WO2017099210A1 - NAPHTHOQUINONE COMPOUND AND NUCLEAR FACTOR KAPPA-B (NF-κB) INHIBITOR COMPRISING SAME AS ACTIVE INGREDIENT - Google Patents

NAPHTHOQUINONE COMPOUND AND NUCLEAR FACTOR KAPPA-B (NF-κB) INHIBITOR COMPRISING SAME AS ACTIVE INGREDIENT Download PDF

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WO2017099210A1
WO2017099210A1 PCT/JP2016/086669 JP2016086669W WO2017099210A1 WO 2017099210 A1 WO2017099210 A1 WO 2017099210A1 JP 2016086669 W JP2016086669 W JP 2016086669W WO 2017099210 A1 WO2017099210 A1 WO 2017099210A1
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hydroxy
group
methyl
naphthoquinone
oxo
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Japanese (ja)
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浩 野崎
山田　昌司
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株式会社ポーラファルマ
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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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C50/00—Quinones
    • C07C50/26—Quinones containing groups having oxygen atoms singly bound to carbon atoms
    • C07C50/32—Quinones containing groups having oxygen atoms singly bound to carbon atoms the quinoid structure being part of a condensed ring system having two rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C50/00—Quinones
    • C07C50/38—Quinones containing —CHO or non—quinoid keto groups

Definitions

  • the present invention relates to a naphthoquinone compound or a pharmaceutically acceptable salt thereof, a nuclear factor kappa B inhibitor (NF- ⁇ B) containing the compound as an active ingredient, and a medicament containing the NF- ⁇ B inhibitor.
  • NF- ⁇ B nuclear factor kappa B inhibitor
  • Nuclear factor kappa B is also called NF- ⁇ B. Excessive secretion of this factor is said to be greatly related to inflammation, rheumatism, malignant transformation of cancer, and the like. Therefore, it is said that it is important to inhibit the action of NF- ⁇ B and prevent this factor from working excessively in the prevention of aging, the treatment of dermatitis, the treatment and prevention of cancer, etc. (For example, see Patent Document 1). From this point of view, various compounds have been screened, and it has been clarified that the naphthoquinone compound contained in the plant body of Plumbago Ziranica has an excellent NF- ⁇ B inhibitory action (Non-patent Document 1).
  • Plumbago Zairanika is a medicinal plant of Ayurveda that is native to India and is known by the popular name of Chitoraka, and is currently available in Japan.
  • action with respect to skin (patent document 2, 3), the effect
  • An object of the present invention is to provide a novel NF- ⁇ B inhibitor.
  • the present inventors isolated and purified the components contained in Plumbago Ziranica and searched for components having strong NF- ⁇ B inhibitory activity, and represented by the following general formula (1).
  • the present invention has been found to have a strong NF- ⁇ B inhibitory action and useful as various pharmaceuticals, and has led to the completion of the invention.
  • the present invention provides the following [1] to [12].
  • An NF- ⁇ B inhibitor comprising as an active ingredient a naphthoquinone compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are the same or different and each represents a hydrogen atom, a hydroxy group, a 2-methyl-5-hydroxy-1,4-naphthoquinone group, an alkyl group optionally having a carbonyl group, an alkenyl group, And a group selected from an alkyl group which may have a hydroxyl group, R 3 represents a hydroxy group or an alkyl group having 1 to 4 carbon atoms, R 4 represents a hydroxy group or an oxo group, (A broken line part shows a single bond or a double bond.)
  • the compound represented by the general formula (1) is 5,5 ′, 5 ′′ -trihydroxy-2,2 ′, 2 ′′ -trimethyl- [7,6 ′: 3 ′, 6 ′. '-Ternaphthalene] -1,1', 1 '', 4,4 ', 4' '-hexone, 8-hydroxy-3-methyl-2- (2-oxo-propyl) -1,4-naphthalenedione 3-methyl-8-hydroxy-7- (isopropenyl) -1,4-naphthalenedione, 8-hydroxy-2,2-dihydro-3-methyl-3- (2-oxo-propyl) -1,4
  • the NF- ⁇ B inhibitor according to [1] which is a compound selected from naphthoquinone, 3,4,8-trihydro-3-methyl-1 (2H) -naphthalenone, diomucinone, bipurbagin, chitranone and isocinanolone.
  • a pharmaceutical composition comprising a naphthoquinone compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • R 1 and R 2 are the same or different and each represents a hydrogen atom, a hydroxy group, a 2-methyl-5-hydroxy-1,4-naphthoquinone group, an alkyl group optionally having a carbonyl group, an alkenyl group, And a group selected from an alkyl group optionally having a hydroxyl group, R 3 represents a hydroxy group or an alkyl group having 1 to 4 carbon atoms, R 4 represents a hydroxy group or an oxo group, (A broken line part shows a single bond or a double bond.)
  • the compound represented by the general formula (1) is 5,5 ′, 5 ′′ -trihydroxy-2,2 ′, 2 ′′ -trimethyl- [7,6 ′: 3 ′, 6 ′. '-Ternaphthalene] -1,1', 1 '', 4,4 ', 4''-hexone, 8-hydroxy-3-methyl-2- (2-oxo-propyl) -1,4-naphthalenedione 3-methyl-8-hydroxy-7- (isopropenyl) -1,4-naphthalenedione, 8-hydroxy-2,2-dihydro-3-methyl-3- (2-oxo-propyl) -1,4
  • the pharmaceutical composition according to [3] which is a compound selected from naphthoquinone, 3,4,8-trihydro-3-methyl-1 (2H) -naphthalenone, diomucinone, bipurbagin, chitranone and isocinanolone.
  • R 1 and R 2 are the same or different and each represents a hydrogen atom, a hydroxy group, a 2-methyl-5-hydroxy-1,4-naphthoquinone group, an alkyl group optionally having a carbonyl group, an alkenyl group, And a group selected from an alkyl group which may have a hydroxyl group, R 3 represents a hydroxy group or an alkyl group having 1 to 4 carbon atoms, R 4 represents a hydroxy group or an oxo group, (A broken line part shows a single bond or a double bond.)
  • the compound represented by the general formula (1) is 5,5 ′, 5 ′′ -trihydroxy-2,2 ′, 2 ′′ -trimethyl- [7,6 ′: 3 ′, 6 ′. '-Ternaphthalene] -1,1', 1 '', 4,4 ', 4''-hexone, 8-hydroxy-3-methyl-2- (2-oxo-propyl) -1,4-naphthalenedione 3-methyl-8-hydroxy-7- (isopropenyl) -1,4-naphthalenedione, 8-hydroxy-2,2-dihydro-3-methyl-3- (2-oxo-propyl) -1,4 -Use according to [6], which is a compound selected from naphthoquinone, 3,4,8-trihydro-3-methyl-1 (2H) -naphthalenone, diomucinone, bipurbagin, chitranone and isocinanolone. [8] A naphthoquinone,
  • R 1 and R 2 are the same or different and each represents a hydrogen atom, a hydroxy group, a 2-methyl-5-hydroxy-1,4-naphthoquinone group, an alkyl group optionally having a carbonyl group, an alkenyl group, And a group selected from an alkyl group which may have a hydroxyl group, R 3 represents a hydroxy group or an alkyl group having 1 to 4 carbon atoms, R 4 represents a hydroxy group or an oxo group, (A broken line part shows a single bond or a double bond.)
  • the compound represented by the general formula (1) is 5,5 ′, 5 ′′ -trihydroxy-2,2 ′, 2 ′′ -trimethyl- [7,6 ′: 3 ′, 6 ′. '-Ternaphthalene] -1,1', 1 '', 4,4 ', 4''-hexone, 8-hydroxy-3-methyl-2- (2-oxo-propyl) -1,4-naphthalenedione 3-methyl-8-hydroxy-7- (isopropenyl) -1,4-naphthalenedione, 8-hydroxy-2,2-dihydro-3-methyl-3- (2-oxo-propyl) -1,4
  • the compound according to [8] which is a compound selected from naphthoquinone, 3,4,8-trihydro-3-methyl-1 (2H) -naphthalenone, diomucinone, bipurbagin, chitranone and isocinanolone.
  • R 1 and R 2 are the same or different and each represents a hydrogen atom, a hydroxy group, a 2-methyl-5-hydroxy-1,4-naphthoquinone group, an alkyl group optionally having a carbonyl group, an alkenyl group, And a group selected from an alkyl group which may have a hydroxyl group, R 3 represents a hydroxy group or an alkyl group having 1 to 4 carbon atoms, R 4 represents a hydroxy group or an oxo group, (A broken line part shows a single bond or a double bond.)
  • the compound represented by the general formula (1) is 5,5 ′, 5 ′′ -trihydroxy-2,2 ′, 2 ′′ -trimethyl- [7,6 ′: 3 ′, 6 ′. '-Ternaphthalene] -1,1', 1 '', 4,4 ', 4''-hexone, 8-hydroxy-3-methyl-2- (2-oxo-propyl) -1,4-naphthalenedione 3-methyl-8-hydroxy-7- (isopropenyl) -1,4-naphthalenedione, 8-hydroxy-2,2-dihydro-3-methyl-3- (2-oxo-propyl) -1,4
  • the method according to [10] which is a compound selected from naphthoquinone, 3,4,8-trihydro-3-methyl-1 (2H) -naphthalenone, diomucinone, bipurbagin, chitranone and isocinanolone.
  • a novel NF- ⁇ B inhibitor and a pharmaceutical composition for treating a disease caused by the enhancement of NF- ⁇ B can be provided.
  • the pharmaceutical composition is useful as a medicament for the treatment of inflammation, pain, tissue fibrosis, or cancer.
  • the NF- ⁇ B inhibitor of the present invention comprises a compound represented by the general formula (1) as an active ingredient.
  • R 1 and R 2 are the same or different and each represents a hydrogen atom, a hydroxy group, a 2-methyl-5-hydroxy-1,4-naphthoquinone group, an alkyl group optionally having a carbonyl group, an alkenyl group, and The group chosen from the alkyl group which may have a hydroxy group is shown.
  • the alkyl group preferably has 1 to 4 carbon atoms, and the alkyl group may be linear or branched.
  • alkyl group examples include a methyl group, an ethyl group, a propyl group, a butyl group, a 1-methylethyl group, and a 1,1-dimethylethyl group.
  • alkyl group having a carbonyl group examples include C1-C4 alkyl groups having a carbonyl group, and a methylcarbonylmethyl group, a methylcarbonylethyl group, and the like are preferable examples. Particularly preferred is a methylcarbonylmethyl group.
  • the alkenyl group preferably has 2 to 4 carbon atoms, and may be linear or branched.
  • alkenyl groups include ethenyl group, propenyl group, butenyl group, 1-methyl-2-ethen-1-yl group and the like. Particularly preferred is a 1-methyl-2-ethen-1-yl group.
  • alkyl group having a hydroxy group include an alkyl group having 1 to 4 carbon atoms having a hydroxy group, preferably a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, and a 2-hydroxy-2-methyl-ethyl group. It can be illustrated.
  • both R 1 and R 2 do not become hydrogen atoms at the same time.
  • the bonding position of R 1 may be any of the 2-position, 3-position and 4-position of the naphthoquinone skeleton of formula (1).
  • the bonding position of R 2 may be any of the 5th, 6th and 7th positions of the naphthoquinone skeleton of the formula (1), but the 7th position is particularly preferred.
  • the 1-position of the naphthoquinone skeleton of the formula (1) is not the position to which R 4 is bonded, but the carbon forming the carbonyl group in the formula (1).
  • R 3 represents a hydroxy group or an alkyl group having 1 to 4 carbon atoms.
  • the alkyl group having 1 to 4 carbon atoms may be linear or branched. Examples of such an alkyl group include a methyl group, an ethyl group, and a propyl group.
  • R 3 is more preferably a hydroxy group or a methyl group.
  • R 4 represents a hydroxy group or an oxo group.
  • R 4 represents an oxo group
  • R 4 and the carbon atom to which R 4 is bonded form a carbonyl group.
  • Examples of the compound represented by the general formula (1) include 5,5 ′, 5 ′′ -trihydroxy-2,2 ′, 2 ′′ -trimethyl- [7,6 ′: 3 ′, 6 ”-Ternaphthalene] -1,1 ′, 1 ′′, 4,4 ′, 4 ′′ -hexone, 8-hydroxy-3-methyl-2- (2-oxo-propyl) -1,4-naphthalene Dione, 3-methyl-8-hydroxy-7- (isopropenyl) -1,4-naphthalenedione, 8-hydroxy-2,2-dihydro-3-methyl-3- (2-oxo-propyl) -1, Preferred examples include 4-naphthoquinone, 3,4,8-trihydro-3-methyl-1 (2H) -naphthalenone, diomucinone, bipurbagin, chitranone, and isocinanolone.
  • Diomushinone (compound 4)
  • a particularly preferred compound is 5,5 ′, 5 ′′ -trihydroxy-2,2 ′, 2 ′′ -trimethyl- [7,6 ′: 3 ′, 6 ′′ -ternaphthalene] -1, 1 ′, 1 ′′, 4,4 ′, 4 ′′ -hexone (compound 1), 8-hydroxy-3-methyl-2- (2-oxo-propyl) -1,4-naphthalenedione (compound 2) 3-methyl-8-hydroxy-7- (isopropenyl) -1,4-naphthalenedione (compound 3), 8-hydroxy-2,2-dihydro-3-methyl-3- (2-oxo-propyl) 1,4-naphthoquinone (compound 7) and 3,4,8-trihydro-3-methyl-1 (2H) -naphthalenone (compound 8).
  • These six compounds are all novel compounds not described in any literature.
  • Examples of the pharmaceutically acceptable salt of the compound represented by the general formula (1) include alkali metal salts such as sodium salt and potassium salt. Further, the compound of the general formula (1) may have an optical isomer, and the optically active form is also included in the present invention.
  • the naphthoquinone compound represented by the above general formula (1) can be isolated and purified from an extract of a plant body of Plumbago Ziranica, and Non-Patent Document 1 (Ohira S., et. Al., “ According to the method described in New naphthoquinone and monoterpenoid from Plumbago zelanica ", Tetrahedron Lett., 55 (2014) 6554-6556), monoterpenes can also be synthesized.
  • the plant body of Plumbago / Zairanika may be whole bark as well as bark and leaves. Particularly preferred is a method of extracting from bark.
  • Plumbago Ziranica is a plant native to India but is also available in Japan as an Ayurvedic medicine.
  • the compound represented by the general formula (1) can be isolated as follows. Add a 10-1000-fold amount of water-containing ethanol (water content 1-80%) or acetone to the whole plant or part of the plant body, soak it for 1-96 hours with cooling and heating if desired, and cool Then, filter and concentrate. . If necessary, liquid-liquid extraction is performed by adding n-hexane and water, and a liquid-liquid extraction process or the like with butanol and water is further performed for concentration.
  • the compound of the present invention can be obtained by purifying the concentrate by silica gel chromatography or Sephadex column chromatography.
  • the elution solvent include a chloroform / methanol mixed system, an ethyl acetate / methanol mixed system, and a water / methanol mixed system, and a gradient can be appropriately performed. Furthermore, these compounds can be identified by NMR, mass spectrometry spectrum, and elemental analysis.
  • composition containing the compound represented by the general formula (1) has an excellent NF- ⁇ B inhibitory action and is a disease caused by the enhancement of NF- ⁇ B It is useful for the treatment of rheumatism, for example, rheumatism treatment, inflammation treatment, especially atopic dermatitis treatment, asthma treatment and cancer treatment.
  • the compound represented by the general formula (1) is processed with a pharmaceutically acceptable carrier such as an excipient, a binder, a dispersant, a coating agent, and the like, and processed into an orally administrable pharmaceutical composition. Can do.
  • the content of the compound represented by the general formula (1) in the preparation is appropriately 5 to 50% by mass.
  • the compound represented by the general formula (1) includes hydrocarbons, ester oils such as spermaceti and jojoba oil, beef tallow, triglycerides such as glyceryl triisooctanoate, higher alcohols, POE alkyl ethers, POE curing.
  • the thus obtained medicine or external medicine is preferably administered in an amount of 10 mg to 500 mg, particularly 10 mg to 200 mg per day.
  • the compound represented by the general formula (1) inhibits the excellent activity of nuclear factor ⁇ B, and therefore suppresses inflammation, fibrosis, and cancer caused by the enhancement of NF- ⁇ B.
  • Can do Particularly in the case of cancer, since anti-cancer properties do not decrease so much in drug resistant cancer, it can be usefully applied to cancer resistant to chemotherapeutic agents.
  • the NF- ⁇ B inhibitor of the present invention suppresses inflammation by a plurality of routes, it is particularly preferable to apply it to topical administration for atopic dermatitis caused by a plurality of factors.
  • Plumbago / Zairanika bark (3 kg) was dipped in acetone (18 L) for about one month after the powder frame.
  • the concentrate 35 g was subjected to silica gel column chromatography and roughly fractionated with a chloroform: methanol system.
  • silica gel column chromatography, Sephadex LH-20 and high performance liquid chromatography (HPLC) were further repeated, and compound 1 (15.3 mg), compound 2 (13.3 mg), compound 3 (14.8 mg) were repeated.
  • Diomucinone (compound 4) (3.7 mg), bipurbagin (compound 5) (4.0 mg), chitranone (compound 6) (32.6 mg), compound 7 (17.3 mg), compound 8 (4.8 mg) , Isosinanolone (Compound 9) (5.5 mg) was obtained. Indication values are described below.
  • the NF- ⁇ B inhibitory action was measured on a 10 ⁇ M solution of the naphthoquinone compound (Compounds 1, 6, 7, 8, 9). The measurement is described in J. Org. Based on Health Science, 55, 311-313. That is, HeLa cells were seeded at a density of 5.0 ⁇ 10 5 cells in a 60 petri dish and incubated for 24 hours. Then, 1 ⁇ g of pNF- ⁇ B-SEAP and 1 ⁇ g of luciferase control vector pGL3 were transformed according to the protocol of Effectene TM Transfection Reagent kit (QIAGEN) and incubated for 17 hours.
  • QIAGEN Effectene TM Transfection Reagent kit
  • the transformant was plated at a density of 0.8 ⁇ 10 4 cells (125 ⁇ l / well), and a measurement sample and TNF- ⁇ were added to a concentration of 40 ng / mL. After 18 hours, 25 ⁇ L of the medium was transferred to another 96-well plate, and SEAP activity was measured according to the protocol of Great EscAPe TM SEAP Reporter System (BD biosciences). In the luciferase activity measurement expressed in a cell, they were carried out according to the protocol of the Steady-Glo R Luciferase Assay System. In the activity evaluation, Luciferase luminescence was used for correction between wells. For positive control, 5 ⁇ M parthenolide was used. The results are shown below. As shown in Table 1, it can be seen that any of the compounds of the present invention has an excellent NF- ⁇ B inhibitory action.
  • Compounds 1 to 7 were examined for anticancer activity.
  • the cells used were A549 lung adenocarcinoma cells, MDA-MB-23 triple negative breast cancer cells, isolated squamous cell carcinoma ⁇ B cells, and ⁇ B cell bankristin-resistant strain ⁇ B-VIN.
  • the assay is described in J. Am. National. Cancer Inst. 1990, 82, 1107-1112. That is, RPMI 1640 medium supplemented with 2 mM L-glutamine, 25 mM Hepes and 10% non-immobilized FBS, 100 ⁇ g / mL streptomycin, 100 IU / mL penicillin and 0.25 ⁇ g / mL amphotericin B at various concentrations.
  • any of the compounds of the present invention exhibited an excellent inhibitory action against all cancers. From this, it is surmised that this anticancer action is derived from the NF- ⁇ B inhibitory action because it is not affected by the resistance factor.
  • the present invention can be applied to medicine.

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Abstract

The present invention addresses the problem of providing a novel nuclear factor κB (NF-κB) inhibitor. An NF-κB inhibitor that comprises, as an active ingredient, a naphthoquinone compound represented by general formula (1) or a pharmaceutically acceptable salt thereof. [In general formula (1): R1 and R2 are the same or different and represent a hydrogen atom or a group selected from the group consisting of a hydroxy group, a 2-methyl-5-hydroxy-1,4-naphthoquinone group, an alkyl or alkenyl group optionally having a carbonyl group and an alkyl group optionally having a hydroxy group; R3 represents a hydroxy group or an alkyl group having 1-4 carbon atoms; R4 represents a hydroxy group or an oxo group; and the broken line represents a single bond or a double bond.)

Description

ナフトキノン化合物及び該化合物を有効成分とする核内因子カッパＢ（ＮＦ－κＢ）阻害剤Naphthoquinone compound and nuclear factor kappa B (NF-κB) inhibitor comprising the compound as an active ingredient
　本発明は、ナフトキノン化合物又は薬学的に許容されるその塩、該化合物を有効成分とする核内因子カッパＢ阻害剤（ＮＦ－κＢ）、及び該ＮＦ－κＢ阻害剤を含有する医薬に関する。 The present invention relates to a naphthoquinone compound or a pharmaceutically acceptable salt thereof, a nuclear factor kappa B inhibitor (NF-κB) containing the compound as an active ingredient, and a medicament containing the NF-κB inhibitor.
　核内因子カッパＢはＮＦ－κＢとも呼ばれ、この因子の過剰分泌は、炎症、リウマチ、癌の悪性化などに大きく係わるとされている。このため、老化防止、皮膚炎の治療、癌の治療と予防などにおいては、ＮＦ－κＢの作用を阻害し、この因子が過剰に働かないようにコントロールすることが重要であると言われている（例えば、特許文献１を参照）。このような観点から、種々の化合物がスクリーニングされ、プラムバゴ・ザイラニカの植物体に含まれているナフトキノン化合物に優れたＮＦ－κＢ阻害作用が存することが明らかになっている（非特許文献１）。 Nuclear factor kappa B is also called NF-κB. Excessive secretion of this factor is said to be greatly related to inflammation, rheumatism, malignant transformation of cancer, and the like. Therefore, it is said that it is important to inhibit the action of NF-κB and prevent this factor from working excessively in the prevention of aging, the treatment of dermatitis, the treatment and prevention of cancer, etc. (For example, see Patent Document 1). From this point of view, various compounds have been screened, and it has been clarified that the naphthoquinone compound contained in the plant body of Plumbago Ziranica has an excellent NF-κB inhibitory action (Non-patent Document 1).
　一方、プラムバゴ・ザイラニカはインドを原産とする、チトラカの俗名で知られているアユルベーダの薬用植物で、現在は日本でも入手可能である。この植物の抽出物等については、皮膚に対する作用（特許文献２、３）、癌に対する作用(特許文献４、非特許文献２)、胃腸疾患に対する作用（特許文献５）などが知られている。 On the other hand, Plumbago Zairanika is a medicinal plant of Ayurveda that is native to India and is known by the popular name of Chitoraka, and is currently available in Japan. About this plant extract etc., the effect | action with respect to skin (patent document 2, 3), the effect | action with respect to cancer (patent document 4, nonpatent literature 2), the effect | action with respect to gastrointestinal disease (patent document 5), etc. are known.
特開２０１４－１４８５３０号公報JP 2014-148530 A 特開２００２－１７９５８１号公報JP 2002-179581 A 特表２０１５－５２９６７９号公報JP-T-2015-529679 特表２０１３－５３２７３３号公報JP 2013-532733 A 特表２０１０－５０８３３９号公報Special table 2010-508339
　本発明は、新規ＮＦ－κＢ阻害剤を提供することを課題とする。 An object of the present invention is to provide a novel NF-κB inhibitor.
　このような状況に鑑みて、本発明者らは、プラムバゴ・ザイラニカに含まれる成分について、単離精製を行い、ＮＦ－κＢ阻害活性の強い成分を探索したところ、下記一般式（１）で表される化合物が強いＮＦ－κＢ阻害作用を有し、種々の医薬として有用であることを見いだし、発明を完成させるに至った。 In view of such circumstances, the present inventors isolated and purified the components contained in Plumbago Ziranica and searched for components having strong NF-κB inhibitory activity, and represented by the following general formula (1). The present invention has been found to have a strong NF-κB inhibitory action and useful as various pharmaceuticals, and has led to the completion of the invention.
　即ち、本発明は、次の〔１〕～〔１２〕を提供するものである。 That is, the present invention provides the following [1] to [12].
〔１〕下記一般式（１）で表されるナフトキノン化合物又は薬学的に許容されるその塩を有効成分とする、ＮＦ－κＢ阻害剤。 [1] An NF-κB inhibitor comprising as an active ingredient a naphthoquinone compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
　（式中、Ｒ1及びＲ2は、同一又は異なって、水素原子、ヒドロキシ基、２－メチル－５－ヒドロキシ－１，４－ナフトキノン基、カルボニル基を有していても良いアルキル基、アルケニル基、及び水酸基を有していても良いアルキル基から選ばれる基を示し、Ｒ3は、ヒドロキシ基又は炭素数１～４のアルキル基を示し、Ｒ4は、ヒドロキシ基又はオキソ基を示し、破線部分は、単結合又は二重結合を示す。） (Wherein R 1 and R 2 are the same or different and each represents a hydrogen atom, a hydroxy group, a 2-methyl-5-hydroxy-1,4-naphthoquinone group, an alkyl group optionally having a carbonyl group, an alkenyl group, And a group selected from an alkyl group which may have a hydroxyl group, R 3 represents a hydroxy group or an alkyl group having 1 to 4 carbon atoms, R 4 represents a hydroxy group or an oxo group, (A broken line part shows a single bond or a double bond.)
〔２〕前記一般式(１)で表される化合物が、５，５’，５’’－トリヒドロキシ－２，２’，２’’－トリメチル－［７，６’：３’，６’’－テルナフタレン］－１，１’，１’’，４，４’，４’’－ヘクスオン、８－ヒドロキシ－３－メチル－２－（２－オキソ－プロピル）－１，４－ナフタレンジオン、３－メチル－８－ヒドロキシ－７－（イソプロペニル）－１，４－ナフタレンジオン、８－ヒドロキシ－２，２－ジヒドロ－３－メチル－３－（２－オキソ－プロピル）－１，４－ナフトキノン、３，４，８－トリヒドロ－３－メチル－１（２Ｈ）－ナフタレノン、ジオムシノン、ビプルバギン、キトラノン及びイソシナノロンから選ばれる化合物である〔１〕に記載のＮＦ－κＢ阻害剤。 [2] The compound represented by the general formula (1) is 5,5 ′, 5 ″ -trihydroxy-2,2 ′, 2 ″ -trimethyl- [7,6 ′: 3 ′, 6 ′. '-Ternaphthalene] -1,1', 1 '', 4,4 ', 4' '-hexone, 8-hydroxy-3-methyl-2- (2-oxo-propyl) -1,4-naphthalenedione 3-methyl-8-hydroxy-7- (isopropenyl) -1,4-naphthalenedione, 8-hydroxy-2,2-dihydro-3-methyl-3- (2-oxo-propyl) -1,4 The NF-κB inhibitor according to [1], which is a compound selected from naphthoquinone, 3,4,8-trihydro-3-methyl-1 (2H) -naphthalenone, diomucinone, bipurbagin, chitranone and isocinanolone.
〔３〕下記一般式（１）で表されるナフトキノン化合物又は薬学的に許容されるその塩及び薬学的に許容される担体を含有する医薬組成物。 [3] A pharmaceutical composition comprising a naphthoquinone compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
（式中、Ｒ1及びＲ2は、同一又は異なって、水素原子、ヒドロキシ基、２－メチル－５－ヒドロキシ－１，４－ナフトキノン基、カルボニル基を有していても良いアルキル基、アルケニル基、及び水酸基を有していても良いアルキル基から選ばれる基を示し、Ｒ3は、ヒドロキシ基又は炭素数１～４のアルキル基を示し、Ｒ4は、ヒドロキシ基又はオキソ基を示し、破線部分は、単結合又は二重結合を示す。） (Wherein R 1 and R 2 are the same or different and each represents a hydrogen atom, a hydroxy group, a 2-methyl-5-hydroxy-1,4-naphthoquinone group, an alkyl group optionally having a carbonyl group, an alkenyl group, And a group selected from an alkyl group optionally having a hydroxyl group, R 3 represents a hydroxy group or an alkyl group having 1 to 4 carbon atoms, R 4 represents a hydroxy group or an oxo group, (A broken line part shows a single bond or a double bond.)
〔４〕前記一般式(１)で表される化合物が、５，５’，５’’－トリヒドロキシ－２，２’，２’’－トリメチル－［７，６’：３’，６’’－テルナフタレン］－１，１’，１’’，４，４’，４’’－ヘクスオン、８－ヒドロキシ－３－メチル－２－（２－オキソ－プロピル）－１，４－ナフタレンジオン、３－メチル－８－ヒドロキシ－７－（イソプロペニル）－１，４－ナフタレンジオン、８－ヒドロキシ－２，２－ジヒドロ－３－メチル－３－（２－オキソ－プロピル）－１，４－ナフトキノン、３，４，８－トリヒドロ－３－メチル－１（２Ｈ）－ナフタレノン、ジオムシノン、ビプルバギン、キトラノン及びイソシナノロンから選ばれる化合物である〔３〕に記載の医薬組成物。
〔５〕ＮＦ－κＢの亢進によって生じる疾患治療用医薬組成物である〔３〕又は〔４〕記載の医薬組成物。
〔６〕下記一般式（１）で表されるナフトキノン化合物又は薬学的に許容されるその塩の、ＮＦ－κＢの亢進によって生じる疾患の治療剤製造のための使用。 [4] The compound represented by the general formula (1) is 5,5 ′, 5 ″ -trihydroxy-2,2 ′, 2 ″ -trimethyl- [7,6 ′: 3 ′, 6 ′. '-Ternaphthalene] -1,1', 1 '', 4,4 ', 4''-hexone, 8-hydroxy-3-methyl-2- (2-oxo-propyl) -1,4-naphthalenedione 3-methyl-8-hydroxy-7- (isopropenyl) -1,4-naphthalenedione, 8-hydroxy-2,2-dihydro-3-methyl-3- (2-oxo-propyl) -1,4 The pharmaceutical composition according to [3], which is a compound selected from naphthoquinone, 3,4,8-trihydro-3-methyl-1 (2H) -naphthalenone, diomucinone, bipurbagin, chitranone and isocinanolone.
[5] The pharmaceutical composition according to [3] or [4], which is a pharmaceutical composition for treating a disease caused by enhancement of NF-κB.
[6] Use of a naphthoquinone compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof for producing a therapeutic agent for a disease caused by enhancement of NF-κB.
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
（式中、Ｒ1及びＲ2は、同一又は異なって、水素原子、ヒドロキシ基、２－メチル－５－ヒドロキシ－１，４－ナフトキノン基、カルボニル基を有していても良いアルキル基、アルケニル基、及び水酸基を有していても良いアルキル基から選ばれる基を示し、Ｒ3は、ヒドロキシ基又は炭素数１～４のアルキル基を示し、Ｒ4は、ヒドロキシ基又はオキソ基を示し、破線部分は、単結合又は二重結合を示す。） (Wherein R 1 and R 2 are the same or different and each represents a hydrogen atom, a hydroxy group, a 2-methyl-5-hydroxy-1,4-naphthoquinone group, an alkyl group optionally having a carbonyl group, an alkenyl group, And a group selected from an alkyl group which may have a hydroxyl group, R 3 represents a hydroxy group or an alkyl group having 1 to 4 carbon atoms, R 4 represents a hydroxy group or an oxo group, (A broken line part shows a single bond or a double bond.)
〔７〕前記一般式(１)で表される化合物が、５，５’，５’’－トリヒドロキシ－２，２’，２’’－トリメチル－［７，６’：３’，６’’－テルナフタレン］－１，１’，１’’，４，４’，４’’－ヘクスオン、８－ヒドロキシ－３－メチル－２－（２－オキソ－プロピル）－１，４－ナフタレンジオン、３－メチル－８－ヒドロキシ－７－（イソプロペニル）－１，４－ナフタレンジオン、８－ヒドロキシ－２，２－ジヒドロ－３－メチル－３－（２－オキソ－プロピル）－１，４－ナフトキノン、３，４，８－トリヒドロ－３－メチル－１（２Ｈ）－ナフタレノン、ジオムシノン、ビプルバギン、キトラノン及びイソシナノロンから選ばれる化合物である〔６〕に記載の使用。
〔８〕ＮＦ－κＢの亢進によって生じる疾患の治療に使用するための下記一般式（１）で表されるナフトキノン化合物又は薬学的に許容されるその塩。 [7] The compound represented by the general formula (1) is 5,5 ′, 5 ″ -trihydroxy-2,2 ′, 2 ″ -trimethyl- [7,6 ′: 3 ′, 6 ′. '-Ternaphthalene] -1,1', 1 '', 4,4 ', 4''-hexone, 8-hydroxy-3-methyl-2- (2-oxo-propyl) -1,4-naphthalenedione 3-methyl-8-hydroxy-7- (isopropenyl) -1,4-naphthalenedione, 8-hydroxy-2,2-dihydro-3-methyl-3- (2-oxo-propyl) -1,4 -Use according to [6], which is a compound selected from naphthoquinone, 3,4,8-trihydro-3-methyl-1 (2H) -naphthalenone, diomucinone, bipurbagin, chitranone and isocinanolone.
[8] A naphthoquinone compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof for use in the treatment of a disease caused by enhancement of NF-κB.
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
（式中、Ｒ1及びＲ2は、同一又は異なって、水素原子、ヒドロキシ基、２－メチル－５－ヒドロキシ－１，４－ナフトキノン基、カルボニル基を有していても良いアルキル基、アルケニル基、及び水酸基を有していても良いアルキル基から選ばれる基を示し、Ｒ3は、ヒドロキシ基又は炭素数１～４のアルキル基を示し、Ｒ4は、ヒドロキシ基又はオキソ基を示し、破線部分は、単結合又は二重結合を示す。） (Wherein R 1 and R 2 are the same or different and each represents a hydrogen atom, a hydroxy group, a 2-methyl-5-hydroxy-1,4-naphthoquinone group, an alkyl group optionally having a carbonyl group, an alkenyl group, And a group selected from an alkyl group which may have a hydroxyl group, R 3 represents a hydroxy group or an alkyl group having 1 to 4 carbon atoms, R 4 represents a hydroxy group or an oxo group, (A broken line part shows a single bond or a double bond.)
〔９〕前記一般式(１)で表される化合物が、５，５’，５’’－トリヒドロキシ－２，２’，２’’－トリメチル－［７，６’：３’，６’’－テルナフタレン］－１，１’，１’’，４，４’，４’’－ヘクスオン、８－ヒドロキシ－３－メチル－２－（２－オキソ－プロピル）－１，４－ナフタレンジオン、３－メチル－８－ヒドロキシ－７－（イソプロペニル）－１，４－ナフタレンジオン、８－ヒドロキシ－２，２－ジヒドロ－３－メチル－３－（２－オキソ－プロピル）－１，４－ナフトキノン、３，４，８－トリヒドロ－３－メチル－１（２Ｈ）－ナフタレノン、ジオムシノン、ビプルバギン、キトラノン及びイソシナノロンから選ばれる化合物である〔８〕に記載の化合物。
〔１０〕下記一般式（１）で表される化合物又は薬学的に許容されるその塩の有効量を投与することを特徴とするＮＦ－κＢの亢進によって生じる疾患の治療方法。 [9] The compound represented by the general formula (1) is 5,5 ′, 5 ″ -trihydroxy-2,2 ′, 2 ″ -trimethyl- [7,6 ′: 3 ′, 6 ′. '-Ternaphthalene] -1,1', 1 '', 4,4 ', 4''-hexone, 8-hydroxy-3-methyl-2- (2-oxo-propyl) -1,4-naphthalenedione 3-methyl-8-hydroxy-7- (isopropenyl) -1,4-naphthalenedione, 8-hydroxy-2,2-dihydro-3-methyl-3- (2-oxo-propyl) -1,4 The compound according to [8], which is a compound selected from naphthoquinone, 3,4,8-trihydro-3-methyl-1 (2H) -naphthalenone, diomucinone, bipurbagin, chitranone and isocinanolone.
[10] A method for treating a disease caused by enhancement of NF-κB, comprising administering an effective amount of a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
（式中、Ｒ1及びＲ2は、同一又は異なって、水素原子、ヒドロキシ基、２－メチル－５－ヒドロキシ－１，４－ナフトキノン基、カルボニル基を有していても良いアルキル基、アルケニル基、及び水酸基を有していても良いアルキル基から選ばれる基を示し、Ｒ3は、ヒドロキシ基又は炭素数１～４のアルキル基を示し、Ｒ4は、ヒドロキシ基又はオキソ基を示し、破線部分は、単結合又は二重結合を示す。） (Wherein R 1 and R 2 are the same or different and each represents a hydrogen atom, a hydroxy group, a 2-methyl-5-hydroxy-1,4-naphthoquinone group, an alkyl group optionally having a carbonyl group, an alkenyl group, And a group selected from an alkyl group which may have a hydroxyl group, R 3 represents a hydroxy group or an alkyl group having 1 to 4 carbon atoms, R 4 represents a hydroxy group or an oxo group, (A broken line part shows a single bond or a double bond.)
〔１１〕前記一般式(１)で表される化合物が、５，５’，５’’－トリヒドロキシ－２，２’，２’’－トリメチル－［７，６’：３’，６’’－テルナフタレン］－１，１’，１’’，４，４’，４’’－ヘクスオン、８－ヒドロキシ－３－メチル－２－（２－オキソ－プロピル）－１，４－ナフタレンジオン、３－メチル－８－ヒドロキシ－７－（イソプロペニル）－１，４－ナフタレンジオン、８－ヒドロキシ－２，２－ジヒドロ－３－メチル－３－（２－オキソ－プロピル）－１，４－ナフトキノン、３，４，８－トリヒドロ－３－メチル－１（２Ｈ）－ナフタレノン、ジオムシノン、ビプルバギン、キトラノン及びイソシナノロンから選ばれる化合物である〔１０〕に記載の方法。
〔１２〕以下のナフトキノン化合物又は薬学的に許容されるその塩。
５，５’，５’’－トリヒドロキシ－２，２’，２’’－トリメチル－［７，６’：３’，６’’－テルナフタレン］－１，１’，１’’，４，４’，４’’－ヘクスオン、８－ヒドロキシ－３－メチル－２－（２－オキソ－プロピル）－１，４－ナフタレンジオン、３－メチル－８－ヒドロキシ－７－（イソプロペニル）－１，４－ナフタレンジオン、８－ヒドロキシ－２，２－ジヒドロ－３－メチル－３－（２－オキソ－プロピル）－１，４－ナフトキノン又は３，４，８－トリヒドロ－３－メチル－１（２Ｈ）－ナフタレノン。 [11] The compound represented by the general formula (1) is 5,5 ′, 5 ″ -trihydroxy-2,2 ′, 2 ″ -trimethyl- [7,6 ′: 3 ′, 6 ′. '-Ternaphthalene] -1,1', 1 '', 4,4 ', 4''-hexone, 8-hydroxy-3-methyl-2- (2-oxo-propyl) -1,4-naphthalenedione 3-methyl-8-hydroxy-7- (isopropenyl) -1,4-naphthalenedione, 8-hydroxy-2,2-dihydro-3-methyl-3- (2-oxo-propyl) -1,4 The method according to [10], which is a compound selected from naphthoquinone, 3,4,8-trihydro-3-methyl-1 (2H) -naphthalenone, diomucinone, bipurbagin, chitranone and isocinanolone.
[12] The following naphthoquinone compound or a pharmaceutically acceptable salt thereof.
5,5 ′, 5 ″ -trihydroxy-2,2 ′, 2 ″ -trimethyl- [7,6 ′: 3 ′, 6 ″ -ternaphthalene] -1,1 ′, 1 ″, 4 , 4 ′, 4 ″ -hexone, 8-hydroxy-3-methyl-2- (2-oxo-propyl) -1,4-naphthalenedione, 3-methyl-8-hydroxy-7- (isopropenyl)- 1,4-naphthalenedione, 8-hydroxy-2,2-dihydro-3-methyl-3- (2-oxo-propyl) -1,4-naphthoquinone or 3,4,8-trihydro-3-methyl-1 (2H) -Naphthalenone.
　本発明によれば、新たなＮＦ－κＢ阻害剤、及び当該ＮＦ－κＢの亢進によって生じる疾患治療用医薬組成物が提供できる。当該医薬組成物は、炎症、痛み、組織の繊維化、又は癌の処置用医薬として有用である。 According to the present invention, a novel NF-κB inhibitor and a pharmaceutical composition for treating a disease caused by the enhancement of NF-κB can be provided. The pharmaceutical composition is useful as a medicament for the treatment of inflammation, pain, tissue fibrosis, or cancer.
　＜１＞本発明のＮＦ－κＢ阻害剤
　本発明のＮＦ－κＢ阻害剤は、前記一般式（１）で表される化合物を有効成分とすることを特徴とする。
　式中Ｒ1及びＲ2は、同一又は異なって、水素原子、ヒドロキシ基、２－メチル－５－ヒドロキシ－１，４－ナフトキノン基、カルボニル基を有していても良いアルキル基、アルケニル基及びヒドロキシ基を有していても良いアルキル基から選ばれる基を示す。
　前記アルキル基としては炭素数１～４のものが好ましく、該アルキル基は、直鎖であっても、分岐を有していても良い。このようなアルキル基としては、メチル基、エチル基、プロピル基、ブチル基、１－メチルエチル基、１，１－ジメチルエチル基などが好適に例示できる。カルボニル基を有するアルキル基としては、カルボニル基を有する炭素数１～４のアルキル基が挙げられ、メチルカルボニルメチル基、メチルカルボニルエチル基などが好適に例示できる。特に好ましいものは、メチルカルボニルメチル基である。アルケニル基としては、炭素数２～４のものが好ましく、直鎖であっても、分岐を有していても良い。このようなアルケニル基としては、エテニル基、プロペニル基、ブテニル基、１－メチル－２－エテン－１－イル基などが好適に例示できる。特に好ましいものは、１－メチル－２－エテン－１－イル基である。
　ヒドロキシ基を有するアルキル基としては、ヒドロキシ基を有する炭素数１～４のアルキル基が挙げられ、ヒドロキシメチル基、ヒドロキシエチル基、ヒドロキシプロピル基、２－ヒドロキシ－２－メチル－エチル基が好適に例示できる。 <1> NF-κB inhibitor of the present invention The NF-κB inhibitor of the present invention comprises a compound represented by the general formula (1) as an active ingredient.
In the formula, R 1 and R 2 are the same or different and each represents a hydrogen atom, a hydroxy group, a 2-methyl-5-hydroxy-1,4-naphthoquinone group, an alkyl group optionally having a carbonyl group, an alkenyl group, and The group chosen from the alkyl group which may have a hydroxy group is shown.
The alkyl group preferably has 1 to 4 carbon atoms, and the alkyl group may be linear or branched. Preferred examples of such an alkyl group include a methyl group, an ethyl group, a propyl group, a butyl group, a 1-methylethyl group, and a 1,1-dimethylethyl group. Examples of the alkyl group having a carbonyl group include C1-C4 alkyl groups having a carbonyl group, and a methylcarbonylmethyl group, a methylcarbonylethyl group, and the like are preferable examples. Particularly preferred is a methylcarbonylmethyl group. The alkenyl group preferably has 2 to 4 carbon atoms, and may be linear or branched. Preferred examples of such alkenyl groups include ethenyl group, propenyl group, butenyl group, 1-methyl-2-ethen-1-yl group and the like. Particularly preferred is a 1-methyl-2-ethen-1-yl group.
Examples of the alkyl group having a hydroxy group include an alkyl group having 1 to 4 carbon atoms having a hydroxy group, preferably a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, and a 2-hydroxy-2-methyl-ethyl group. It can be illustrated.
　Ｒ1及びＲ2の両方が同時に水素原子にならないことが好ましい。 It is preferred that both R 1 and R 2 do not become hydrogen atoms at the same time.
　Ｒ1の結合位置は式（１）のナフトキノン骨格の２位、３位及び４位のいずれの位置でもよい。Ｒ2の結合位置は、式（１）のナフトキノン骨格の５位、６位及び７位のいずれでもよいが、７位が特に好ましい。ここで、式（１）のナフトキノン骨格の１位は、Ｒ4の結合している位置でなく、式（１）中のカルボニル基を形成している炭素である。 The bonding position of R 1 may be any of the 2-position, 3-position and 4-position of the naphthoquinone skeleton of formula (1). The bonding position of R 2 may be any of the 5th, 6th and 7th positions of the naphthoquinone skeleton of the formula (1), but the 7th position is particularly preferred. Here, the 1-position of the naphthoquinone skeleton of the formula (1) is not the position to which R 4 is bonded, but the carbon forming the carbonyl group in the formula (1).
　Ｒ3は、ヒドロキシ基又は炭素数１～４のアルキル基を示す。炭素数１～４のアルキル基としては、直鎖であっても、分岐を有していてもよい。このようなアルキル基としては、メチル基、エチル基、プロピル基が挙げられる。Ｒ3としては、ヒドロキシ基又はメチル基がより好ましい。 R 3 represents a hydroxy group or an alkyl group having 1 to 4 carbon atoms. The alkyl group having 1 to 4 carbon atoms may be linear or branched. Examples of such an alkyl group include a methyl group, an ethyl group, and a propyl group. R 3 is more preferably a hydroxy group or a methyl group.
　Ｒ4は、ヒドロキシ基又はオキソ基を示す。Ｒ4がオキソ基を示すとき、Ｒ4と、Ｒ4が結合している炭素原子は、カルボニル基を形成する。 R 4 represents a hydroxy group or an oxo group. When R 4 represents an oxo group, R 4 and the carbon atom to which R 4 is bonded form a carbonyl group.
　このような一般式（１）で表される化合物としては、例えば５，５’，５’’－トリヒドロキシ－２，２’，２’’－トリメチル－［７，６’：３’，６’’－テルナフタレン］－１，１’，１’’，４，４’，４’’－ヘクスオン、８－ヒドロキシ－３－メチル－２－（２－オキソ－プロピル）－１，４－ナフタレンジオン、３－メチル－８－ヒドロキシ－７－（イソプロペニル）－１，４－ナフタレンジオン、８－ヒドロキシ－２，２－ジヒドロ－３－メチル－３－（２－オキソ－プロピル）－１，４－ナフトキノン、３，４，８－トリヒドロ－３－メチル－１（２Ｈ）－ナフタレノン、ジオムシノン、ビプルバギン、キトラノン、イソシナノロン等が好適に例示できる。 Examples of the compound represented by the general formula (1) include 5,5 ′, 5 ″ -trihydroxy-2,2 ′, 2 ″ -trimethyl- [7,6 ′: 3 ′, 6 ”-Ternaphthalene] -1,1 ′, 1 ″, 4,4 ′, 4 ″ -hexone, 8-hydroxy-3-methyl-2- (2-oxo-propyl) -1,4-naphthalene Dione, 3-methyl-8-hydroxy-7- (isopropenyl) -1,4-naphthalenedione, 8-hydroxy-2,2-dihydro-3-methyl-3- (2-oxo-propyl) -1, Preferred examples include 4-naphthoquinone, 3,4,8-trihydro-3-methyl-1 (2H) -naphthalenone, diomucinone, bipurbagin, chitranone, and isocinanolone.
　以下に、より好ましい化合物の化学構造を示す。 The chemical structure of a more preferable compound is shown below.
Figure JPOXMLDOC01-appb-C000011
 ５，５’，５’’－トリヒドロキシ－２，２’，２’’－トリメチル－［７，６’：３’，６’’－テルナフタレン］－１，１’，１’’，４，４’，４’’－ヘクスオン（化合物１）
Figure JPOXMLDOC01-appb-C000011
 5,5 ′, 5 ″ -trihydroxy-2,2 ′, 2 ″ -trimethyl- [7,6 ′: 3 ′, 6 ″ -ternaphthalene] -1,1 ′, 1 ″, 4 , 4 ′, 4 ″ -hexon (compound 1)
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
８－ヒドロキシ－３－メチル－２－（２－オキソ－プロピル）－１，４－ナフタレンジオン（化合物２） 8-hydroxy-3-methyl-2- (2-oxo-propyl) -1,4-naphthalenedione (compound 2)
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
３－メチル－８－ヒドロキシ－７－（イソプロペニル）－１，４－ナフタレンジオン（化合物３） 3-Methyl-8-hydroxy-7- (isopropenyl) -1,4-naphthalenedione (Compound 3)
Figure JPOXMLDOC01-appb-C000014
 ジオムシノン（化合物４）
Figure JPOXMLDOC01-appb-C000014
 Diomushinone (compound 4)
Figure JPOXMLDOC01-appb-C000015
 ビプルバギン（化合物５）
Figure JPOXMLDOC01-appb-C000015
 Bipulbagin (Compound 5)
Figure JPOXMLDOC01-appb-C000016
 キトラノン（化合物６）
Figure JPOXMLDOC01-appb-C000016
 Chitranone (Compound 6)
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
８－ヒドロキシ－２，２－ジヒドロ－３－メチル－３－（２－オキソ－プロピル）－１，４－ナフトキノン（化合物７） 8-hydroxy-2,2-dihydro-3-methyl-3- (2-oxo-propyl) -1,4-naphthoquinone (compound 7)
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
３，４，８－トリヒドロ－３－メチル－１（２Ｈ）－ナフタレノン（化合物８） 3,4,8-trihydro-3-methyl-1 (2H) -naphthalenone (compound 8)
Figure JPOXMLDOC01-appb-C000019
 イソシナノロン（化合物９）
Figure JPOXMLDOC01-appb-C000019
 Isosinanolone (Compound 9)
　このうち、特に好ましい化合物は、５，５’，５’’－トリヒドロキシ－２，２’，２’’－トリメチル－［７，６’：３’，６’’－テルナフタレン］－１，１’，１’’，４，４’，４’’－ヘクスオン（化合物１）、８－ヒドロキシ－３－メチル－２－（２－オキソ－プロピル）－１，４－ナフタレンジオン（化合物２）、３－メチル－８－ヒドロキシ－７－（イソプロペニル）－１，４－ナフタレンジオン（化合物３）、８－ヒドロキシ－２，２－ジヒドロ－３－メチル－３－（２－オキソ－プロピル）－１，４－ナフトキノン（化合物７）、３，４，８－トリヒドロ－３－メチル－１（２Ｈ）－ナフタレノン（化合物８）である。これらの６つの化合物はいずれも文献未記載の新規化合物である。 Of these, a particularly preferred compound is 5,5 ′, 5 ″ -trihydroxy-2,2 ′, 2 ″ -trimethyl- [7,6 ′: 3 ′, 6 ″ -ternaphthalene] -1, 1 ′, 1 ″, 4,4 ′, 4 ″ -hexone (compound 1), 8-hydroxy-3-methyl-2- (2-oxo-propyl) -1,4-naphthalenedione (compound 2) 3-methyl-8-hydroxy-7- (isopropenyl) -1,4-naphthalenedione (compound 3), 8-hydroxy-2,2-dihydro-3-methyl-3- (2-oxo-propyl) 1,4-naphthoquinone (compound 7) and 3,4,8-trihydro-3-methyl-1 (2H) -naphthalenone (compound 8). These six compounds are all novel compounds not described in any literature.
　一般式（１）で表される化合物の薬学的に許容される塩としては、ナトリウム塩、カリウム塩等のアルカリ金属塩が挙げられる。また、一般式（１）の化合物には、光学異性体が存在する場合があり、光学活性体も本発明に含まれる。 Examples of the pharmaceutically acceptable salt of the compound represented by the general formula (1) include alkali metal salts such as sodium salt and potassium salt. Further, the compound of the general formula (1) may have an optical isomer, and the optically active form is also included in the present invention.
　前記の一般式（１）に表されるナフトキノン化合物は、プラムバゴ・ザイラニカの植物体の抽出物より、単離精製することができるし、非特許文献１（Ｏｈｉｒａ　Ｓ．，ｅｔ．ａｌ．，”Ｎｅｗ　ｎａｐｈｔｈｏｑｕｉｎｏｎｅ　ａｎｄ　ｍｏｎｏｔｅｒｐｅｎｏｉｄ　ｆｒｏｍ　Ｐｌｕｍｂａｇｏ　ｚｅｙｌａｎｉｃａ”，Ｔｅｔｒａｈｅｄｒｏｎ　Ｌｅｔｔ．，５５（２０１４）６５５４－６５５６）に記載の方法に従って、モノテルペン類を原料として、合成することもできる。プラムバゴ・ザイラニカの植物体は全草のほか、樹皮や葉でもよく、特に好ましいのは樹皮から抽出する方法である。なお、プラムバゴ・ザイラニカはインド原産の植物ではあるが、アユルベーダ薬として日本においても入手可能である。 The naphthoquinone compound represented by the above general formula (1) can be isolated and purified from an extract of a plant body of Plumbago Ziranica, and Non-Patent Document 1 (Ohira S., et. Al., “ According to the method described in New naphthoquinone and monoterpenoid from Plumbago zelanica ", Tetrahedron Lett., 55 (2014) 6554-6556), monoterpenes can also be synthesized. The plant body of Plumbago / Zairanika may be whole bark as well as bark and leaves. Particularly preferred is a method of extracting from bark. Plumbago Ziranica is a plant native to India but is also available in Japan as an Ayurvedic medicine.
　かかる植物体から、以下のように一般式（１）に表される化合物を単離出来る。植物体の全草又は一部に１０～１０００倍量の含水エタノール（含水率１～８０％）やアセトン等の溶媒を加え、所望により加熱、攪拌を加えながら、１～９６時間浸漬し、冷却した後、濾過・濃縮する。。必要に応じて、ｎ－ヘキサンと水を加えて液液抽出し、更にブタノールと水で液液抽出等する工程を加え濃縮する。該濃縮物をシリカゲルクロマトグラフィーやＳｅｐｈａｄｅｘカラムクロマトグラフィー等で精製することにより本発明化合物を得ることができる。この場合、溶出溶媒としては、クロロホルム・メタノール混液系、酢酸エチル・メタノール混液系、水・メタノール混液系などが好ましく例示でき、適宜、グラジエントを行うことも可能である。更に、これらの化合物の同定はＮＭＲ、質量分析スペクトル、元素分析で行うことができる。 From such a plant body, the compound represented by the general formula (1) can be isolated as follows. Add a 10-1000-fold amount of water-containing ethanol (water content 1-80%) or acetone to the whole plant or part of the plant body, soak it for 1-96 hours with cooling and heating if desired, and cool Then, filter and concentrate. . If necessary, liquid-liquid extraction is performed by adding n-hexane and water, and a liquid-liquid extraction process or the like with butanol and water is further performed for concentration. The compound of the present invention can be obtained by purifying the concentrate by silica gel chromatography or Sephadex column chromatography. In this case, preferable examples of the elution solvent include a chloroform / methanol mixed system, an ethyl acetate / methanol mixed system, and a water / methanol mixed system, and a gradient can be appropriately performed. Furthermore, these compounds can be identified by NMR, mass spectrometry spectrum, and elemental analysis.
＜２＞一般式（１）で表される化合物を含有する医薬組成物
　かくして得られた一般式（１）の化合物は優れたＮＦ－κＢ阻害作用を有し、ＮＦ－κＢの亢進によって生じる疾患の治療、例えばリウマチ治療、炎症治療、特にアトピー性皮膚炎治療や喘息治療、癌治療に有用である。
　前記一般式（１）で表される化合物は、賦形剤、結合剤、分散剤、被覆剤などの薬学的に許容される担体とともに加工して、経口投与可能な医薬組成物に加工することができる。この場合、一般式（１）で表される化合物の製剤における含有量は５～５０質量％が適当である。
　更に、前記一般式（１）で表される化合物は、炭化水素類、鯨蝋、ホホバ油などのエステル油類、牛脂、グリセリルトリイソオクタネート等のトリグリセリド、高級アルコール、ＰＯＥアルキルエーテル、ＰＯＥ硬化ヒマシ油、ＰＯＥソルビタン脂肪酸エステル、ＰＯＥ脂肪酸エステル、ソルビタン脂肪酸エステル、グリセリルモノ脂肪酸エステルなどの非イオン界面活性剤、ＳＬＳのようなアニオン界面活性剤、プロピレングリコール、ポリエチレングリコール、グリセリンなどの多価アルコールなどの任意成分とともに加工して、皮膚外用剤にできる。
　かくして得られた医薬或いは外用医薬は１日に１０ｍｇ～５００ｍｇ、特に１０ｍｇ～２００ｍｇ投与されることが好ましい。 <2> Pharmaceutical composition containing the compound represented by the general formula (1) The compound of the general formula (1) thus obtained has an excellent NF-κB inhibitory action and is a disease caused by the enhancement of NF-κB It is useful for the treatment of rheumatism, for example, rheumatism treatment, inflammation treatment, especially atopic dermatitis treatment, asthma treatment and cancer treatment.
The compound represented by the general formula (1) is processed with a pharmaceutically acceptable carrier such as an excipient, a binder, a dispersant, a coating agent, and the like, and processed into an orally administrable pharmaceutical composition. Can do. In this case, the content of the compound represented by the general formula (1) in the preparation is appropriately 5 to 50% by mass.
Further, the compound represented by the general formula (1) includes hydrocarbons, ester oils such as spermaceti and jojoba oil, beef tallow, triglycerides such as glyceryl triisooctanoate, higher alcohols, POE alkyl ethers, POE curing. Castor oil, POE sorbitan fatty acid ester, POE fatty acid ester, sorbitan fatty acid ester, nonionic surfactant such as glyceryl monofatty acid ester, anionic surfactant such as SLS, polyhydric alcohol such as propylene glycol, polyethylene glycol, glycerin, etc. It can be processed together with any of these ingredients to make a skin external preparation.
The thus obtained medicine or external medicine is preferably administered in an amount of 10 mg to 500 mg, particularly 10 mg to 200 mg per day.
　このような使用態様において、一般式（１）で表される化合物は、優れた核内因子κＢの活性を阻害する為、ＮＦ－κＢの亢進によって生じる、炎症、繊維化、癌を抑制することができる。特に癌においては、薬剤耐性癌にも抗がん特性があまり減じないので、化学療法剤抵抗性の癌などに有用に適用できる。又、本発明のＮＦ－κＢ抑制剤は、複数のルートで炎症を抑えるので、皮膚外用投与では、複数の因子が原因となっているアトピー性皮膚炎などに適用することが特に好ましい。 In such a use mode, the compound represented by the general formula (1) inhibits the excellent activity of nuclear factor κB, and therefore suppresses inflammation, fibrosis, and cancer caused by the enhancement of NF-κB. Can do. Particularly in the case of cancer, since anti-cancer properties do not decrease so much in drug resistant cancer, it can be usefully applied to cancer resistant to chemotherapeutic agents. In addition, since the NF-κB inhibitor of the present invention suppresses inflammation by a plurality of routes, it is particularly preferable to apply it to topical administration for atopic dermatitis caused by a plurality of factors.
　以下に、実施例を挙げて、本発明について更に詳細に説明を加える。
実施例１ Hereinafter, the present invention will be described in more detail with reference to examples.
Example 1
　プラムバゴ・ザイラニカの樹皮（３ｋｇ）を粉枠後、アセトン（１８Ｌ）に約一ヶ月浸漬した。その濃縮物（３５ｇ）をシリカゲルカラムクロマトグラフィーに付し、クロロホルム：メタノール系で粗分画した。得られた画分について、さらにシリカゲルカラムクロマトグラフィー、Ｓｅｐｈａｄｅｘ　ＬＨ－２０及び高速液体クロマトグラフィー（ＨＰＬＣ）を繰り返し、化合物１（１５．３ｍｇ）、化合物２（１３．３ｍｇ）、化合物３（１４．８ｍｇ）、ジオムシノン（化合物４）（３．７ｍｇ），ビプルバギン（化合物５）（４．０ｍｇ）、キトラノン(化合物６)（３２．６ｍｇ）、化合物７（１７．３ｍｇ）、化合物８（４．８ｍｇ）、イソシナノロン（化合物９）（５．５ｍｇ）を得た。示性値は以下に記す。 Plumbago / Zairanika bark (3 kg) was dipped in acetone (18 L) for about one month after the powder frame. The concentrate (35 g) was subjected to silica gel column chromatography and roughly fractionated with a chloroform: methanol system. For the obtained fraction, silica gel column chromatography, Sephadex LH-20 and high performance liquid chromatography (HPLC) were further repeated, and compound 1 (15.3 mg), compound 2 (13.3 mg), compound 3 (14.8 mg) were repeated. ), Diomucinone (compound 4) (3.7 mg), bipurbagin (compound 5) (4.0 mg), chitranone (compound 6) (32.6 mg), compound 7 (17.3 mg), compound 8 (4.8 mg) , Isosinanolone (Compound 9) (5.5 mg) was obtained. Indication values are described below.
化合物１　黄色結晶
C33H20O9
Exact Mass: 560.1107
Mol. Wt.: 560.5065
1H-NMR(400MHz,CDCl3): δ2.08(3H,s), 2.23(3H,s), 2.23(3H,s), 6.84(1H,d,J=1.2Hz), 6.86(1H,d,J=1.2Hz), 7.50(1H,d,J=7.2Hz), 7.50(1H,d,J=7.2Hz), 7.72(1H,m), 7.72(1H,m), 7.76(1H,d,J=7.6Hz), 7.77(1H,d,J=7.6Hz), 7.81(1H,d,J=7.6Hz), 12.30(1H,s,-OH), 12.47(1H,s,-OH), 12.49(1H,s,-OH)
13C-NMR(100MHz,CDCl3): δ14.5, 16.5, 16.5, 115.1, 115.3, 115.3, 118.6, 118.6, 118.7, 128.6, 131.2, 131.4, 131.9, 131.9, 132.4, 135.4, 135.5, 136.9, 137.6, 137.8, 141.4, 147.8, 149.7, 149.9, 158.4, 158.9, 159.2, 183.8, 184.4, 184.5, 188.5, 190.3, 190.4 Compound 1 yellow crystals
C 33 H 20 O 9
Exact Mass: 560.1107
Mol. Wt .: 560.5065
1 H-NMR (400 MHz, CDCl 3 ): δ2.08 (3H, s), 2.23 (3H, s), 2.23 (3H, s), 6.84 (1H, d, J = 1.2Hz), 6.86 (1H, d, J = 1.2Hz), 7.50 (1H, d, J = 7.2Hz), 7.50 (1H, d, J = 7.2Hz), 7.72 (1H, m), 7.72 (1H, m), 7.76 (1H, d, J = 7.6Hz), 7.77 (1H, d, J = 7.6Hz), 7.81 (1H, d, J = 7.6Hz), 12.30 (1H, s, -OH), 12.47 (1H, s, -OH ), 12.49 (1H, s, -OH)
13 C-NMR (100 MHz, CDCl 3 ): δ14.5, 16.5, 16.5, 115.1, 115.3, 115.3, 118.6, 118.6, 118.7, 128.6, 131.2, 131.4, 131.9, 131.9, 132.4, 135.4, 135.5, 136.9, 137.6 , 137.8, 141.4, 147.8, 149.7, 149.9, 158.4, 158.9, 159.2, 183.8, 184.4, 184.5, 188.5, 190.3, 190.4
化合物２　黄色結晶
C14H12O4
Exact Mass: 244.0736
Mol. Wt.: 244.2427
1H-NMR(400MHz,CDCl3): δ2.13(3H,s), 2.34(3H,s), 3.80(2H,s), 7.22(1H,dd,J=8.1,1.4Hz), 7.59(1H,t,J=8.0Hz), 7.64(1H,dd,J=7.4,1.4Hz), 11.95(1H,s,-OH)
13C-NMR(100MHz,CDCl3): δ13.4, 30.2, 41.1, 114.7, 119.2, 123.9, 132.1, 136.2, 140.3, 147.2, 161.3, 183.9, 189.1, 203.0 Compound 2 yellow crystals
C 14 H 12 O 4
Exact Mass: 244.0736
Mol. Wt .: 244.2427
1 H-NMR (400 MHz, CDCl 3 ): δ2.13 (3H, s), 2.34 (3H, s), 3.80 (2H, s), 7.22 (1H, dd, J = 8.1,1.4Hz), 7.59 ( 1H, t, J = 8.0Hz), 7.64 (1H, dd, J = 7.4,1.4Hz), 11.95 (1H, s, -OH)
13 C-NMR (100 MHz, CDCl 3 ): δ13.4, 30.2, 41.1, 114.7, 119.2, 123.9, 132.1, 136.2, 140.3, 147.2, 161.3, 183.9, 189.1, 203.0
化合物３　黄色粉末
C14H12O3
Exact Mass: 228.0786
Mol. Wt.: 228.2433
1H-NMR(400MHz,CDCl3): δ2.19(3H,s), 2.19(3H,s), 5.32(2H,s), 6.80(1H,d,J=1.5Hz), 7.53(1H,d,J=7.8Hz), 7.60(1H,d,J=7.8Hz),  12.68(1H,s,-OH)
13C-NMR(100MHz,CDCl3): δ16.4, 22.6, 114.9, 117.8, 119.2, 130.8, 135.1, 135.6, 138.9, 141.6, 149.6, 159.1, 184.6, 190.7 Compound 3 yellow powder
C 14 H 12 O 3
Exact Mass: 228.0786
Mol. Wt .: 228.2433
1 H-NMR (400 MHz, CDCl 3 ): δ2.19 (3H, s), 2.19 (3H, s), 5.32 (2H, s), 6.80 (1H, d, J = 1.5Hz), 7.53 (1H, d, J = 7.8Hz), 7.60 (1H, d, J = 7.8Hz), 12.68 (1H, s, -OH)
13 C-NMR (100 MHz, CDCl 3 ): δ16.4, 22.6, 114.9, 117.8, 119.2, 130.8, 135.1, 135.6, 138.9, 141.6, 149.6, 159.1, 184.6, 190.7
ジオムシノン（化合物４）
C12H12O4
Exact Mass: 220.0736
Mol. Wt.: 220.2213
1H-NMR(400MHz,CDCl3): δ1.24(3H,s), 2.76(1H,d,J=17.4Hz), 3.40(1H,d,J=17.0Hz), 3.50(1H,dd,J=8.0,4.0Hz), 4.02(1H,dd,J=8.0,4.0Hz), 7.27(1H,d,J=9.2Hz),  7.56(1H,d,J=7.6Hz), 7.66(1H,t,J=7.8Hz)
13C-NMR(100MHz,CDCl3): δ21.4, 46.5, 50.5, 67.8, 117.5, 118.7, 124.0, 133.9, 137.0, 161.2, 200.9, 202 Diomushinone (compound 4)
C 12 H 12 O 4
Exact Mass: 220.0736
Mol. Wt .: 220.2213
1 H-NMR (400 MHz, CDCl 3 ): δ1.24 (3H, s), 2.76 (1H, d, J = 17.4Hz), 3.40 (1H, d, J = 17.0Hz), 3.50 (1H, dd, J = 8.0,4.0Hz), 4.02 (1H, dd, J = 8.0,4.0Hz), 7.27 (1H, d, J = 9.2Hz), 7.56 (1H, d, J = 7.6Hz), 7.66 (1H, (t, J = 7.8Hz)
13 C-NMR (100 MHz, CDCl 3 ): δ21.4, 46.5, 50.5, 67.8, 117.5, 118.7, 124.0, 133.9, 137.0, 161.2, 200.9, 202
ビプルバギン（化合物５）　黄色結晶
C22H14O6
Exact Mass: 374.0790
Mol. Wt.: 374.3430
1H-NMR(400MHz,CDCl3): δ2.08(6H,s), 7.30(2H,dd,J=8.1,1.2Hz), 7.68(2H,t,J=8.1Hz), 7.73(2H,d,J=1.0Hz), 11.82(2H,s,-OH)
13C-NMR(100MHz,CDCl3): δ14.5, 114.9, 119.2, 124.6, 132.2, 136.6, 139.9, 147.8, 161.8, 183.6, 187.7 Bipulbagin (Compound 5) Yellow crystals
C 22 H 14 O 6
Exact Mass: 374.0790
Mol. Wt .: 374.3430
1 H-NMR (400 MHz, CDCl 3 ): δ 2.08 (6H, s), 7.30 (2H, dd, J = 8.1, 1.2 Hz), 7.68 (2H, t, J = 8.1 Hz), 7.73 (2H, d, J = 1.0Hz), 11.82 (2H, s, -OH)
13 C-NMR (100 MHz, CDCl 3 ): δ14.5, 114.9, 119.2, 124.6, 132.2, 136.6, 139.9, 147.8, 161.8, 183.6, 187.7
キトラノン（化合物６）　黄色粉末
C22H14O6
Exact Mass: 374.0790
Mol. Wt.: 374.3430
1H-NMR(400MHz,CDCl3): δ2.07(3H,s), 2.23(3H,s), 6.86(1H,s), 7.48(1H,d,J=8.6Hz), 7.48(1H,d,J=7.7Hz), 7.64(1H,t-like), 7.72(1H,d,J=7.3Hz), 7.76(1H,d,J=8.0Hz), 11.94(1H,s,-OH), 12.29(1H,s,-OH)
13C-NMR(100MHz,CDCl3): δ14.6, 16.5, 114.9, 115.2, 118.6, 119.3, 124.3, 128.6, 132.0, 132.4, 135.4, 136.3, 136.9, 141.3, 147.7, 149.9, 158.4, 161.5, 187.6, 187.7, 184.1, 184.4 Chitranone (Compound 6) Yellow powder
C 22 H 14 O 6
Exact Mass: 374.0790
Mol. Wt .: 374.3430
1 H-NMR (400 MHz, CDCl 3 ): δ2.07 (3H, s), 2.23 (3H, s), 6.86 (1H, s), 7.48 (1H, d, J = 8.6Hz), 7.48 (1H, d, J = 7.7Hz), 7.64 (1H, t-like), 7.72 (1H, d, J = 7.3Hz), 7.76 (1H, d, J = 8.0Hz), 11.94 (1H, s, -OH) , 12.29 (1H, s, -OH)
13 C-NMR (100 MHz, CDCl 3 ): δ14.6, 16.5, 114.9, 115.2, 118.6, 119.3, 124.3, 128.6, 132.0, 132.4, 135.4, 136.3, 136.9, 141.3, 147.7, 149.9, 158.4, 161.5, 187.6 , 187.7, 184.1, 184.4
化合物７　黄色粉末
C14H14O4
Exact Mass: 246.0892
Mol.Wt: 246.2586
1H-NMR(400MHz, CDCl3): δ1.27(3H,s), 2.20(3H,s), 2.50(1H,d,J=18.2Hz), 2.69(1H,d,J=16.8Hz),3.37(1H,d,J=18.2Hz), 3.75(1H,d,J=12.9Hz),7.26(1H,d,J=1.3Hz), 7.60(1H,dd,J=7.5,1.3Hz),7.66(1H,t,J=7.7Hz), 12.03(1H,s,-OH)
13C-NMR(100Hz,CDCl3): δ26.3, 46.0, 48.6, 50.5, 50.5, 117.5, 119.2, 123.6, 133.2, 136.9, 161.2, 198.7, 202.8, 206.2 Compound 7 yellow powder
C 14 H 14 O 4
Exact Mass: 246.0892
Mol.Wt: 246.2586
1 H-NMR (400 MHz, CDCl 3 ): δ1.27 (3H, s), 2.20 (3H, s), 2.50 (1H, d, J = 18.2 Hz), 2.69 (1H, d, J = 16.8 Hz) , 3.37 (1H, d, J = 18.2Hz), 3.75 (1H, d, J = 12.9Hz), 7.26 (1H, d, J = 1.3Hz), 7.60 (1H, dd, J = 7.5,1.3Hz) , 7.66 (1H, t, J = 7.7Hz), 12.03 (1H, s, -OH)
13 C-NMR (100 Hz, CDCl 3 ): δ26.3, 46.0, 48.6, 50.5, 50.5, 117.5, 119.2, 123.6, 133.2, 136.9, 161.2, 198.7, 202.8, 206.2
化合物８　黄色オイル
C11H12O4
Exact Mass:208.0736
Mol. Wt:208.2106
1NMR(400MHz,CDCl3): δ1.29(3H,s), 2.80(1H,d,J=17Hz), 3.01(1H,d,J=17.1Hz), 4.77(1H,s)),7.10(1H,d,J=7.7Hz), 7.10(1H,d,J=8.3Hz), 7.52(1H,d,J=8.0Hz)
13C-NMR(100MHz,CDCl3): δ22.0, 49.8, 74.0, 75.3, 114.7, 117.5, 117.7, 137.2, 143.4, 162.5, 202.3 Compound 8 yellow oil
C 11 H 12 O 4
Exact Mass: 208.0736
Mol. Wt: 208.2106
1 NMR (400MHz, CDCl 3 ): δ1.29 (3H, s), 2.80 (1H, d, J = 17Hz), 3.01 (1H, d, J = 17.1Hz), 4.77 (1H, s)), 7.10 (1H, d, J = 7.7Hz), 7.10 (1H, d, J = 8.3Hz), 7.52 (1H, d, J = 8.0Hz)
13 C-NMR (100 MHz, CDCl 3 ): δ22.0, 49.8, 74.0, 75.3, 114.7, 117.5, 117.7, 137.2, 143.4, 162.5, 202.3
イソシナノロン（化合物９）　緑色オイル
C11H12O3
Exact Mass:192.0786
Mol.Wt:192.2112
1NMR(400MHz,CDCl3): δ1.11,(3H,d,J=6.8Hz), 2.36(1H,m), 2.49(1H,dd,J=17.7,4.1Hz), 2.79( 1H,q,J=11.0,6.7Hz), 4.64(1H,d,J=2.2Hz), 6.86(2H,m), 7.42(1H,t,J=8.1Hz), 12,36(1H,s,-OH)
13C-NMR(100Hz,CDCl3): δ15.8, 34.1, 40.3, 70.5, 114.6, 117.4, 118.7, 136.6, 145.0, 162.0, 204.9
実施例２ Isosinanolone (Compound 9) Green oil
C 11 H 12 O 3
Exact Mass: 192.0786
Mol.Wt: 192.2112
1 NMR (400MHz, CDCl 3 ): δ1.11, (3H, d, J = 6.8Hz), 2.36 (1H, m), 2.49 (1H, dd, J = 17.7,4.1Hz), 2.79 (1H, q , J = 11.0,6.7Hz), 4.64 (1H, d, J = 2.2Hz), 6.86 (2H, m), 7.42 (1H, t, J = 8.1Hz), 12,36 (1H, s, -OH )
13 C-NMR (100 Hz, CDCl 3 ): δ 15.8, 34.1, 40.3, 70.5, 114.6, 117.4, 118.7, 136.6, 145.0, 162.0, 204.9
Example 2
　前記ナフトキノン化合物（化合物１、６、７、８、９）の１０μＭの溶液について、ＮＦ－κＢ抑制作用を測定した。測定は、Ｊ．Ｈｅａｌｔｈ　Ｓｃｉｅｎｃｅ、５５、３１１～３１３に基づいて行った。即ち、ＨｅＬａ細胞を６０シャーレに５．０×１０5 ｃｅｌｌｓの密度でまき、２４時間インキュベートした。その後、ｐＮＦ－κＢ－ＳＥＡＰ　１μｇ及びｕｃｉｆｅｒａｓｅ　ｃｏｎｔｒｏｌ　ｖｅｃｔｏｒであるｐＧＬ３　１μｇをＥｆｆｅｃｔｅｎｅTM　Ｔｒａｎｓｆｅｃｔｉｏｎ　Ｒｅｇｅｎｔ　ｋｉｔ（ＱＩＡＧＥＮ社）のプロトコールに従って形質転換を行い、１７時間インキュベートした。その形質転換体を０．８×１０4ｃｅｌｌｓ（１２５μｌ／ｗｅｌｌ）の密度でまき、測定試料及び、ＴＮＦ－αを４０ｎｇ／ｍＬの濃度になるよう添加した。１８時間後、培地２５μＬを別の９６－ｗｅｌｌ　ｐｌａｔｅに移し、Ｇｒｅａｔ　ＥｓｃＡＰｅTM　ＳＥＡＰ　Ｒｅｐｏｒｔｅｒ　Ｓｙｓｔｅｍ（ＢＤ　ｂｉｏｓｃｉｅｎｃｅｓ社）のプロトコールに従って、ＳＥＡＰ活性測定を行った。また、細胞中に発現するｌｕｃｉｆｅｒａｓｅ活性測定においては、Ｓｔｅａｄｙ－ＧｌｏR　Ｌｕｃｉｆｅｒａｓｅ　Ａｓｓａｙ　Ｓｙｓｔｅｍのプロトコールに従って行った。活性評価に際しては、ｗｅｌｌ間の補正にＬｕｃｉｆｅｒａｓｅ発光量を用いた。なお、陽性コントロールにはパルテノライド（Ｐａｒｔｈｅｎｏｌｉｄｅ）５μＭを用いた。結果を以下に示す。
　表１に示すように、いずれの本発明化合物も優れたＮＦ－κＢ抑制作用を有することがわかる。 The NF-κB inhibitory action was measured on a 10 μM solution of the naphthoquinone compound (Compounds 1, 6, 7, 8, 9). The measurement is described in J. Org. Based on Health Science, 55, 311-313. That is, HeLa cells were seeded at a density of 5.0 × 10 5 cells in a 60 petri dish and incubated for 24 hours. Then, 1 μg of pNF-κB-SEAP and 1 μg of luciferase control vector pGL3 were transformed according to the protocol of Effectene ™ Transfection Reagent kit (QIAGEN) and incubated for 17 hours. The transformant was plated at a density of 0.8 × 10 4 cells (125 μl / well), and a measurement sample and TNF-α were added to a concentration of 40 ng / mL. After 18 hours, 25 μL of the medium was transferred to another 96-well plate, and SEAP activity was measured according to the protocol of Great EscAPe ™ SEAP Reporter System (BD biosciences). In the luciferase activity measurement expressed in a cell, they were carried out according to the protocol of the Steady-Glo R Luciferase Assay System. In the activity evaluation, Luciferase luminescence was used for correction between wells. For positive control, 5 μM parthenolide was used. The results are shown below.
As shown in Table 1, it can be seen that any of the compounds of the present invention has an excellent NF-κB inhibitory action.
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
　化合物１～７について、抗がん活性を調べた。使用した細胞はＡ５４９肺腺癌細胞、ＭＤＡ－ＭＢ－２３トリプルネガティブ乳癌細胞、分離扁平上皮癌κＢ細胞、κＢ細胞のバンクリスチン耐性株κＢ－ＶＩＮの４種を用いた。アッセイはＪ．Ｎａｔｉｏｎ．Ｃａｎｃｅｒ　Ｉｎｓｔ．１９９０，８２，１１０７～１１１２に記載の方法に従った。即ち、２ｍＭのＬ－グルタミン、２５ｍＭのＨｅｐｅｓ及び１０％非動化ＦＢＳ、１００μｇ／ｍＬのストレプトマイシン、１００ＩＵ／ｍＬのペニシリン及び０．２５μｇ／ｍＬのアンフォテリシンＢを添加したＲＰＭＩ１６４０培地で、各種の濃度の検体を加え、７２時間での阻害率を計測し、ＩＣ50を算出した。
　表２に示すように、いずれの本発明化合物も全ての癌に対して優れた抑制作用を示していた。これより、耐性因子の影響を受けないことより、この抗がん作用はＮＦ－κＢ抑制作用に由来するものであることが推測される。 Compounds 1 to 7 were examined for anticancer activity. The cells used were A549 lung adenocarcinoma cells, MDA-MB-23 triple negative breast cancer cells, isolated squamous cell carcinoma κB cells, and κB cell bankristin-resistant strain κB-VIN. The assay is described in J. Am. Nation. Cancer Inst. 1990, 82, 1107-1112. That is, RPMI 1640 medium supplemented with 2 mM L-glutamine, 25 mM Hepes and 10% non-immobilized FBS, 100 μg / mL streptomycin, 100 IU / mL penicillin and 0.25 μg / mL amphotericin B at various concentrations. A sample was added, the inhibition rate at 72 hours was measured, and IC 50 was calculated.
As shown in Table 2, any of the compounds of the present invention exhibited an excellent inhibitory action against all cancers. From this, it is surmised that this anticancer action is derived from the NF-κB inhibitory action because it is not affected by the resistance factor.
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000021
　本発明は医薬に応用できる。 The present invention can be applied to medicine.

Claims (12)

  1. 　下記一般式（１）で表されるナフトキノン化合物又は薬学的に許容されるその塩を有効成分とする、ＮＦ－κＢ阻害剤。
    Figure JPOXMLDOC01-appb-C000001
     　（式中、Ｒ1及びＲ2は、同一又は異なって、水素原子、ヒドロキシ基、２－メチル－５－ヒドロキシ－１，４－ナフトキノン基、カルボニル基を有していても良いアルキル基、アルケニル基、及び水酸基を有していても良いアルキル基から選ばれる基を示し、Ｒ3は、ヒドロキシ基又は炭素数１～４のアルキル基を示し、Ｒ4は、ヒドロキシ基又はオキソ基を示し、破線部分は、単結合又は二重結合を示す。）     An NF-κB inhibitor comprising a naphthoquinone compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
    Figure JPOXMLDOC01-appb-C000001
     (Wherein R 1 and R 2 are the same or different and each represents a hydrogen atom, a hydroxy group, a 2-methyl-5-hydroxy-1,4-naphthoquinone group, an alkyl group optionally having a carbonyl group, an alkenyl group, And a group selected from an alkyl group which may have a hydroxyl group, R 3 represents a hydroxy group or an alkyl group having 1 to 4 carbon atoms, R 4 represents a hydroxy group or an oxo group, (A broken line part shows a single bond or a double bond.)
  2. 　前記一般式(１)で表される化合物が、５，５’，５’’－トリヒドロキシ－２，２’，２’’－トリメチル－［７，６’：３’，６’’－テルナフタレン］－１，１’，１’’，４，４’，４’’－ヘクスオン、８－ヒドロキシ－３－メチル－２－（２－オキソ－プロピル）－１，４－ナフタレンジオン、３，４－ジメチル－８－ヒドロキシ－７－（イソプロペニル）－（４Ｈ）－ナフタレノン、８－ヒドロキシ－７－（２’－ヒドロキシ－２’－メチル）エチル－３－メチル－１，４－ナフタレンジオン、８－ヒドロキシ－２，２－ジヒドロ－３－メチル－３－（２－オキソ－プロピル）－１，４－ナフトキノン、３，４，８－トリヒドロ－３－メチル－１（２Ｈ）－ナフタレノン、プルンバギン、ジオムシノン、ビプルバギン、キトラノン及びイソシナノロンから選ばれる化合物である請求項１に記載のＮＦ－κＢ阻害剤。 The compound represented by the general formula (1) is 5,5 ′, 5 ″ -trihydroxy-2,2 ′, 2 ″ -trimethyl- [7,6 ′: 3 ′, 6 ″ -tel Naphthalene] -1,1 ′, 1 ″, 4,4 ′, 4 ″ -hexone, 8-hydroxy-3-methyl-2- (2-oxo-propyl) -1,4-naphthalenedione, 3, 4-Dimethyl-8-hydroxy-7- (isopropenyl)-(4H) -naphthalenone, 8-hydroxy-7- (2′-hydroxy-2′-methyl) ethyl-3-methyl-1,4-naphthalenedione 8-hydroxy-2,2-dihydro-3-methyl-3- (2-oxo-propyl) -1,4-naphthoquinone, 3,4,8-trihydro-3-methyl-1 (2H) -naphthalenone, Plumbagin, geomucinone, bipurbaghin, kitra NF-[kappa] B inhibitor according to claim 1 which is a compound selected from the emissions and Isoshinanoron.
  3. 　下記一般式（１）で表されるナフトキノン化合物又は薬学的に許容されるその塩及び薬学的に許容される担体を含有する医薬組成物。
    Figure JPOXMLDOC01-appb-C000002
     （式中、Ｒ1及びＲ2は、同一又は異なって、水素原子、ヒドロキシ基、２－メチル－５－ヒドロキシ－１，４－ナフトキノン基、カルボニル基を有していても良いアルキル基、アルケニル基、及び水酸基を有していても良いアルキル基から選ばれる基を示し、Ｒ3は、ヒドロキシ基又は炭素数１～４のアルキル基を示し、Ｒ4は、ヒドロキシ基又はオキソ基を示し、破線部分は、単結合又は二重結合を示す。）     A pharmaceutical composition comprising a naphthoquinone compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
    Figure JPOXMLDOC01-appb-C000002
     (Wherein R 1 and R 2 are the same or different and each represents a hydrogen atom, a hydroxy group, a 2-methyl-5-hydroxy-1,4-naphthoquinone group, an alkyl group optionally having a carbonyl group, an alkenyl group, And a group selected from an alkyl group which may have a hydroxyl group, R 3 represents a hydroxy group or an alkyl group having 1 to 4 carbon atoms, R 4 represents a hydroxy group or an oxo group, (A broken line part shows a single bond or a double bond.)
  4. 　前記一般式(１)で表される化合物が、５，５’，５’’－トリヒドロキシ－２，２’，２’’－トリメチル－［７，６’：３’，６’’－テルナフタレン］－１，１’，１’’，４，４’，４’’－ヘクスオン、８－ヒドロキシ－３－メチル－２－（２－オキソ－プロピル）－１，４－ナフタレンジオン、３，４－ジメチル－８－ヒドロキシ－７－（イソプロペニル）－（４Ｈ）－ナフタレノン、８－ヒドロキシ－７－（２’－ヒドロキシ－２’－メチル）エチル－３－メチル－１，４－ナフタレンジオン、８－ヒドロキシ－２，２－ジヒドロ－３－メチル－３－（２－オキソ－プロピル）－１，４－ナフトキノン、３，４，８－トリヒドロ－３－メチル－１（２Ｈ）－ナフタレノン、プルンバギン、ジオムシノン、ビプルバギン、キトラノン及びイソシナノロンから選ばれる化合物である請求項３に記載の医薬組成物。 The compound represented by the general formula (1) is 5,5 ′, 5 ″ -trihydroxy-2,2 ′, 2 ″ -trimethyl- [7,6 ′: 3 ′, 6 ″ -tel Naphthalene] -1,1 ′, 1 ″, 4,4 ′, 4 ″ -hexone, 8-hydroxy-3-methyl-2- (2-oxo-propyl) -1,4-naphthalenedione, 3, 4-Dimethyl-8-hydroxy-7- (isopropenyl)-(4H) -naphthalenone, 8-hydroxy-7- (2′-hydroxy-2′-methyl) ethyl-3-methyl-1,4-naphthalenedione 8-hydroxy-2,2-dihydro-3-methyl-3- (2-oxo-propyl) -1,4-naphthoquinone, 3,4,8-trihydro-3-methyl-1 (2H) -naphthalenone, Plumbagin, geomucinone, bipurbaghin, kitra The pharmaceutical composition of claim 3 which is a compound selected from the emissions and Isoshinanoron.
  5. 　ＮＦ－κＢの亢進によって生じる疾患治療用医薬組成物である請求項３又は４記載の医薬組成物。 The pharmaceutical composition according to claim 3 or 4, which is a pharmaceutical composition for treating a disease caused by enhancement of NF-κB.
  6. 　下記一般式（１）で表されるナフトキノン化合物又は薬学的に許容されるその塩の、ＮＦ－κＢの亢進によって生じる疾患の治療剤製造のための使用。
    Figure JPOXMLDOC01-appb-C000003
     （式中、Ｒ1及びＲ2は、同一又は異なって、水素原子、ヒドロキシ基、２－メチル－５－ヒドロキシ－１，４－ナフトキノン基、カルボニル基を有していても良いアルキル基、アルケニル基、及び水酸基を有していても良いアルキル基から選ばれる基を示し、Ｒ3は、ヒドロキシ基又は炭素数１～４のアルキル基を示し、Ｒ4は、ヒドロキシ基又はオキソ基を示し、破線部分は、単結合又は二重結合を示す。）     Use of a naphthoquinone compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof for producing a therapeutic agent for a disease caused by enhancement of NF-κB.
    Figure JPOXMLDOC01-appb-C000003
     (Wherein R 1 and R 2 are the same or different and each represents a hydrogen atom, a hydroxy group, a 2-methyl-5-hydroxy-1,4-naphthoquinone group, an alkyl group optionally having a carbonyl group, an alkenyl group, And a group selected from an alkyl group which may have a hydroxyl group, R 3 represents a hydroxy group or an alkyl group having 1 to 4 carbon atoms, R 4 represents a hydroxy group or an oxo group, (A broken line part shows a single bond or a double bond.)
  7. 　前記一般式(１)で表される化合物が、５，５’，５’’－トリヒドロキシ－２，２’，２’’－トリメチル－［７，６’：３’，６’’－テルナフタレン］－１，１’，１’’，４，４’，４’’－ヘクスオン、８－ヒドロキシ－３－メチル－２－（２－オキソ－プロピル）－１，４－ナフタレンジオン、３，４－ジメチル－８－ヒドロキシ－７－（イソプロペニル）－（４Ｈ）－ナフタレノン、８－ヒドロキシ－７－（２’－ヒドロキシ－２’－メチル）エチル－３－メチル－１，４－ナフタレンジオン、８－ヒドロキシ－２，２－ジヒドロ－３－メチル－３－（２－オキソ－プロピル）－１，４－ナフトキノン、３，４，８－トリヒドロ－３－メチル－１（２Ｈ）－ナフタレノン、プルンバギン、ジオムシノン、ビプルバギン、キトラノン及びイソシナノロンから選ばれる化合物である請求項６に記載の使用。 The compound represented by the general formula (1) is 5,5 ′, 5 ″ -trihydroxy-2,2 ′, 2 ″ -trimethyl- [7,6 ′: 3 ′, 6 ″ -tel Naphthalene] -1,1 ′, 1 ″, 4,4 ′, 4 ″ -hexone, 8-hydroxy-3-methyl-2- (2-oxo-propyl) -1,4-naphthalenedione, 3, 4-Dimethyl-8-hydroxy-7- (isopropenyl)-(4H) -naphthalenone, 8-hydroxy-7- (2′-hydroxy-2′-methyl) ethyl-3-methyl-1,4-naphthalenedione 8-hydroxy-2,2-dihydro-3-methyl-3- (2-oxo-propyl) -1,4-naphthoquinone, 3,4,8-trihydro-3-methyl-1 (2H) -naphthalenone, Plumbagin, geomucinone, bipurbaghin, kitra Use according to claim 6, which is a compound selected from the emissions and Isoshinanoron.
  8. 　ＮＦ－κＢの亢進によって生じる疾患の治療に使用するための下記一般式（１）で表されるナフトキノン化合物又は薬学的に許容されるその塩。
    Figure JPOXMLDOC01-appb-C000004
     （式中、Ｒ1及びＲ2は、同一又は異なって、水素原子、ヒドロキシ基、２－メチル－５－ヒドロキシ－１，４－ナフトキノン基、カルボニル基を有していても良いアルキル基、アルケニル基、及び水酸基を有していても良いアルキル基から選ばれる基を示し、Ｒ3は、ヒドロキシ基又は炭素数１～４のアルキル基を示し、Ｒ4は、ヒドロキシ基又はオキソ基を示し、破線部分は、単結合又は二重結合を示す。）     A naphthoquinone compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof for use in the treatment of a disease caused by enhancement of NF-κB.
    Figure JPOXMLDOC01-appb-C000004
     (Wherein R 1 and R 2 are the same or different and each represents a hydrogen atom, a hydroxy group, a 2-methyl-5-hydroxy-1,4-naphthoquinone group, an alkyl group optionally having a carbonyl group, an alkenyl group, And a group selected from an alkyl group which may have a hydroxyl group, R 3 represents a hydroxy group or an alkyl group having 1 to 4 carbon atoms, R 4 represents a hydroxy group or an oxo group, (A broken line part shows a single bond or a double bond.)
  9. 　前記一般式(１)で表される化合物が、５，５’，５’’－トリヒドロキシ－２，２’，２’’－トリメチル－［７，６’：３’，６’’－テルナフタレン］－１，１’，１’’，４，４’，４’’－ヘクスオン、８－ヒドロキシ－３－メチル－２－（２－オキソ－プロピル）－１，４－ナフタレンジオン、３，４－ジメチル－８－ヒドロキシ－７－（イソプロペニル）－（４Ｈ）－ナフタレノン、８－ヒドロキシ－７－（２’－ヒドロキシ－２’－メチル）エチル－３－メチル－１，４－ナフタレンジオン、８－ヒドロキシ－２，２－ジヒドロ－３－メチル－３－（２－オキソ－プロピル）－１，４－ナフトキノン、３，４，８－トリヒドロ－３－メチル－１（２Ｈ）－ナフタレノン、プルンバギン、ジオムシノン、ビプルバギン、キトラノン及びイソシナノロンから選ばれる化合物である請求項８に記載の化合物。 The compound represented by the general formula (1) is 5,5 ′, 5 ″ -trihydroxy-2,2 ′, 2 ″ -trimethyl- [7,6 ′: 3 ′, 6 ″ -tel Naphthalene] -1,1 ′, 1 ″, 4,4 ′, 4 ″ -hexone, 8-hydroxy-3-methyl-2- (2-oxo-propyl) -1,4-naphthalenedione, 3, 4-Dimethyl-8-hydroxy-7- (isopropenyl)-(4H) -naphthalenone, 8-hydroxy-7- (2′-hydroxy-2′-methyl) ethyl-3-methyl-1,4-naphthalenedione 8-hydroxy-2,2-dihydro-3-methyl-3- (2-oxo-propyl) -1,4-naphthoquinone, 3,4,8-trihydro-3-methyl-1 (2H) -naphthalenone, Plumbagin, geomucinone, bipurbaghin, kitra A compound according to claim 8 which is a compound selected from the emissions and Isoshinanoron.
  10. 　下記一般式（１）で表される化合物又は薬学的に許容されるその塩の有効量を投与することを特徴とするＮＦ－κＢの亢進によって生じる疾患の治療方法。
    Figure JPOXMLDOC01-appb-C000005
     （式中、Ｒ1及びＲ2は、同一又は異なって、水素原子、ヒドロキシ基、２－メチル－５－ヒドロキシ－１，４－ナフトキノン基、カルボニル基を有していても良いアルキル基、アルケニル基、及び水酸基を有していても良いアルキル基から選ばれる基を示し、Ｒ3は、ヒドロキシ基又は炭素数１～４のアルキル基を示し、Ｒ4は、ヒドロキシ基又はオキソ基を示し、破線部分は、単結合又は二重結合を示す。）     A method for treating a disease caused by enhancement of NF-κB, comprising administering an effective amount of a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof.
    Figure JPOXMLDOC01-appb-C000005
     (Wherein R 1 and R 2 are the same or different and each represents a hydrogen atom, a hydroxy group, a 2-methyl-5-hydroxy-1,4-naphthoquinone group, an alkyl group optionally having a carbonyl group, an alkenyl group, And a group selected from an alkyl group which may have a hydroxyl group, R 3 represents a hydroxy group or an alkyl group having 1 to 4 carbon atoms, R 4 represents a hydroxy group or an oxo group, (A broken line part shows a single bond or a double bond.)
  11. 　前記一般式(１)で表される化合物が、５，５’，５’’－トリヒドロキシ－２，２’，２’’－トリメチル－［７，６’：３’，６’’－テルナフタレン］－１，１’，１’’，４，４’，４’’－ヘクスオン、８－ヒドロキシ－３－メチル－２－（２－オキソ－プロピル）－１，４－ナフタレンジオン、３，４－ジメチル－８－ヒドロキシ－７－（イソプロペニル）－（４Ｈ）－ナフタレノン、８－ヒドロキシ－７－（２’－ヒドロキシ－２’－メチル）エチル－３－メチル－１，４－ナフタレンジオン、８－ヒドロキシ－２，２－ジヒドロ－３－メチル－３－（２－オキソ－プロピル）－１，４－ナフトキノン、３，４，８－トリヒドロ－３－メチル－１（２Ｈ）－ナフタレノン、プルンバギン、ジオムシノン、ビプルバギン、キトラノン及びイソシナノロンから選ばれる化合物である請求項１０に記載の方法。 The compound represented by the general formula (1) is 5,5 ′, 5 ″ -trihydroxy-2,2 ′, 2 ″ -trimethyl- [7,6 ′: 3 ′, 6 ″ -tel Naphthalene] -1,1 ′, 1 ″, 4,4 ′, 4 ″ -hexone, 8-hydroxy-3-methyl-2- (2-oxo-propyl) -1,4-naphthalenedione, 3, 4-Dimethyl-8-hydroxy-7- (isopropenyl)-(4H) -naphthalenone, 8-hydroxy-7- (2′-hydroxy-2′-methyl) ethyl-3-methyl-1,4-naphthalenedione 8-hydroxy-2,2-dihydro-3-methyl-3- (2-oxo-propyl) -1,4-naphthoquinone, 3,4,8-trihydro-3-methyl-1 (2H) -naphthalenone, Plumbagin, geomucinone, bipurbaghin, kitra The method of claim 10 which is a compound selected from the emissions and Isoshinanoron.
  12. 　以下のナフトキノン化合物又は薬学的に許容されるその塩。
    ５，５’，５’’－トリヒドロキシ－２，２’，２’’－トリメチル－［７，６’：３’，６’’－テルナフタレン］－１，１’，１’’，４，４’，４’’－ヘクスオン、８－ヒドロキシ－３－メチル－２－（２－オキソ－プロピル）－１，４－ナフタレンジオン、３，４－ジメチル－８－ヒドロキシ－７－（イソプロペニル）－（４Ｈ）－ナフタレノン、８－ヒドロキシ－７－（２’－ヒドロキシ－２’－メチル）エチル－３－メチル－１，４－ナフタレンジオン、８－ヒドロキシ－２，２－ジヒドロ－３－メチル－３－（２－オキソ－プロピル）－１，４－ナフトキノン又は３，４，８－トリヒドロ－３－メチル－１（２Ｈ）－ナフタレノン。     The following naphthoquinone compounds or pharmaceutically acceptable salts thereof.
    5,5 ′, 5 ″ -trihydroxy-2,2 ′, 2 ″ -trimethyl- [7,6 ′: 3 ′, 6 ″ -ternaphthalene] -1,1 ′, 1 ″, 4 , 4 ′, 4 ″ -hexone, 8-hydroxy-3-methyl-2- (2-oxo-propyl) -1,4-naphthalenedione, 3,4-dimethyl-8-hydroxy-7- (isopropenyl) )-(4H) -naphthalenone, 8-hydroxy-7- (2′-hydroxy-2′-methyl) ethyl-3-methyl-1,4-naphthalenedione, 8-hydroxy-2,2-dihydro-3- Methyl-3- (2-oxo-propyl) -1,4-naphthoquinone or 3,4,8-trihydro-3-methyl-1 (2H) -naphthalenone.
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CN113416128A (en) * 2021-07-07 2021-09-21 吕梁学院 Method for separating and purifying juglone in walnut shells

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