89%). 1- (2-FLUORO-4,6-DIMETOXYphenyl) CYCLEXANOL
[0126] 19.52 g of 2-bromo-1-fluoro-3,5-dimethoxybenzene were weighed in a 500 ml round-bottom flask dried in an oven equipped with a stir bar, septum, a thermometer, and inlet nitrogen. The nitrogen atmosphere was established and maintained. To the solution, 200 ml of a 0.5 M solution of lithium chloride in anhydrous 0.5 M were slowly added. The clear pale yellow solution was placed in an ice water / acetone bath and the reaction temperature was maintained between -15 °. C and -10 ° C. To the reaction mixture was added 45 mL of a 2.0 M solution (iodometric titration) of isopropyl magnesium chloride in diethyl ether, dropwise over 20 min, using a syringe pump . The reaction was stirred at 20 ° C to 15 ° C for 60 min. The colorless solution became quickly at the beginning of the addition, then slowly became a light yellow color. LC-MS analysis of an aliquot that was sharply cooled with 5% H2O / MeOH to 60 minutes indicated that the reaction was 50% complete. At this point, 5 mL of a 2.0 M solution of isopropylmagnesium chloride in Et20 was added via syringe. LC-MS analysis of an aliquot that was sharply cooled with 5% H2O / MeOH to 60 min after the addition indicated that the reaction was 80% complete. After waiting another 30 minutes, the light yellow solution was transferred to the next reaction via a cannula.
[0127] 7.48 g of cyclohexanone were weighed in an oven-dried, 1,000 ml 3-neck round-bottom flask equipped with a stir bar, septum, a thermometer, and nitrogen inlet. The nitrogen atmosphere was established and maintained. For the solids, 125 ml of a 0.6 M lanthanum trichloride complex solution with 2 equivalents of lithium chloride in anhydrous THF was added. The solution was stirred at room temperature for 2.5 h. After this period, the clear amber solution was cooled in a water / acetone ice bath and the temperature of the solution was maintained between -5 ° C and 0 ° C during the addition. The solution described above of 2,4-dimethoxy-6-methylphenyl magnesium chloride complex with lithium chloride was transferred to the reaction mixture through a cannula. The amber reaction mixture was stirred between 0 ° C and 5 ° C for 2 h. The reaction mixture was cooled to -10 ° and brusquely cooled by adding a mixture of 100 g of ice in 100 ml of saturated aqueous NH4Cl. An exotherm increased the moderate temperature to 5o C before cooling again. A white emulsion was formed in the aqueous layer. To the mixture, 20 ml of concentrated hydrochloric acid were added. The emulsion did not dissolve. The phases were separated, and the aqueous phase was extracted again with 2 x 200 ml of MTBE. The combined organics were washed with 1 x 200 ml of a 1: 1 mixture of brine and 1 M aqueous NaOH. A small amount of orange gummy material was separated at the solvent interface and was discarded. The remaining organic phase was washed with 200 ml of brine and dried over Na2SO4. The excess solvent was removed in vacuo to provide 21.96 g of a dark amber liquid. The liquid was diluted with 25 mL of heptane and purified by chromatography on 450 g of a Supelco VersaPakTM silica gel column (gradient elution from 0 to 33% ethyl acetate / heptane over 15 column volumes). Isolated 13.14 g, pale yellow liquid (68% yield). 3,5-DIMETOXYBENZENE 2-CYCLOEXYL-1-FLUORIDE
[0128] 13.04 g of 1- (2-fluoro-4,6-dimethoxyphenyl) cyclohexanol were weighed in a 500 mL round-bottom flask equipped with a stir bar and a septum cap. For the solids 250 ml of 9: 1 EtOAc: HOAc were added. The solution was sparged with nitrogen for 5 min and loaded with 2.58 g of 10% by weight of palladium on carbon. A hydrogen atmosphere through the reaction mixture was established and maintained with a balloon. The reaction was stirred at 70 ° C for 20 h, after which LCMS analysis indicated that the reduction was complete. The catalyst was removed by filtration through a B / Whatman GF glass fiber filter and the solids were thoroughly washed with 200 ml of EtOAc. The filtrate was poured into a separatory funnel and washed with 200 ml of 2.5 M aqueous sodium hydroxide, 200 ml of water, and 200 ml of brine, dried over Na2SO4, and concentrated by rotary evaporation to provide a liquid. clear, colorless (11.67 g). The liquid was diluted with heptane and purified by chromatography to provide 8.67 g of a clear colorless oil (71%). 4-CYCLEEXYL-5-FLUOROBENZENE-1,3-DIOL (4,5CHFR)
[0129] 8.51 g of 4-cyclohexyl-1,3-dimethoxy-5-fluorobenzene and 32.93 g of tetrabutylammonium iodide were weighed in a 500 mL 2-neck round-bottom flask dried in an oven equipped with a stir bar, thermometer, nitrogen inlet, and septum. The nitrogen atmosphere was established and maintained throughout the reaction. 200 ml of anhydrous CH2 Cl2 was added to the flask. The mixture was cooled to -78 ° C in a dry ice / acetone bath. To the rapidly stirred mixture, 90 ml of a 1.0 M boron trichloride solution in CH2 Cl2 was added over 30 min, using a syringe pump. The mixture was stirred at -78 ° C for 15 min, then stirred at -2 ° C for 3 h. Analysis by 2.5 h LC-MS showed that all the starting material had converted to the product. The reaction was quenched by the slow addition of 100 ml of water and the mixture was stirred at room temperature 15 min. At this point, 50 ml of methanol was added to dissolve the solids, and the mixture was stirred at room temperature for 30 min. The organic solvents were removed by rotary evaporation at 50 ° C. The remaining aqueous mixture was diluted with 400 ml of water and extracted with MTBE (3 x 150 ml). The combined organic layers were extracted with 3 x 150 ml of 1.0 M aqueous NaOH. The combined aqueous extracts were made acidic by adding 40 ml of concentrated hydrochloric acid. The acidic solution was extracted with three 150 ml portions of MTBE. The combined extracts were washed with brine and dried over Na2SO4. The excess solvent was removed on a rotary evaporator. The residue was dissolved in 10% ethyl acetate / heptane and purified by chromatography on 330 g of an Isco RediSepTM silica gel column (gradient elution of 10 to 50% ethyl acetate / heptane). The collected fractions were concentrated and the resulting solids recrystallized from 30 ml of 1: 1 of 1,2-dichloroethane: hot heptane to provide 3.31 g of colorless orthorhombic crystals. After removing the solvent from the filtrate, the residue was recrystallized from 12 ml of 1: 1 of 1,2-dichloroethane: hot heptane to provide a second collection of 2.76 g of small white crystals. A third collection of 472 mg of small pink crystals (the mother liquor is red) was obtained in a similar way. The first and second collections were identical by NMR 1H, LC-MS, and TLC and were combined to provide the product. The white crystalline solid, 6.07 g. 81% yield. 1H NMR (DMSO-de, 400 MHz) δ: 9.43 (d, J = 1.4 Hz, 1H), 9.32 (d, J = 0.5 Hz, 1H), 6.99 (dd, J = 2.3, 1.2 Hz, 1H), 5.91 (dd, J = 13, 2.3 Hz, 1H), 2.85 (tt, J = 12, 3.3 Hz, 1H), from 1.62 to 1.83 (m, 5H), from 1.47 to 1.57 (m, 2H), from 1.10 to 1.33 (m, 3H). COMPARATIVE EXAMPLE 3: 2-ETHYL-1,5-DIHYDROXY-3-TRIFLUOROMETHYL BENZENE (4.5 ETFMR)
1- (2-IODO-4,6-DIMETOXY-PHENYL) -ETHANONE
[0130] To a solution of acetyl chloride (3.12 g, 39 mmol) in dichloromethane (100 mL) was added AICl3 (6.34 g, 47 mmol) at 0 ° C for 30 min. 1-iodo-3,5-dimethoxy-benzene (10.5 g, 39 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 1 h. Then, ice water (60 ml) was added. The aqueous layer was extracted with dichloromethane (2 x 30 ml), dried over sodium sulfate and concentrated, and purified by column chromatography (elution with petroleum ether / ethyl acetate = from 20: 1 to about 1 : 1), to provide the title compound (6 g, 50%). 1 - (2,4-DIMETOXI-6-T RIFLUOROMETHYL-PHENYL) -ETHANONE
[0131] A mixture of 1 - (2-iodo-4,6-dimethoxy-phenyl) -ethanone (3.17 g, 10.1 mmol), difluoro-fluoro-acetic acid methyl ester (7.9 g , 41.1 mmol) and Cui (3.8 g, 20 mmol) in NMP (50 mL) was heated to 120 ° C under nitrogen overnight. The mixture was filtered and diluted with water (200 ml), and extracted with ethyl acetate (3 x 50 ml). The organic layers were washed with brine (50 ml), dried over sodium sulfate and concentrated and purified by column chromatography (elution with petroleum ether: ethyl acetate = from 20: 1 to about 10: 1) to provide the title compound (1.6 g, 64%). 2-ETHYL-1,5-DIMETOXY-3-T RIFLUOROMETHYL BENZENE
[0132] Zinc (8.4 g, 0.13 mol) was added over 10 min to a solution of 1 - (2,4-dimethoxy-6-trifluoromethyl-phenyl) -ethanone (1.6 g, 6.4 mmol) in ethyl ether (20 mL) and concentrated hydrogen chloride (20 mL) at 0 ° C. The mixture was stirred at room temperature for 2 h. The mixture was filtered, extracted with ethyl ether (3 x 50 ml), washed with brine (30 ml), dried over sodium sulfate and concentrated, and purified by column chromatography (elution with petroleum ether) to provide the title compound (0.4 g, 27%). 2-ETYL-1,5-DIHYDROXY-3-TRIFLUOROMETHYL-BENZENE (4.5 ETFMR)
[0133] BBr3 (12 mL, 0.67 mol / L) was added to a mixture of 2-ethyl-1,5-dimethoxy-3-trifluoromethyl-benzene (0.4 g, 1.9 mmol) in dichloromethane (10 ml), and the mixture was stirred at room temperature for 4 h. methanol (5 ml) was slowly added to the mixture at 0 ° C, and the mixture was concentrated to provide an oily residue, which was diluted with water (20 ml), extracted with dichloromethane (4x10 ml), washed with brine (10 ml), concentrated and purified by preparative HPLC to provide the title compound (140 mg, 40%). LC-MS 205 (M-1). NMR 1H (400 MHz, CDCIs) δ 6.69 (d, J = 2.0 Hz, 1H), 6.48 (d, J = 2.0 Hz, 1 H), 5.06 (s, 1H) , 4.99 (s, 1H), 2.70 (q, J = 7.6 Hz, 2H), 1.16 (t, J = 7.6 Hz, 3H). 19R NMR (400 MHz, CDCIs) δ -60.2 (s). COMPARATIVE EXAMPLE 4: 4-CYCLEEXYL-3-T RIFLUOROMETHYL-BENZENE-1, 3-DIOL (4.5CHTFM R)
1 -IODE-3,5-DIMETOXI-BENZENE
[0134] A mixture of 1-bromo-3,5-dimethoxy-benzene (9.6 g, 44 mmol), Cul (0.7 g, 3.6 mmol), Nal (13.3 g, 88 mmol) and MeNHCH2CH2NHMe (0.78 mL) in 1,4-dioxane (80 mL) was degassed and filled with nitrogen in a sealed tube. The reaction mixture was heated to 120 ° C for 20 h. The mixture was cooled to room temperature. Water (100 ml) was added, and the mixture was extracted with ethyl acetate (2 x 60 ml). The organic layers were washed with brine (50 ml), dried over sodium sulfate, and concentrated to provide the title compound (10 g, 86%). 1,3-DIMETOXI-5-T RIFLUOROMETHYL-BENZENE
[0135] A mixture of 1-iodo-3,5-dimethoxy-benzene (1.6 g, 6.0 mmol), difluoro-fluoro-acetic acid methyl ester (3.1 mL, 24 mmol), and Cul (3.4 g, 18 mmol) in NMP (30 ml) was heated to 120 ° C for 16 h, then the mixture was cooled to room temperature and water (50 ml) was added. The mixture was extracted with ethyl acetate (200 ml), washed with water (2 x 50 ml), and the organic layer was dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (elution with petroleum ether) to provide the title compound (0.54 g, 44%). 2-BROMO-1,5,5-DIMETOXI-3-T RIFLUOROMETHYL-BENZENE
[0136] A mixture of NBS (2.75 g, 16.9 mmol) and 1,3-dimethoxy-5-trifluoromethyl-benzene (3.5 g, 16.9 mmol) in dichloromethane was stirred at room temperature for 16 H. The mixture was concentrated and purified by column chromatography (elution with petroleum ether: ethyl acetate = 5: 1) to provide the title compound (4 g, 83%). NMR 1H (400 MHz, CDCIs) δ 6.84 (d, J = 2.8 Hz, 1H), 6.63 (d, J = 2.8 Hz, 1H), 3.91 (s, 3H), 3.84 (s, 3H). NMR 19F (360 MHz, CDCI3) δ -62.7 (s). 2-CYCLE-HEX-1-ENYL-1,5-DIMETOXI-3-TRIFLUOROMETHYL BENZENE
[0137] To a mixture of 2-bromo-1,5-dimethoxy-3-trifluoromethyl-benzene (50 mg, 0.175 mmol), Pd (PPh3) 2Cl2 (12 mg, 0.0175 mmol), and K2CO3 (97 mg , 0.7 mmol) in mixed solvents (DMF / MeOH, 3: 1, 1.2 mL) in a sealed tube, 2-cyclohex-1-enyl-4,4,5,5-tetramethyl- [1.3.2] dioxaborolane (73 mg, 0.35 mmol). The tube was degassed and filled with N2 (3 x) and sealed under an N2 atmosphere. The tube was heated in an oil bath at 100 ° C for 6 h. After being cooled to room temperature, the reaction mixture was diluted with ethyl acetate / hexane and water. The organic layer was washed with brine, dried with Na2SO4, concentrated, and purified by preparative TLC (ethyl acetate / hexane, 8: 2) to provide the title compound (22 mg, 44%). 2-CYCLEEXYL-I, 5-DIMETOXY-3-T RIFLUOROMETHYL-BENZENE
[0138] 2-Cyclohex-1-enyl-1,5-dimethoxy-3-trifluoromethyl-benzene (800 mg, 2.8 mmol) and MeOH (40 mL) was loaded into a 200 ml round-bottom flask mL equipped with a stir bar and a septum cap. The solution was sparged with nitrogen for 5 min. To the mixture of 10 wt% palladium on carbon (400 mg) was added. The flask was aspirated and filled with a hydrogen balloon. The reaction mixture was stirred at 50 ° C for 16 h. The reaction mixture was filtered and concentrated to provide a residue, which was purified by silica gel column chromatography with ethyl acetate / hexanes to provide the title compound (480 mg, 59%) as a white solid. 4-CYCLEEXYL-3-TRIFLUOROMETHYL-BENZENE-1,3-DIOL (4,5CHTFMR)
[0139] To a solution of 4-cyclopentyl-1,3-dimethoxy-5-methylbenzene (480 mg, 1.67 mmol) in anhydrous CH2 Cl2 (15 mL) at -78 ° in a dry ice / acetone bath was added boron tribromide (1.25 g, 5.0 mmol). The reaction mixture was stirred at -78 ° for 5 min and slowly warmed to room temperature overnight. The reaction mixture was quenched by the slow addition of water (50 ml). The mixture was extracted with ether (3 x). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated to provide a residue, which was purified by silica gel column chromatography with ethyl acetate / hexanes to provide the title compound (300 mg, 69 %). LC-MS: 259 (M-1). NMR 1H (400 MHz, CDCI3) δ 6.69 (d, 1H), 6.40 (d, 1H), 5.11 (s, 1H), 5.07 (s, 1H), 2.88 (m , 1H), 1.99 (m, 2H), 1.69 (m, 4H), 1.29 (m, 4H). EXAMPLE 5: 4-HEXIL-5-METHYL-BENZENE-1,3-DIOL (4.5HMR)
[0140] The title compound can be prepared using methods analogous to those described in the Examples and general synthetic schemes. LC-MS: 209.0 (M + 1). NMR 1H (DMSO-de, 400 MHz) δ 8.87 (s, 1H), 8.79 (s, 2H), 6.07 (d, 1H), 5.98 (d, 1H), 2.34 (s, 2H), 2.07 (s, 3H), 1.23 (m, 8H), 0.83 (t, 3H). EXAMPLE 6: 4-ISOPROPIL-5-METHYL-BENZENE-1,3-DIOL (4.5IPMR)
[0141] The title compound can be prepared using methods analogous to those described in the Examples and general synthetic schemes. NMR 1H (DMSO-de, 400 MHz) δ 8.83 (s, 1H), 8.78 (s, 1H), 6.05 (d, 1H), 5.94 (d, 1H), 3.04 (m, 1H), 2.09 (s, 3H), 1.20 (s, 3H), 1.18 (s, 3H). EXAMPLE 7: 4-BUTYL-5-METHYL-BENZENE-1,3-DIOL (4.5BMR)
[0142] The title compound can be prepared using methods analogous to those described in the Examples and general synthetic schemes. LC-MS: 180.8 (M + 1). NMR 1H (DMSO-de, 400 MHz) δ 8.87 (s, 1H), 8.78 (s, 1H), 6.07 (d, 1H), 5.98 (d, 1H), 2.37 (t, 2H), 2.07 (s, 3H), 1.28 (m, 4H), 0.85 (t, 3H). COMPARATIVE EXAMPLE 8: 4-BENZYL-5-METHYL-BENZENE-1,3-DIOL (4,5BNMR)
[0143] The title compound can be prepared using methods analogous to those described in the Examples and general synthetic schemes. NMR 1H (400 MHz) CDCI3) δ 7.27 (m, 2H), 7.17 (m, 3H), 6.30 (d, 1H), 6.22 (d, 1H), 4.73 (s , 1H), 4.68 (s, 1H), 3.97 (s, 2H), 2.21 (s, 3H). EXAMPLE 9: 4-CYCLOPROPIL-5-METHYL-BENZENE-1,3-DIOL (4,5CPRMR)
[0144] The title compound can be prepared using methods analogous to those described in the Examples and general synthetic schemes. NMR 1H (DMSO-de, 400 MHz) δ 8.85 (s, 1H), 8.66 (s, 1H), 6.04 (d, 1H), 5.99 (d, 1H), 2.17 (s, 3H), 1.35 (m, 1H), 0.75 (m, 2H), 0.45 (m, 2H). EXAMPLE 10: 4-CYCLOPENTYLMETHIL-5-METHYL-BENZENE-1,3-DIOL (4.5MCPMR)
[0145] The title compound can be prepared using methods analogous to those described in the Examples and general synthetic schemes. LC-MS: 207.0 (M + 1). NMR 1H (DMSO-dθ, 400 MHz) δ 8.85 (s, 1H), 8.79 (s, 1H), 6.08 (s, 1H), 5.99 (s, 1H), 2.39 (d, 2H), 2.08 (s, 3H), 1.99 (m, 1H), 1.52 (m, 6H), 1.18 (m, 2H). EXAMPLE 11: 4-CICLOPENTIL-5-METHYL-BENZENE-1,3-DIOL (4,5CPMR)
[0146] The title compound can be prepared using methods analogous to those described in the Examples and general synthetic schemes. LC-MS: 193.1 (M + 1). NMR 1H (400 MHz) CDCI3) δ 6.23 (d, 1H), 6.13 (d, 1H), 4.63 (s, 1H), 4.58 (s, 1H), 3.25 (m , 1H), 2.27 (s, 3H), 1.88 (m, 6H), 1.67 (m, 2H). COMPARATIVE EXAMPLE 12: 4-ETHYL-5-METHYL-BENZENE-1,3-DIOL (4,5EMR)
[0147] The title compound can be prepared using methods analogous to those described in the Examples and general synthetic schemes. LC-MS: 152.8 (M + 1). NMR 1H (DMSO-de, 400 MHz) δ 8.87 (s, 1H), 8.76 (s, 1H), 6.08 (s, 1H), 5.99 (s, 1H), 2.38 (q, 2H), 2.08 (s, 3H), 0.93 (t, 3H). EXAMPLE 13: 4-SEC-BUTYL-5-METHYL-BENZENE-1,3-DIOL (4,5SBMR)
[0148] The title compound can be prepared using methods analogous to those described in the Examples and general synthetic Schemes. LC-MS: 181.15 (M + 1). 1H NMR (, 400 MHz, CD3OD) δ 6.21 (s, 1H), 6.11 (s, 1H), 4.80 (m, 2H), 2.92 (m, 1H), 1.80 ( m, 2H), 1.26 (d, 3H), 0.82 (t, 3H). COMPARATIVE EXAMPLE 14: 4- (1-PHENYLETYL) -5-METHYL-BENZENE-1,3-DIOL (4,5PEMR)
[0149] The title compound can be prepared using methods analogous to those described in the Examples and general synthetic Schemes. LC-MS: 229.0 (M + 1). NMR 1H (400 MHz, CDCI3) δ 7.32 (m, 3H), 7.25 (m, 2H), 6.29 (d, 1H), 6.13 (d, 1H), 4.64 (s , 1H), 4.50 (m, 2H), 2.32 (s, 3H), 1.63 (t, 3H). COMPARATIVE EXAMPLE 15: 4- (2,2,2-TRIFLUORO-ETHYL) -5-METHYL-BENZENE-1,3-DIOL (4,5TFEMR)
[0150] The title compound can be prepared using methods analogous to those described in the Examples and general synthetic schemes. 1H NMR (, 400 MHz, CD3OD) δ 6.16 (s, 2H), 3.43 (q, 2H), 2.20 (s, 3H). COMPARATIVE EXAMPLE 16: 4-CICLOEXIL-5-FLUOROBENZENE-1,3-DIOL (4,5EFR)
[0151] The title compound can be prepared using methods analogous to those described in the Examples and general synthetic schemes. 1H NMR (DMSO-de, 400 MHz) δ: 9.48 (s, 1H), 9.33 (s, 1H), 6.12 (dd, J = 2.3, 1.3 Hz, 1H), 5.96 (dd, J = 12, 2.3 Hz, 1H), 2.85 (qd, J = 7.4, 1.2 Hz, 2H), 1.01 (t, J = 7.4 Hz , 3H). COMPARATIVE EXAMPLE 17: 2-BENZIL-1,5-DIHYDROXY-3-TRIFLUOROMETHYL BENZENE (4.5BNTFMR)
[0152] LC-MS: 267 (M-1). NMR 1H (400 MHz, CDCI3) δ from 7.14 to 7.28 (m, 5H), 6.81 (d, J = 2.0 Hz, 1H), 6.52 (s, 1H), 5, 11 (s, 1H), 4.98 (s, 1H), 4.11 (s, 2H). NMR 19F (360 MHz, CDCI3) δ -59.7 (s). EXAMPLE 18: MUSHROOM TYROSINASE INHIBITION ANALYSIS
[0153] 10 pM compound, 300 pM L-tyrosine, and 84 units / mL mushroom tyrosinase (Sigma T3824) were combined in 0.05 M potassium monophosphate buffer at pH = 6.5, and incubated for 15 min at room temperature. The absorbance was recorded at 490 nm. The percentage (%) of tyrosinase inhibition was calculated as follows: (AbSDMSo - Abscmpd) / AbSDMso X100. The analysis was performed for several compounds described herein, as well as for the control compounds of resorcinol 4-ethyl (4ER), 4-isopropylresorcinol (4IPR), 4-hexylresorcinol (4HR), 4-cyclohexylresorcinol (4CHR), 5- methylylorcinol (5MR), cojic acid (KA) and hydroquinone (HQ), their structures are shown below. The results are shown in Table 1.
TABLE 1 MUSHROOM TYROSINASE (% OF REMAINING ENZYMATIC ACTIVITY)
EXAMPLE 19: ANALYSIS OF MAMMALIAN TYROSOSINE INHIBITION
[0154] B16F1 cells are grown in Dulbecco's Modified Eagle's Medium (DMEM), 10% FBS, 10% CO2 P / S and 37 ° C for 90% confluence. The cell lysate is prepared with 150 mM NaCI; 20 mM Tris-HCI, pH = 7.4; and 1% Triton-X100. The analysis is carried out in buffer (0.05 M potassium monophosphate buffer, pH = 6.5, 600 µM L-tyrosine, 15 µm L-Dopa, 0.325 mg / mL B16F1 cell lysate) with the compound at 10 µM. After mixing, the reaction mixture is incubated at 37 ° C for 8 h and the absorbance measured at 490 nm. The percentage (%) of tyrosinase inhibition is calculated as follows: (AbsoMso - AbScmpd) / AbSDMSO X 1 00. EXAMPLE 20: MELANINAB16 ANALYSIS
[0155] B16F1 cells were grown in phenol free of 10% DMEM FBS, 10% P / S CO2 and 37 ° C. After trypsinization, cells were seeded into 3,000 cells per well in a 96-well plate and left to set overnight. 1 mM theophylline was used to stimulate melanogenesis, and the compound of interest was added. After 72 hours of growth at 10% CO2 and 37 ° C, the absorbance medium was measured at 405 nm and corrected for cell viability measured with calcein-AM. The percentage (%) of the melanin content was calculated as follows: (AbSDMso / CalceinDMso - AbScmpd / Calceincmpd) / AbsoMso / CalceinDMso X 100. The analysis was performed for several compounds described in the present, as well as for the 4ER control compounds , 4IPR, 4HR, 4CHR, 5MR, cojic acid, and hydroquinone. The results are shown in Table 2. TABLE 2 MEANS OF MELANINAB16 (% MELANINE)

EXAMPLE 21: ANALYSIS OF CO-CULTURE OF MELANOCYTE-HACAT
[0156] Darkly pigmented human neonatal epidermal melanocytes (HEMn-DP, Invitrogen) were cultured in 254 medium with HMGS-2 and P / S supplement at 37 ° C and 5% CO2. HaCaT cells were cultured in DMEM, 10% FBS, P / S at 37 ° C, 5% CO2. Co-culture was performed in 50% melanocyte medium + 50% keratinocyte medium (EpiLife with EDGS, P / S). The cells were plated in 40K (HaCaT) and 30K (HEMn-DP) co-culture medium per well in a 24-well plate. After 24h incubation at 37 ° C and 5% CO2, the medium was changed to M153 (MCDB153 Sigma M7403 with NaHCOsa pH to 7.1, 2 mM tyrosine, 10 nM NDP-aMSH, 3 ng / mL of bFGF, 2.8 µg / ml hydrocortisone, 10 µg / ml insulin, 10 µg / ml transferrin, and P / S), treated with the compound, and incubated for 72 h at 37 ° C and 5% CO2. After measuring cell viability with Calcein-AM (RFU Ex / Em = 488/525 nm), cells were lysed in 1 h at 65 ° C with 1 N NaOH + 10% DMSO. The absorbance of the clarified lysate was measured at 405 nm and 660 nm. The percentage (%) of melanin was calculated as follows: (((Abs405DMso - Abs66ÜDMso) I CalceinDMso) - (Abs405comp - Abs660comp) / Calceincomp)) I (Abs405DMso - Abs66θDMso) I CalceinoMso x 100. At a concentration of 10 pM, a percentage (%) of cellular melanin was 42% in the presence of the compound 4.5CHMR. EXAMPLE 22: MATTEK SKIN 3D EQUIVALENTS
[0157] The MelanoDerm analysis (Mel-300-B) was conducted according to the manufacturer's instructions (MatTek Corporation). Every two days, the test articles were administered in the EPI-100-NMM-113 culture medium, and the positive control, 25 µl of 2% cojic acid was topically applied. After 14 days, the viability of the tissue and cell morphology was visually checked and the melanin from the tissue was extracted and quantified against a standard curve. The percentage (%) of melanin was calculated as follows: (MelaninDMso -Melanincomp) / MelaninoMso x 100. The analysis was performed for several compounds described herein, as well as for the control compounds 4ER, 4IPR, 4HR, 4CHR, acid cojic and hydroquinone. The results are shown in Table 3. TABLE 3 MATTEK ANALYSIS (% MELANINE)

EXAMPLE 23: CLINICAL EVALUATION FOR DARK CIRCLES (NON-PATHOLOGICAL}
[0158] Female individuals with light to moderate dark circles under their edges are recruited for the study after providing informed consent. The study is conducted in accordance with all applicable government regulations and institutional policies. An expert classifier and individuals assess the severity of the dark circles under the eyes, before applying the test products. A composition containing one or more compounds, as described herein, is topically applied to the area of skin around an eye and a composition not containing the compounds described herein, around the contralateral eye as a control. Treatment assignments are randomized across the panel, and neither the individual nor the classifier is aware of the treatment code. One hour after applying the product, the classifier and individual separately assess the appearance of the dark circles under the eyes. EXAMPLE 24: CLINICAL EVALUATION FOR SWELLING (HAND - PATHOLOGICAL)
[0159] A set of female individuals with puffiness under the eyes is recruited after providing informed consent. The study is conducted in accordance with all applicable government regulations and institutional policies. A composition containing a compound described herein is applied under one eye, and a composition without the compound, as described herein, is applied under the other eye as a control. Individuals use the product for 4 weeks, returning at week 2 for another dermatological evaluation. After 2 and 4 weeks of using the product, individuals and the dermatologist evaluate the improvement in eye puffiness compared to baseline observations. EXAMPLE 25: CLINICAL EVALUATION FOR THE SIGNS OF AGING (HAND - PATHOLOGICAL)
[0160] A number of male and female individuals are recruited after providing informed consent. The study is conducted in accordance with all applicable government regulations and institutional policies. The expert classifiers trained in visual and tactile assessments evaluate the different signs of aging of each individual's face through classification on a semi-structured scale. Each individual is characterized by a quantitative profile of their signs of aging and two expert classifiers evaluate each parameter at each point in time. A composition containing a compound described herein is applied to a section of the face, and a composition without the compound as described herein is applied to another section of the face as a control. Individuals use the product for 4 weeks, returning at week 2 and 4 weeks for an evaluation by the classifiers.
[0161] The average values and standard deviation are calculated, as well as the variations of the parameter in relation to before the application (expressed in percentage). A paired Student's t test is used to determine the meaning of the results. Although the present compositions and methods are described with reference to their specific variations, it should be understood by those skilled in the art that various changes can be produced and equivalents can be replaced without departing from the true spirit and scope of the compositions and methods described in the present. In addition, many modifications can be produced to adapt a special situation, material, material composition, process, stage or stages of the process, to the object, spirit and scope of the compounds and methods described herein. All patents and publications mentioned above are hereby incorporated by reference.

权利要求:
Claims (12)
[0001]
1. COSMETIC COMPOSITION, or dermatological, characterized by comprising:
[0002]
2. NON-THERAPEUTIC METHOD TO REDUCE OR TREAT SIGNS OF SKIN AGING, or to reduce the appearance of signs of skin aging, characterized by understanding the administration, to an individual who exhibits this skin condition, the composition, as defined in the claim 1.
[0003]
3. NON-THERAPEUTIC METHOD TO PREVENT, LIGHTEN OR REDUCE THE APPEARANCE OF VISIBLE SKIN DISCONTINUITIES, characterized by understanding the administration, to an individual who exhibits said skin conditions, the composition, as defined in claim 1, in which the visible discontinuities on the skin are associated with aging, age-related damage, or pigmentation disorders.
[0004]
4. METHOD, according to claim 3, characterized by the visible discontinuities being associated with pigmentation disorders, which are selected from the group containing irregular pigmentation, aging spots, signs of age and melasma.
[0005]
METHOD according to any one of claims 3 to 4, characterized in that the signs of aging are treated or reduced simultaneously.
[0006]
6. NON-THERAPEUTIC METHOD TO PREVENT, CLARE OR REDUCE THE APPEARANCE OF VISIBLE DISCONTINUITIES IN THE SKIN, resulting from the aging or melasma process, characterized by understanding the administration, to an individual exhibiting the said skin condition, the composition, as defined in claim 1.
[0007]
7. METHOD, according to claim 6, characterized by the signs of aging being reduced or treated simultaneously.
[0008]
METHOD, according to any one of claims 6 to 7, characterized by the discontinuities visible in the skin being selected from the group containing irregular pigmentation, aging spots and signs of age.
[0009]
9. COMPOSITION, according to claim 1, characterized by comprising a compound selected from the group consisting of:
[0010]
10. COMPOSITION, according to claim 9, characterized by the dermatological condition being vitiligo or melasma.
[0011]
11. USE OF A COMPOSITION, as defined in any one of claims 1 to 10, characterized in that it is for the manufacture of a medicament to reduce or treat signs of skin aging or to reduce the appearance of signs of skin aging.
[0012]
12. USE OF A COMPOSITION, as defined in any one of claims 1 to 13, characterized in that it is for the manufacture of a medicament to prevent, lighten or reduce the appearance of visible discontinuities of the skin.

类似技术:

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BR112015021033B1|2020-08-04|COSMETIC COMPOSITION, NON-THERAPEUTIC METHODS TO REDUCE OR TREAT SKIN AGING SIGNS AND TO PREVENT, LIGHTEN OR REDUCE THE APPEARANCE OF VISIBLE SKIN DISCONTINUITIES AND USES OF A COMPOSITION

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同族专利:

---

公开号 | 公开日

---

BR112015021033A2|2017-07-18|

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EA201591367A1|2016-02-29|

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BR112015021033A8|2019-11-26|

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JP2016510757A|2016-04-11|

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EP2964182A2|2016-01-13|

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US10470986B2|2019-11-12|

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CA2902506A1|2014-09-12|

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WO2014138471A2|2014-09-12|

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EA031098B1|2018-11-30|

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CN105142603A|2015-12-09|

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EP2964182B1|2018-02-14|

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WO2014138471A3|2014-12-04|

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CN105142603B|2018-10-19|

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US20140256830A1|2014-09-11|

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MX2015011966A|2016-04-07|

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ZA201506589B|2017-01-25|

---

US20160000669A1|2016-01-07|

---

MX355430B|2018-04-18|

---

JP6313791B2|2018-04-18|

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law|

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2018-05-15| B07B| Technical examination (opinion): publication cancelled|

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2019-07-23| B06U| Preliminary requirement: requests with searches performed by other patent offices: suspension of the patent application procedure|

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2020-04-07| B09A| Decision: intention to grant|

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2020-08-04| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 06/03/2014, OBSERVADAS AS CONDICOES LEGAIS. |

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2021-02-09| B25A| Requested transfer of rights approved|Owner name: UNILEVER IP HOLDINGS B.V. (NL) |

优先权:

---

申请号 | 申请日 | 专利标题

---

US201361775384P| true| 2013-03-08|2013-03-08|

---

US61/775,384|2013-03-08|

---

PCT/US2014/021390|WO2014138471A2|2013-03-08|2014-03-06|Resorcinol compounds for dermatological use|

---