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WO2001068576A1 - Composes dermatologiques - Google Patents

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Publication number
WO2001068576A1
WO2001068576A1 PCT/US2000/006373 US0006373W WO0168576A1 WO 2001068576 A1 WO2001068576 A1 WO 2001068576A1 US 0006373 W US0006373 W US 0006373W WO 0168576 A1 WO0168576 A1 WO 0168576A1
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WO
WIPO (PCT)
Prior art keywords
dimethyl
norbornane
substituted
disease
compound
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Ceased
Application number
PCT/US2000/006373
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English (en)
Inventor
Wu Yun Ren
David A. Brown
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Applied Genetics Inc
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Applied Genetics Inc
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Filing date
Publication date
Application filed by Applied Genetics Inc filed Critical Applied Genetics Inc
Priority to PCT/US2000/006373 priority Critical patent/WO2001068576A1/fr
Priority to EP00917846A priority patent/EP1261572A4/fr
Priority to AU2000238755A priority patent/AU2000238755A1/en
Publication of WO2001068576A1 publication Critical patent/WO2001068576A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C31/27—Polyhydroxylic alcohols containing saturated rings
    • C07C31/278—Polycyclic with condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/22—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system
    • C07C35/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with hydroxy on a condensed ring system having two rings
    • C07C35/28—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with hydroxy on a condensed ring system having two rings the condensed ring system containing seven carbon atoms
    • C07C35/29—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with hydroxy on a condensed ring system having two rings the condensed ring system containing seven carbon atoms being a (2.2.1) system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

Definitions

  • the present invention relates to novel monocyclic and bicyclic monoterpene diols that stimulate melanogenesis in mammalian skin, hair, wool or fur, and, are useful for treating or preventing various skin and proliferative disorders, neurodegenerative diseases, and diseases regulated by the nitric oxide/cyclic GMP/protein kinase G pathway.
  • U.S. Patent 5,352,440 is directed to increasing melanin synthesis in melanocytes and increasing pigmentation by administration of certain diacylglycerol compounds .
  • U.S. Patent 5,532,001 is directed to increasing pigmentation in mammalian skin via administration of certain DNA fragments.
  • U.S. Patent 5,554,359 is directed to increasing levels of melanin in melanocytes by administration of lysosomotropic agents.
  • the present invention is directed to compounds having the structure :
  • A is a substituted or unsubstituted cyclic terpene
  • R 1# R 2 , R 8 and R 9 are all -OH;
  • R 3 , R 4 , R 5 , R 6 , R 7 an ⁇ R 10 are each independently hydrogen, or a linear or branched, cyclic, bicyclic or polycyclic group containing from one atom to fifty atoms, at least one of which is carbon, nitrogen, oxygen, or sulfur.
  • Another aspect of the present invention concerns stimulation of melanogenesis in mammalian skin, hair, wool or fur, by administering to a locus in need of such stimulation an effective amount of one or more of the compounds described above .
  • Another aspect of the present invention concerns treatment of proliferative, tumorous or cancerous disorders in mammals, including but not limited to such conditions of a dermatological nature, by administering to a mammal in need of such treatment an effective amount of one or more of the compounds described above .
  • a further aspect of the present invention concerns treatment of neurodegenerative disorders or nerve damage in mammals by administering to a mammal in need of such treatment an effective amount of one or more of the compounds described above.
  • Another aspect of the present invention concerns treatment of diseases regulated by the nitric oxide/cyclic GMP/protein kinase G pathway in mammals by administering to a mammal in need of such treatment an effective amount of one or more of the compounds described above.
  • Figure 1 is a photograph of treated human skin as described in Example 7.
  • the compounds of the present invention have the structures described above.
  • the A cyclic terpene portion is monocyclic or bicyclic, more preferably bicyclic.
  • A is a substituted or unsubstituted moiety having the skeleton of (+) or (- ) -camphenes; ( +) or (-) -camphor; (-) -yff-pinenes and 2- or 3-carenes; (-)-myrtenol or (-) -myrtanol ; or (-)-verbenol or (-) -verbenone and their derivatives, some of which are shown below.
  • R 3 , R 4 , R 5 , R 6 , R 7 and R 10 are each independently hydrogen, or a linear or branched, cyclic, bicyclic or polycyclic group containing from one atom to fifty atoms, at least one of which is carbon, nitrogen, oxygen, or sulfur.
  • R groups include linear or branched alkyl, particularly alkyl, linear or branched alkenyl, linear or branched alkynyl, cycloalkyl, aryl, aralkyl, polynuclear groups such as tetralin, decalin or pyrene, and heterocyclic groups containing nitrogen, sulfur and/or oxygen, such as pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, 3- pyrroline, pyridine, pyrimidine, purine, quinoline, isoquinoline or carbazole.
  • any of the foregoing groups may be optionally substituted with groups such as halogens, amino, nitro, hydroxyl or sulfhydryl.
  • groups such as halogens, amino, nitro, hydroxyl or sulfhydryl.
  • non-cyclic terpene backbone portion of the present compounds they preferably have one of the structures shown immediately below:
  • R is hydrogen or methyl
  • Particularly preferred compounds include (-)-2,2- dimethyl-3-hydroxy-3-hydroxymethyl-norbornane; (+) -2,2- dimethyl-3-hydroxy-3-hydroxymethyl-norbornane; (-) -2,2- dimethyl-3- (2 , 3-dihydroxy-propan-3-yl) -norbornane; and (+) -2 , 2-dimethyl-3- (2 , 3-dihydroxy-propan-3-yl) - norbornane .
  • the present invention is based on the unique observation that the present compounds effectively and efficiently induce melanogenesis in mammalian cells, which has several consequences.
  • increasing melanogenesis leads to increasing the melanin content of melanocytes, and hence results in increased pigmentation or darkened color of the skin, hair, wool or fur.
  • hypopigmentation disorders such as albinism, vitiligo, etc.
  • increasing the pigmentation of skin according to the present invention will protect such skin from subsequent UV light damage, sunburn, photoaging and development of skin cancers.
  • the present invention may be used to treat hyperproliferative disorders such as actinic keratosis, basal cell carcinoma, squamous cell carcinoma, fibrous histiocytoma, dermatofibrosarcoma protuberans, hemangioma, nevus flammeus, xanothoma, Kaposi ' s sarcoma, mastocytosis, mycosis fungoides, lentigo, nevocellular nevus, lentigo maligna, malignant melanoma, and metastatic carcinoma.
  • hyperproliferative disorders such as actinic keratosis, basal cell carcinoma, squamous cell carcinoma, fibrous histiocytoma, dermatofibrosarcoma protuberans, hemangioma, nevus flammeus, xanothoma, Kaposi ' s sarcoma, mastocytosis, mycosis fungoides, lentigo,
  • the present methods and compositions are also useful in the treatment of diseases characterized by inflammation and disturbance of keratinization, including psoriasis vulgaris, psoriasis eosinophilia, acne vulgaris, acne conglobata, acne fulminans, osteoma cutis, nodulocystic acne, cystic acne and benign and premalignant dermatoses .
  • the compounds also effectively and efficiently increase differentiation of neuronal cells, including increased neuronal dendricity and neuronal tyrosine hydroxylase activity, which has several consequences.
  • increasing dendricity leads to increased neuronal communication, thereby increasing neuronal function and performance.
  • the present invention is useful for treating diseases or disorders marked by reduction of neuronal dendricity and function, including but not limited to Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, or any other neurodegenerative disease, or physical or toxic damage to brain, spinal or peripheral nerve cells.
  • the present invention is useful for restoring or optimizing neuronal communication, function or performance.
  • the present invention is particularly useful for treating Parkinson's disease which is specifically marked by depletion of dopamine synthesis.
  • the present invention is useful for treating neuronal proliferative, tumorous, or cancerous disorders, or said disorders in any other cell type that might be similarly affected.
  • the present invention is useful for treating additional neurodegenerative disorders or neuropathies including but not limited to diffuse cerebral cortical atrophy, Lewy- body dementia, Pick disease, mesolimbocortical dementia, thalamic degeneration, Huntington chorea, cortical- striatal-spinal degeneration, cortical-basal ganglionic degeneration, cerebrocerebellar degeneration, familial dementia with spastic paraparesis, polyglucosan body disease, Shy-Drager syndrome, olivopontocerebellar atrophy, progressive supranuclear palsy, dystonia musculorum deformans, Hallervorden-Spatz disease, Meige syndrome, familial tremors, Gilles de la Tourette syndrome, acanthocytic chorea, Friedreich ataxia, Holmes familial cortical cerebellar atrophy, Gerstmann
  • the compounds of this invention appear to act by direct stimulation of nitric, oxide synthase (NOS) activity, thus generating NO de novo.
  • NOS nitric, oxide synthase
  • the compounds of the present invention will provide a preferred alternative method of treatment for conditions presently treated by NO donors.
  • heart disease including stable angina pectoris, unstable angina, myocardial infarction, and myocardial failure associated with myocardial ischemia, atherosclerosis, vascular hypertrophy, and thrombosis (Cooe and Dzau, 1997, A ⁇ u. .Rev. Med. 48:489-509; Thadani, 1997, Cardiovasc . Drugs 10:735);
  • NO/cGMP/PKG pathway mediates melanogenesis induced by ultraviolet light (Romero- Graillet, et al . , 1996, J “ . Biol . Chem. 271:28052-28056; Romero-Graillet, et al . , 1997, J “ . Clin . Invest . 99:635- 642) and aliphatic and alicyclic diols (United States patent application S.N. 08/933,143, entitled “Dermatalogical Compositions and Methods” filed September 18, 1997) .
  • the present invention contemplates the use of one or more of the above-mentioned compounds as an active ingredient for various uses.
  • the active ingredient (s) is combined with an acceptable carrier to form a topical formulation which may be placed on the skin for dermatological uses.
  • Topical formulations may include ointments, lotions, pastes, creams, gels, drops, suppositories, sprays, liquids, shampoos, powders and transdermal patches. Thickeners, diluents, emulsifiers, dispersing aids or binders may be used as needed.
  • one function of the carrier is to enhance skin penetration of the active ingredient (s) , and should be capable of delivering the active ingredient (s) to melanocytes under in vivo conditions.
  • Suitable carriers are well known to one of ordinary skill, and include liposomes, ethanol, dimethylsulfoxide (DMSO) , petroleum jelly (petrolatum), mineral oil (liquid petrolatum) , water, dimethylformamide, dekaoxyethylene-oleylether, oleic acid, 2-pyrrolidone and Azone ® brand penetration enhancer (Upjohn) .
  • a particularly preferred composition includes an active ingredient (s) as described above, with one of 2-pyrrolidone, oleic acid and/or Azone ® as penetration enhancer, solubilized in a base of water, ethanol, propanol and/or propylene glycol (the latter component having properties of a carrier, penetration enhancer and an active ingredient as described herein) .
  • the compositions of the present invention may also include other active ingredients, as well as inert or inactive ingredients.
  • compositions include an active ingredient (s) in conjunction with one or more melanogenesis-enhancing agents such as -hydroxy acids, salts and derivatives thereof; ⁇ -keto acids, salts and derivatives thereof; ⁇ -hydroxy acids, salts and derivatives thereof; retinoids, salts and derivatives thereof; Vitamin A and related compounds; acids; phenol; and methoxypropyl-gluconamide, as more fully described in co-pending application Serial No. filed April
  • the dose regimen will depend on a number of factors which may readily be determined, such as severity and responsiveness of the condition to be treated, but will normally be one or more doses per day, with a course of treatment lasting from several days to several months, or until a cure is effected or a diminution of disease state is achieved, or a cosmetically desired degree of melanogenesis (tanning) is achieved, depending on the application.
  • dose regimen will depend on a number of factors which may readily be determined, such as severity and responsiveness of the condition to be treated, but will normally be one or more doses per day, with a course of treatment lasting from several days to several months, or until a cure is effected or a diminution of disease state is achieved, or a cosmetically desired degree of melanogenesis (tanning) is achieved, depending on the application.
  • One of ordinary skill may readily determine optimum dosages, dosing methodologies and repetition rates.
  • topical formulations such as creams, lotions, solutions, etc.
  • a concentration of active ingredient of from about 0.01% to about 50%, preferably from about 0.1% to about 10%.
  • unit dosage form compositions according to the present invention will contain from about 0.01 mg to about 100 mg of active ingredient, preferably about 0.1 mg to about 10 mg of active ingredient.
  • compositions of the present invention also contemplate the use of one or more of the above-mentioned compounds as an active ingredient to stimulate neuronal differentiation, dendricity, and/or tyrosine hydroxylase activity (with resultant increased dopamine synthesis) and/or to treat disease conditions related to the NO/cGMP/PKG pathway.
  • the active ingredient (s) is given orally, intravenously, or transdermally in an acceptable formulation.
  • a particularly preferred carrier for some formulations is 1, 2-propylene glycol since it is an excellent solvent for certain compounds in this invention. Additionally, 1, 2-propylene glycol as carrier has itself, as described in this invention, similar but lesser activity than the preferred active ingredient (s) .
  • compositions of the present invention may also include other active ingredients, as well as inert or inactive ingredients.
  • the dose regimen will depend on a number of factors which may readily be determined, such as severity and responsiveness of the condition to be treated, but will normally be one or more doses per day, with a course of treatment lasting from several days to several months, or until a cure is effected or a diminution of disease state is achieved.
  • One of ordinary skill may readily determine optimum dosages, dosing methodologies and repetition rates.
  • unit dosage form compositions according to the present invention will contain from about 0.01 mg to about 100 mg of active ingredient, preferably about 0.1 mg to about 10 mg of active ingredient.
  • Topical formulations (such as creams, lotions, solutions, etc.) may have a concentration of active ingredient of from about 0.01% to about 50%, preferably from about 0.1% to about 10%.
  • Another aspect of the present invention is based on the observation that the subject compounds which stimulate melanin production act via the Nitric Oxide/cyclic Guanosine Monophosphate/Protein Kinase G ("NO/cGMP/PKG”) pathway.
  • NO/cGMP/PKG Nitric Oxide/cyclic Guanosine Monophosphate/Protein Kinase G
  • the present invention includes not only the compounds described above, but any compound which acts via the NO/cGMP/PKG pathway to stimulate melanin synthesis by increasing cellular production of NO, cGMP or PKG.
  • agents which decrease cellular production of NO, cGMP or PKG will decrease or suppress melanin production and pigmentation in mammalian skin, hair, fur or wool, and the present invention is also directed to those compositions and methods.
  • Such is useful in, for example, the lightening of skin, hair, wool or fur for cosmetic purposes, or the treatment of hyperpigmentation or uneven pigmentation disorders such as vitiligo, dermal melanocytosis, Franceschetti-Jadassohn Syndrome, etc.
  • the formulation and dosing would be as described above with respect to pigmentation applications .
  • Discovery of the pathway through which the present compounds act also leads to methods for screening compounds for melanogenic activity and potency, or for their ability to reduce or suppress melanogenesis, based on measurement of generation of nitric oxide (NO) or measurement of nitric oxide synthesis (NOS) activity.
  • Methods for measurement of NO or NOS include but are not limited to the following well known methods.
  • Measurement of NO is usually based on the fact that NO rapidly decomposes to nitrate and nitrite in aqueous solution.
  • Nitrate reductase is added to culture media or cell extracts to ensure complete conversion of nitrate to nitrite.
  • Griess reagents sulfanilamide and N- [1- naphthyl] -ethylenediamine are then added to convert nitrite into a deep purple azo compound that absorbs maximally at 540 nm (Schmidt, et al . , 1995, Biochemica
  • Reactions are typically carried out in a 96-well format with absorbances read on a microtiter plate reader.
  • DAN reagent (2,3- diaminonaphthalene) is added followed by NaOH which converts nitrite into the fluorescent compound 1 (H) - naphthotriazole .
  • H fluorescent compound 1
  • NOS activity is measured by adding [ 3 H] -arginine to intact tissues or protein extracts, and measuring release of 3 H resulting from the conversion of arginine to citrulline during the enzymatic formation of NO by NOS (Baudouin and Tachon, 1996, J. Invest . Derma tol . 106:428-
  • cGMP may be measured by commercially available immunoassay (see Romero-Graillet, et al . , 1996, J. Biol . Chem. 271:28052-
  • PKG may be measured by cyclic GMP dependent kination of a primary histone target (see Hidaka, et al . , Biochemistry 1984, 23, 5036-5041)
  • Compounds according to the present invention may be synthesized in a number of ways known to one of ordinary skill. For example, a series of novel monocyclic and bicyclic monoterpenoid 1,2-diol derivatives (la,b-6a,b below) may be synthesized from (+) or (-) -camphenes , (+) or (-) -camphor, ( - ) - ⁇ -pinenes, 2- or 3-carenes, (-)- myrtenol, (-)-verbenol and their derivatives.
  • the one step syntheses of (+) - and (-)-lb and 3b are accomplished by cis-hydroxylation of (+) and (-)-camphene and (-)- ⁇ -pinene with osmium tetroxide and hydrogen peroxide or N-methylmorpholine N-oxide in t-butanol.
  • the same technology may be applied to (+) and (-) -camphor and (-) -verbenone; in that case a Wittig reaction is used to convert the ketone to the corresponding olefin, and then the above described cis-hydroxylation is done to give 2b and 4b.
  • (+) or (-) la to 6a are achieved in four-steps from (+) or (-)-camphene and (-)- ⁇ -pinene and corresponding olefins of (+) or (-) -camphor, (-)- verbenone or 2- or 3-carene prepared as described above.
  • (+) or (-)-V (10 g, 0.06 mole for (+) -V or 13 gm, 0.08 mole for (-)-V) in 150 ml of tert-butyl alcohol were added 30% hydrogen peroxide in water (8 ml for (+) -V and 9.1 ml for (-)-V) and 125 mg of osmium tetroxide as catalyst.
  • This mixture was stirred and maintained at 0°C in a ice bath for 4 hours, and then at room temperature for 20 hrs.
  • Cloudman S91 mouse melanoma cells were obtained from ATCC and cultured in MEM (BioWhittaker) with 10% calf serum (BioWhittaker or HyClone) .
  • Media was changed to MEM with 2% calf serum concomitant with addition of treatments.
  • Treatments were dissolved in ethanol as 0.5M solutions which was added in appropriate volumes directly to cell culture media (Brown, et al . , 1998, J. Invest . Dermatol . 110:48-437).
  • the compounds of this invention result both in induction of cell cycle arrest and differentiation of S91 mouse melanoma cells, indicating that they have potential use as chemotherapeutic differentiation agents. It can be seen in Table 1, that following a 6 day treatment period, the compounds of this invention result in a reduction of cell numbers below that of untreated controls.
  • the compounds of this invention are considered to be cytostatic (induce cell cycle arrest) rather than cytotoxic since: (i) they did not result in a reduction of cell number below the number originally plated (0.05 X 10 6 viable cells/treatment), (ii) reductions of cell number relative to controls were accompanied by induction of the multipolar phenotype and induction of tyrosinase, both well-known markers of differentiation, and, (iii) there was no apparent detachment of cells from dishes as indicated by a lack of cells floating in the media. In contrast, 3-ethyl-2- aldehyde-pinane resulted in detachment of cells from dishes with little induction of markers of differentiation (Table 1) .
  • novel monoterpene diols of this invention will have a similar activity in neuronal cells. Furthermore, it is contemplated that the novel monoterpene diols of this invention will have the potential to treat diseases remedied by stimulation of the nitric oxide/cyclic GMP/protein kinase G as described for monoterpene diols in PCT/US98/05346.
  • Each formulation contained 50% ⁇ -hydroxy acid (AHA) face cream (CVS generic containing 8% AHA; therefore final concentration of AHA in formulation was 4%) , 35% isopropyl alcohol (Fisher) , the indicated amounts of each compound (Table 2) , and deionized water as required to bring the volume up to 100%.
  • the vehicle control solution contained 50% AHA face cream, 35% isopropyl alcohol, and 15% deionized water. Ten ul of each formulation was applied twice per day for 10 days, followed by application of 10 ul once per day for the remainder of the application period.
  • the treatment spots were along the anterior forearm which correspond to the region of the forearm closest to the body when at rest.
  • the Vehicle control was closest the elbow and VI- was closest the wrist, with the other treatment spots along the arm in the order given in Table 2.
  • the treated individual was Caucasian with an untanned (pale) forearm prior to treatment.
  • results show that 11+ and VI- were 5- and 10-fold more potent, respectively, than (2R, 3S) - (-) -PD with regards to induction of tanning when applied to human skin (compare 14 day 0. IM treatment results in Table 2) .
  • results for induction of melanogenesis in human skin by these compounds parallel those for induction of melanogenesis in cell culture (Table 1) .
  • (IR) -2 , 3 -c/e-BD which was only about 2-fold more potent than (2R, 3S) - ( - ) -PD in cell culture (see Table 20 in PCT/US98/05346) , was 5-fold more potent when applied to human skin (compare 14 day 0. IM treatment results in Table 2) .
  • VI- The family of compounds embodied by this invention and related inventions are thought to exert their effects via the nitric oxide signal transduction pathway (discussed above) . Therefore, it is contemplated that the relatively high potency of VI- may be related, in part, to its structural similarity to tetrahydrobiopterin with regards to a protruding propanediol substituent group.

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  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des diols monoterpéniques mono- et bicycliques stimulant la mélanogénèse dans la peau, les cheveux, les poils, la laine ou la fourrure de mammifères, et permettant de traiter ou de prévenir différentes affections cutanées, différents troubles proliférants, différentes maladies neurodégénératives, ainsi que des maladies régulées par la voie oxyde nitrique/GMP cyclique/protéine kinase G.
PCT/US2000/006373 2000-03-10 2000-03-10 Composes dermatologiques Ceased WO2001068576A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
PCT/US2000/006373 WO2001068576A1 (fr) 2000-03-10 2000-03-10 Composes dermatologiques
EP00917846A EP1261572A4 (fr) 2000-03-10 2000-03-10 Composes dermatologiques
AU2000238755A AU2000238755A1 (en) 2000-03-10 2000-03-10 Dermatological compounds

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PCT/US2000/006373 WO2001068576A1 (fr) 2000-03-10 2000-03-10 Composes dermatologiques

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AU (1) AU2000238755A1 (fr)
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US8440237B2 (en) 2009-04-27 2013-05-14 Mary Kay Inc. Botanical anti-acne formulations
LU92126B1 (fr) * 2012-12-31 2014-07-01 Cesa Alliance Sa Composé pharmaceutique pour la prévention et le traitement d'un trouble ou d'une maladie de la mémoire, neurodégénérative ou neuronale
US9138401B2 (en) 2011-12-19 2015-09-22 Mary Kay Inc. Combination of plant extracts to improve skin tone
CN106977387A (zh) * 2012-06-05 2017-07-25 高丽大学校产学协力团 含有马鞭草烯酮衍生物的神经退行性疾病治疗或者预防用药物组合物
US10500152B2 (en) 2014-03-10 2019-12-10 Mary Kay Inc. Skin lightening compositions

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US10682381B2 (en) 2009-04-27 2020-06-16 Mary Kay Inc. Botanical formulations
US8440237B2 (en) 2009-04-27 2013-05-14 Mary Kay Inc. Botanical anti-acne formulations
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KR102104155B1 (ko) 2012-12-31 2020-04-24 세사 알리안스 에스.에이. 인지성, 신경퇴행성 또는 뉴런성 질환의 예방 및 치료를 위한 4-히드록시-2-메틸-5-(프로판-2-일리덴)시클로헥스-3-엔카르브알데히드
KR20150102117A (ko) * 2012-12-31 2015-09-04 세사 알리안스 에스.에이. 인지성, 신경퇴행성 또는 뉴런성 질환의 예방 및 치료를 위한 4-히드록시-2-메틸-5-(프로판-2-일리덴)시클로헥스-3-엔카르브알데히드
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CN104884052A (zh) * 2012-12-31 2015-09-02 切萨联盟有限公司 4-羟基-2-甲基-5-(丙-2-亚基)环己-3-烯甲醛用于预防及治疗认知、神经退行性或神经元疾病
CN104884052B (zh) * 2012-12-31 2021-06-25 切萨联盟有限公司 4-羟基-2-甲基-5-(丙-2-亚基)环己-3-烯甲醛用于预防及治疗认知、神经退行性或神经元疾病
WO2014102090A1 (fr) 2012-12-31 2014-07-03 Cesa Alliance S.A. 4-hydroxy-2-méthyl-5-(propan-2-ylidène)cyclohex-3-ènecarbaldéhyde pour la prévention et le traitement d'une maladie cognitive, neurodégénérative ou neuronale
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