WO2008020490A1 - Dérivé de l'artocarpine ou composé similaire à l'artocarpine et composition de pousse/repousse des cheveux, composition cosmétique de blanchiment de la peau, produit pharmaceutique servant d'agent anticancéreux, antiphlogistique/analgésique, antipyrétique ou antiallergique et - Google Patents

Dérivé de l'artocarpine ou composé similaire à l'artocarpine et composition de pousse/repousse des cheveux, composition cosmétique de blanchiment de la peau, produit pharmaceutique servant d'agent anticancéreux, antiphlogistique/analgésique, antipyrétique ou antiallergique et Download PDF

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Publication number
WO2008020490A1
WO2008020490A1 PCT/JP2007/000815 JP2007000815W WO2008020490A1 WO 2008020490 A1 WO2008020490 A1 WO 2008020490A1 JP 2007000815 W JP2007000815 W JP 2007000815W WO 2008020490 A1 WO2008020490 A1 WO 2008020490A1
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Prior art keywords
altocarpine
ability
inhibition
artocarpine
pharmaceutical
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PCT/JP2007/000815
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English (en)
Japanese (ja)
Inventor
Tetsuji Nagahata
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Kansai Koso Co., Ltd.
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Publication of WO2008020490A1 publication Critical patent/WO2008020490A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74—Biological properties of particular ingredients
    • A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
    • A61K2800/782—Enzyme inhibitors; Enzyme antagonists

Definitions

  • the present invention relates to an altocarpine derivative and an altocarpine analog, and a hair restoration composition containing the same, a hair restoration composition, a whitening cosmetic composition, and an anticancer agent, anti-inflammatory analgesic, antipyretic agent or antiallergy
  • the present invention relates to a pharmaceutical agent and a pharmaceutical agent for treating pigmented skin lesions.
  • Artcarpin which can be extracted and purified by a known method from the plant of the genus Artcarpas, is a testosterone-5 1 reductase activity inhibiting ability, It is known that it has an effect of suppressing sebum secretion and a whitening effect (see Patent Document 1), and a cancer cell growth inhibition and suppressive action (see Patent Document 2).
  • Altocarpine further exhibits cycloxygenase inhibitory activity and 5_lipoxygenase inhibitory activity, and is also known to be useful as an anti-inflammatory analgesic, antipyretic or antiallergic agent (Patent Document 3). See).
  • Patent Document 1 International Publication No. 0 0/4 5 7 8 2 Pamphlet
  • Patent Document 2 Japanese Patent Laid-Open No. 2 0 0 3 _ 1 9 2 5 90
  • Patent Document 3 Japanese Patent Laid-Open No. 2 0 0 4 _ 2 3 1 5 8 7
  • the present invention relates to testosterone-15 reductase activity inhibitory ability, cancer cell growth inhibitory and inhibitory action, cycloxygenase inhibitory ability, 5-lipoxygenase inhibitory ability, normal melanocyte growth inhibitory ability, and normal Fibroblast growth suppression
  • the object is to provide a substance with institution.
  • the inventor of the present invention has also demonstrated excellent testosterone mono-reductase even in the altocarpine derivatives that are novel compounds and the altocarpine analogs synthesized when synthesizing altocarpine.
  • the present invention relates to testosterone-15 reductase activity inhibiting ability, cancer cell growth inhibiting and inhibiting action, cycloxygenase inhibiting ability, 5-lipoxygenase inhibiting ability, normal melanocyte growth inhibiting ability And altocarpine derivatives having the ability to inhibit normal five-mouth blast growth.
  • the present invention provides testosterone-5 1 reductase activity inhibitory activity, cell growth inhibitory and inhibitory activity, cycloxygenase inhibitory activity, 5-lipoxygenase inhibitory activity, normal melanocyte growth inhibitory, And an altocarpine analog having the ability to inhibit normal fibroblast growth.
  • the altocarpine derivative means a compound formed by changing a part of the altocarpine molecule, that is, a p-nyl group or a 3_methyl_1-butenyl group or the like in the altocarpine molecule.
  • Altocarpine-like compounds are compounds synthesized when synthesizing altocarpine and altocarpine derivatives. Specifically, altocarpine hydrogenated, demethylated, methoxyadducted, methyl , Acetylated, dihydroxylated, dimethyl ether adduct, epoxidized, hydroxylated, and the like.
  • the present invention provides a hair-growth composition, a hair-care composition, a whitening cosmetic composition, an anticancer agent, an anti-inflammatory analgesic, an antipyretic agent, containing at least one of the above-described altocarpine derivative or an altocarpine-like compound. It is a drug as an antiallergic agent and a drug for the treatment of pigmented skin lesions. The invention's effect
  • a medicament for treating a lesion can be provided.
  • the altocarpine derivative a compound in which one or more of R 1, R 2 and R 3 of the compound A represented by the following structural formula is a prenyl group and / or 3-methyl-1-butenyl group (the following structural formula 1 To 6), a compound in which a sugar such as glucose is introduced into one or more of the three hydroxyl groups (OH groups) (the following structural formulas 7 to 9), and one or more of R 1, R 2 and R 3 Is a prenyl group or / and 3_methyl_1-butenyl group, and a compound in which a sugar such as glucose is introduced into one or more of the three hydroxyl groups (OH group) (the following structural formula 10, 1 1).
  • the sugar added to the structural formulas 7 to 9 is not limited to the above glucose.
  • cedoheptulose, fructose, galactose, ribulose, talose, allose, lipose Monosaccharides such as apios, disaccharides such as maltose, lactose and sucrose, oligosaccharides such as fructo-oligosaccharides and galacto-oligosaccharides, and polysaccharides such as starch can be added.
  • examples of the altocarpine-like compound include compounds represented by the following structural formulas 12 to 24.
  • the altocarpine derivative or the altocarpine analog in the embodiment of the present invention is not limited to testosterone monoliths as will be apparent from the examples described later.
  • Ductase (hereinafter referred to as “TSR”) Because it has activity inhibiting ability, it can be expected to have hair growth, nourishing, whitening, sebum secretion suppression, etc.
  • Desirable effects can be achieved by blending with various cosmetics and pharmaceuticals such as detergents, soaps, nutrition creams, and skin-whitening agents.
  • the blending ratio and form of the altocarpine derivative or altocarpine analog in the case of making a cosmetic can be appropriately selected depending on the type of cosmetic described above.
  • the above-described hair growth / hair restoration agent may further contain a conventionally known hair growth / hair growth promoting substance, an antibacterial agent, a refreshing agent, and a moisturizing agent.
  • Hair growth ⁇ The hair revitalizing promoting substances such as vitamin B 6, vitamin E and derivatives thereof, derivatives thereof and Contact glycyrrhizic acid, nicotinic acid esters such as downy nicotinate Njiru, cyclo Suporin acids, Karupuroniumu chloride, cepharanthine, Okisendoron, Examples thereof include diazoxide, minoxidil, ethynyl estradiol, estradiol, and animal and plant extracts containing these.
  • antibacterial agent examples include hinokitiol, pirotoolamine, pyrothione zinc, hexaclonal fen, phenol, benzalkonium chloride, cetylpyridinium chloride, undecylenic acid, trichlorocarbanilide and the like.
  • Examples of the refreshing agent include menthol.
  • Examples of humectants include glycerin, propylene glycol, 1,3-butylene glycol, and sorb! Le Manni! , Polyhydric alcohols such as polyethylene glycol and propylene glycol, NMF components such as amino acid, sodium lactate, and sodium pyridocarponate, hyaluronic acid, collagen, elastin, chondroitin sulfate, fibronectin, ceramides, hepa Examples include phosphorus-like substances and water-soluble polymer substances such as chitosan.
  • Various additives may be added to the hair-restoring / hair-care agent.
  • Additives include oils and fats, surfactants, alcohols, fatty acids, preservatives, antioxidants, dyes, fragrances, UV absorbers, chelating agents, pH adjusting agents, buffering agents, purified water, etc.
  • the blending amount can be appropriately selected.
  • an anticancer agent can be obtained by a production method according to a conventional method using a pharmaceutically acceptable production aid or the like.
  • the administration method of the anticancer agent in the embodiment of the present invention preferably includes, for example, injection into cancer cells and mucous membranes and application as an external preparation.
  • an injection for example, it can be produced by using a pharmaceutical ingredient such as a water for injection, a physiological saline, a solubilizing agent such as propylene glycol, a solubilizing agent, a pH adjusting agent, and a stabilizer.
  • a pharmaceutical ingredient such as a water for injection, a physiological saline, a solubilizing agent such as propylene glycol, a solubilizing agent, a pH adjusting agent, and a stabilizer.
  • solubilizers and solubilizers such as alcohol and fatty acid esters, adhesives such as strong lpoxyvinyl polymers and polysaccharides, emulsifiers, stabilizers and other pharmaceutical ingredients. can do.
  • the dosage of the anticancer agent in the embodiment of the present invention can be appropriately selected according to the administration method, the type and size of cancer cells, the age, sex, mode, etc. of the patient.
  • the altocarpine derivative or the alto-rubin-like compound in the embodiment of the present invention has the ability to inhibit cycloxygenase and the ability to inhibit 5-lipoxygenase, as will be apparent from Examples described later. It can be made into an anti-inflammatory analgesic, antipyretic, anti-allergic agent by a production method according to a conventional method using pharmacologically and pharmaceutically acceptable production aids.
  • the anti-inflammatory analgesic, antipyretic, and antiallergic agent can be administered by, for example, internal use with tablets or force pushers, suppositories, injection into the skin, application as an external preparation, etc. .
  • excipients such as lactose, sucrose, calcium phosphate, gelatin, polyvinylpyrrolidone, gum arabic, carboxymethyl cell mouth It can be produced using a formulation component such as a binder such as starch, a disintegrant such as starch, agar, or gelatin powder, or a lubricant such as magnesium stearate or calcium stearate.
  • capsules can be produced using pharmaceutical ingredients such as gelatin, purified water, simple syrup, gum arabic and the like.
  • suppositories can be produced using ingredients for pharmaceutical preparation such as cacao butter, lauric fat, glyce gelatin and polyethylene glycol.
  • an injection for example, it is manufactured using a pharmaceutical ingredient such as a water solution for injection, a physiological saline, propylene glycol, or a solubilizing agent, a solubilizing agent, a pH adjusting agent, or a stabilizer. be able to.
  • a pharmaceutical ingredient such as a solubilizer or solubilizer such as alcohol or fatty acid ester, a strong siloxane polymer, an adhesive such as a polysaccharide, an emulsifier, or a stabilizer. can do.
  • the dosage of the anti-inflammatory analgesic, antipyretic, and antiallergic agent in the embodiment of the present invention can be appropriately selected according to the administration method, the treatment target, the age, sex, mode, etc. of the patient.
  • the altocarpine derivative or the alto-rubin-like compound in the embodiment of the present invention has a normal melanocyte growth inhibitory ability and a normal fibroblast growth inhibitory ability, as will be apparent from Examples described later.
  • Caffeole's plaques, small Wrinkles / Wusen's plaques, and neurofibromas it is basically caused by hyperplasia due to age-related changes in the epidermis, but clinically it is pigmented on the skin.
  • Seborrheic keratosis and senile pigment spots that appear to be lesions, nevus pigmentation such as flat nevus, pigmented nevus, Ota nevus, blue nevus, ectopic Mongolia, post-inflammation pigmentation It can be used as a drug for treating pigmented skin lesions such as symptom.
  • the drug for treating pigmented skin lesions can be administered, for example, by oral administration, suppository, subcutaneous injection, or application as an external preparation.
  • These drugs for the treatment of pigmented skin lesions can be produced according to conventional methods using pharmacologically and pharmaceutically acceptable manufacturing aids.
  • external preparations ointments, creams, lotions, tapes And various other forms.
  • a solubilizing agent such as alcohol or fatty acid ester or a solubilizing agent, a strong ruboxyvinyl polymer, a pressure sensitive adhesive such as a polysaccharide, an emulsifying agent, a stabilizer or the like is used.
  • oral preparations include various forms such as tablets and capsules.
  • Tablets include, for example, excipients such as lactose, sucrose, calcium phosphate, binders such as gelatin, polyvinylpyrrolidone, gum arabic, and carboxymethylcellulose, disintegrants such as starch, agar, and gelatin powder, It can be produced using a pharmaceutical ingredient such as a lubricant such as magnesium thearate and calcium stearate.
  • capsules can be produced using, for example, pharmaceutical ingredients such as gelatin, purified water, simple syrup, and gum arabic.
  • an injection in order to form an injection, for example, it can be produced using a pharmaceutical ingredient such as a water for injection, physiological saline, a solubilizing agent such as propylene glycol, a solubilizing agent, a pH adjusting agent, a stabilizer. it can.
  • a suppository can be produced using, for example, pharmaceutical ingredients such as cacao butter, lauric fat, glyce mouth gelatin, and polyethylene glycol.
  • the dosage of the pigmented skin lesion treatment agent in the embodiment of the present invention may be appropriately selected according to the administration method, the size of the lesioned part, the age, sex, mode, etc. of the patient. it can.
  • enzyme activity was measured using microsomes (TSR) derived from the liver of female rats, and the ability of each compound to inhibit TSR activity was measured.
  • Enzyme activity was measured in 1 O Omm o I / L sodium phosphate buffer (pH 6.5), at a starting concentration of 150 mo I / L testosterone, 1 mmo I / L dithiotray. ! Each was added to pre-incubate at 37 ° C. After 10 minutes, add NAD PH so that the concentration at the start of the enzyme reaction is 1 67 jmo I / L, and then add a microsodium solution so that the added protein is 0.25 mg. Started. Three After reacting at 7 ° C.
  • the TSR activity inhibition ability is measured by preincubating the compounds represented by structural formulas 1 to 24 so that the concentration at the start of the reaction is 10 ppm, respectively. It was added before and the other conditions were the same to measure the enzyme reaction rate, and the inhibition rate was calculated from the ratio of the enzyme reaction rate measured above when the above compounds represented by structural formulas 1 to 24 were not included. Obtained by calculation. The results are shown in Table 1.
  • TSR activity inhibitory ability was measured like Example 1.
  • FIG. The results are shown in Table 2.
  • the altocarpine derivatives represented by the above structural formulas 1 to 24 and the altocarpine analogs are B 1 6 from the respective compounds shown in Table 4 conventionally known as antitumor compounds. It can be seen that it has an excellent antitumor action against melanoma cells, and it is useful to use these as an active ingredient of anticancer agents.
  • the cyclooxygenase solution 5I was put in the glass tube, stirred by PORTEX, and immediately put obliquely in a 37 ° C incubator. After reacting for 1 minute, 250 I of a mixed solution consisting of jetyl ether: methanol: 1 M citrate (30: 4: 1) was added, and the reaction was stopped by stirring with Portex to extract the product. Next, after adding Na 2 S0 4 to the obtained product for dehydration, 50 I of the organic layer was charged into thin layer chromatography (TLC), and further hexane: jetyl ether: acetic acid. (30: 20: 1).
  • TLC thin layer chromatography
  • the obtained TLC plate was wrapped in a wrap and applied to a B AS imging plate (manufactured by Fuji Film) in a cassette and left in the dark for 2 hours. Then, the radioactivity in BAS, issued calculate the activity from the conversion of the product of Arakidon acid was determined cycloalkyl O key Shige kinase IC M. The results are shown in Table 5. Further, as a control, a similar test was conducted for commercially available indomethacin and nordihydroguaiaretic acid instead of the compounds represented by the structural formulas 1 to 24. The results are shown in Table 6.
  • [ 14 C] arachidonic acid 2 I dissolved in ethanol and 10 ⁇ I of the compounds represented by the above structural formulas 1 to 24 dissolved in ethanol at a predetermined concentration were placed in a glass tube, and ethanol was distilled off with nitrogen. After that, add 100 I of reaction buffer (1 OmM BES, 10 mM PIPES, 1 mM EDTA, 0.7 mM CaCl 2 , pH 6.8) and 10 ⁇ I of the supernatant. Stir.
  • the 5-lipoxygenase solution 50 UI was placed in the glass tube, stirred with PORTEX, and immediately placed obliquely in a 37 ° C incubator. After reacting for exactly 2 minutes, add 2 50 I of a mixed solution consisting of jetyl ether: methanol: 1 M citrate (30: 4: 1) and stop by stirring with Portex. The product was extracted. Next, 50 UI of the organic layer containing the obtained product was charged into TLC, and further developed with hexane: jetyl ether: acetic acid (30: 20: 1). Subsequently, prostaglandin B 2 , prostaglandin E 2 , and prostaglandin D 2 were added to confirm the R f value.
  • the obtained TLC plate was wrapped in a wrap, applied to BAS imagingp Iate (manufactured by Fuji Film) in a cassette, and left in a dark place for 2 hours.
  • BAS imagingp Iate manufactured by Fuji Film
  • the radioactivity was measured with BAS, the activity was calculated from the amount of arachidonic acid converted to the product, and 5_lipoxygenase IC 5Q was obtained.
  • Table 5 The results are shown in Table 5.
  • a similar test was conducted for commercially available indomethacin and nordihydroguaiaretic acid instead of the compounds represented by the above structural formulas 1 to 24. The results are shown in Table 7.
  • the growth inhibitory effect of altocarpine was examined by the following method using normal human skin melanocytes (manufactured by Cell Systems) and normal human skin fibrocells (manufactured by Cell Systems).
  • the above human melanocytes and fibroblasts were inoculated at 5 ⁇ 10 4 cells / ml on each well of a 1 2 well plate (BEGTON DI CK I NSON), and each was cultured in a synthetic culture medium containing a growth factor.
  • an altocarpine derivative dissolved in DMSO (dimethyl sulfoxide) as a solvent and a similar compound were added at a final concentration of 2.5 ⁇ g / mI.
  • DMSO dimethyl sulfoxide
  • Table 8 shows the experimental results using the above cells.
  • the altocarpine derivatives and the altocarpine analogs represented by structural formulas 1 to 24 have excellent ability to suppress normal melanocyte proliferation and ability to inhibit normal fibroblast growth.
  • Reckling Hausen's disease Caffeole plaques small wrinkles / ⁇ usen plaques, nerve line fibrosis, seborrheic keratosis, senile pigment spots, flat nevus, pigmented nevus, Ota It is useful to use as an active ingredient in the treatment of pigmented skin lesions such as nevus pigmentation such as nevus, blue nevus, ectopic mongolia, and post-inflammation pigmentation.
  • the altocarpine derivative and the altocarpine analog are excellent in testosterone-5-reductase activity inhibitory activity, cell growth inhibitory and inhibitory activity, cycloxygenase inhibitory activity and 5—Lipoxygena It has the ability to inhibit the growth of normal melanocytes, the ability to inhibit normal melanocyte growth, and the ability to inhibit normal fibroblast growth. It is useful as an active ingredient of medicine as an allergic agent and a medicine for treating pigmented skin lesions.

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Abstract

L'invention concerne une substance ayant une aptitude à inhiber une activité de la testostérone-5α-réductase, une aptitude à inhiber ou à réduire la prolifération de cellules cancéreuses, une aptitude à inhiber une cyclooxygénase, une aptitude à inhiber une 5-lipoxygénase, une aptitude à inhiber la prolifération de mélanocytes normaux et une aptitude à inhiber la prolifération de fibroblastes normaux. Un composé produit en modifiant une partie d'une molécule d'artocarpine ou d'un composé similaire à l'artocarpine (par exemple une forme hydrogénée, une forme déméthylée, une forme méthoxylée, une forme méthylée, une forme acétylée, une forme dihydroxylée, une forme de produit d'addition avec l'éther de diméthyle, une forme époxylée et une forme hydroxylée de l'artocarpine) est excellent en ce qui concerne les aptitudes susmentionnées.
PCT/JP2007/000815 2006-08-17 2007-07-31 Dérivé de l'artocarpine ou composé similaire à l'artocarpine et composition de pousse/repousse des cheveux, composition cosmétique de blanchiment de la peau, produit pharmaceutique servant d'agent anticancéreux, antiphlogistique/analgésique, antipyrétique ou antiallergique et WO2008020490A1 (fr)

Applications Claiming Priority (2)

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JP2006-222752 2006-08-17
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CN103833716A (zh) * 2013-12-26 2014-06-04 江南大学 具癌细胞抑制活性的化合物及其制备方法与用途
CN104016956A (zh) * 2014-06-17 2014-09-03 广西师范学院 5,2′,4′-三羟基-7-甲基-3-烃基黄酮类似物及其制备方法和应用
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* Cited by examiner, † Cited by third party
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CN103709130A (zh) * 2012-10-07 2014-04-09 复旦大学 具有胰脂肪酶抑制活性的天然产物的合成方法及其应用
CN103709130B (zh) * 2012-10-07 2015-05-13 复旦大学 具有胰脂肪酶抑制活性的天然产物的合成方法及其应用
US9975964B2 (en) 2013-12-02 2018-05-22 Ostrich Pharma Kk Antibody against alopecia-inducing substance as antigen, composition and production method
US10246520B2 (en) 2013-12-02 2019-04-02 Ostrich Pharma Kk Antibody against alopecia-inducing substance as antigen, composition and production method
CN103833716A (zh) * 2013-12-26 2014-06-04 江南大学 具癌细胞抑制活性的化合物及其制备方法与用途
CN103833716B (zh) * 2013-12-26 2015-10-28 江南大学 具癌细胞抑制活性的化合物及其制备方法与用途
CN104016956A (zh) * 2014-06-17 2014-09-03 广西师范学院 5,2′,4′-三羟基-7-甲基-3-烃基黄酮类似物及其制备方法和应用

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