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WO2003018013A1 - Derives de stilbene ayant une activite inhibitrice du cytochrome p450 1b1, sel pharmaceutiquement acceptable de ces derives, methode de preparation desdits derives et composition les contenant - Google Patents

Derives de stilbene ayant une activite inhibitrice du cytochrome p450 1b1, sel pharmaceutiquement acceptable de ces derives, methode de preparation desdits derives et composition les contenant Download PDF

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Publication number
WO2003018013A1
WO2003018013A1 PCT/KR2002/000977 KR0200977W WO03018013A1 WO 2003018013 A1 WO2003018013 A1 WO 2003018013A1 KR 0200977 W KR0200977 W KR 0200977W WO 03018013 A1 WO03018013 A1 WO 03018013A1
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chemical formula
cytochrome
compound
stilbene derivative
pyridyl
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WO2003018013B1 (fr
Inventor
Sang-Hee Kim
Young-Jin Chun
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Promeditech Inc
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Promeditech Inc
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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a stilbene derivative having cytochrome P450 1B1 inhibitory activity, pharmaceutically acceptable salt thereof, method for preparing the same, and composition including the same.
  • Cytochrome P450 catalyzes phase I oxidative metabolism of a number of xenobiotics such as drugs, carcinogens, or pesticides, and of a number of endogenous compounds such as steroids or eicosanoids (Ortiz de Montellano, P.R. Cytochrome P450; Structure, Mechanism, and Biochemistry 2 nd ed.; Plenum Press: New York, 1995). Cytochrome P450 1 subfamily including 1A1 , 1A2 and
  • cytochrome P450 1B1 is expressed preferentially in steroidogenic tissues such as the adrenal, testis and ovary, and in steroid- sensitive tissue such as the breast, prostate, testis and embryonic cells (Savas, U., et al., Carcinogenesis 14: 2013-2018, 1993).
  • cytochrome P450 1A1 cytochrome P450 1 B1 is involved in the metabolic activation of polycyclic aromatic hydrocarbons such as benzo[a]pyrene, dibenzo[a,/]pyrene, 7,12- dimethylbenz[a]anthracene (DMBA) and 5-methylchrysene (Shimada, T., et al., Cancer Res.
  • Cytochrome P450 1 B1 is more active than cytochrome P450 1A1 in converting DMBA to the carcinogenic metabolite 3,4- dihydrodiol 1,2-epoxide.
  • the expression of cytochrome P450 1B1 is regulated by Ah receptor-mediated signal pathway, and 2,3,7,8-tetrachlorodibenzo-p-dioxin, a potent agonist of Ah receptor, activates a transcription of cytochrome P450 1 B1.
  • cytochrome P450 1 B1 is known as a main metabolic enzyme for 17 ⁇ - estradiol (E2).
  • 4-OHE2 is also known to be a long- acting estrogen (Barnea, E. R., et al., Steroids 41 :643-656, 1993) and the role of 4-OHE2 as a tumor-inducing substance has been explained by Cavalieri (Cavalieri, E.L., et al., Proc. Natl. Acad. Sci. USA 94: 10937-10942, 1997).
  • 4-OHE2 can be oxidized to E2-3,4-semiquinone and E2-3,4-quinone, which binds to N 7 -guanine of
  • DNA to thereby form depurinating DNA adducts. Therefore, the resulting apurinic sites in DNA can results in mutations in critical gene.
  • a selective inhibitor of cytochrome P450 1B1 may prevent or decrease the formation of tumors in several tissues, especially in mammary glands. Moreover, the inhibitor can be used as a pharmaceutical tool to elucidate the function of cytochrome P450.
  • various compounds have been tested for this purpose (Shimada, T., et al., Chem. Res. Toxicol. 11 : 1048-1056, 1998). However, only a few potently selective inhibitors have been known with respect to specific P450 enzymes.
  • a rhapontigenin a natural hydroxystilbene having a structure of the chemical formula 3
  • cytochrome 3 a selective inhibitor of cytochrome
  • the compound of the following chemical formula 1 its salts, a method for preparing the same, and the use of the compound as a whitening agent and a melanin formation inhibitor are disclosed in Korean patent application Nos. 2000- 78490 and 2000-78491.
  • the present invention is directed to a new use of the compounds as strong and selective inhibitors of cytochrome P450 1 B1 which functions under a completely different pharmacological mechanism compared with the mechanism of the melanin formation inhibitor.
  • the present invention also directed to a novel compound of chemical formula 2.
  • the main object of the present invention is to develop a strong and selective inhibitor of cytochrome P450 1 B1 for preventing chemical carcinogenesis in mammals, in particular the occurrence of a breast cancer or an ovarian cancer.
  • the present invention provides a pharmaceutical composition including stilbene derivatives having a chemical formula 1 which has strong and selective inhibitory activity to cytochrome P450 1B1. [Chemical formula 1]
  • Ri , R 2 and R 3 independently represent hydrogen, hydroxy or methoxy group and, and Ri and R 3 cannot be hydroxy groups at the same time.
  • M represents (i) R -substituted 2-pyridyl, 3-pyridyl or 4-pyridyl; (ii) R 4 -substituted 2-furyl, 3-furyl, 2-pyrrole, 3-pyrrole, 2-thiophenyI, or 3- thiophenyl; or
  • R 4 , R 5 , Re, R 7 , Re, and Rg independently represent hydrogen, hydroxy, halogen or C ⁇ -4 alkoxy group, and Ri to Rg substituents cannot be hydrogen at the same time.
  • the present invention also provides a novel compound of chemical formula 2. [Chemical formula 2]
  • M' represents R -substituted 2-thiophenyl, or 3- thiophenyl
  • R-i, R 2 , R 3 and R 4 represents the same functional groups defined in chemical formula 1
  • Ri to R 4 substituents cannot be hydrogen at the same time.
  • Fig. 1 is a graph showing the IC 50 values of stilbene derivatives according to the present invention with respect to the activities of cytochrome P450 1A1 , cytochrome P450 1A2, or cytochrome P450 1B1; and
  • Fig. 2 is a graph showing the ratios of IC 50 values(1A1/1B1, 1A2/1B1) of stilbene derivatives according to the present invention with respect to the activities of cytochrome P450 1A1 , cytochrome P450 1A2, or cytochrome P450 1 B1.
  • the stilbene derivative of the chemical formula 1 can be prepared by a method comprising the steps of (1) producing olefin mixture by reacting phosphonate derivative of chemical formula 4 with aromatic aldehyde of chemical formula 5 in the presence of base and catalyst in an organic solvent, (2) purifying the olefin mixture by removing the excess aldehyde, and (3) transforming the olefin mixture into trans isomer by adding iodine to the olefin compound and refluxing the olefin mixture in an organic solvent.
  • R represents hydrogen or lower alkyl
  • Ri to Rg and M represent the same functional groups defined above.
  • reaction equation 1 [Reaction equation 1]
  • the preparing method comprises the steps of:
  • the phosphonate(4) and aromatic aldehyde(5) can react with mole ratio of 1 :1 to 1 :2, preferably with mole ratio of about 1 :1.2 in the presence of a strong base such as KOH and catalyst such as 18-crownether-6 of catalytic amount, and in an organic solvent such as dichloromethane(CH 2 Cl2) in step (1). Then, the olefin mixture(6) having Z/E ratio of about 1 :3 to 1 :5 by TLC intensity is obtained through Honer-Wadsworth -Emmons reaction.
  • the structure of the phenyl ring (M) depends on the kind of the aromatic aldehyde(5).
  • step (2) the excess aldehyde( ⁇ ) is removed from the olefin mixture(6) by, for example, being treated with Girard's reagent T and acetic acid in an organic solvent such as dichloromethane. Then, insoluble substances can be removed from the product by filtration, and the residue solution is dissolved in an organic solvent, and washed with salt water. Then the organic solvent is removed under low pressure to obtain the stilbene derivatives in the form of E- and Z-isomer mixture. The obtained product has the purity of more than 98% according to NMR analysis.
  • step (3) the Z/E mixture(6) obtained from step (2) is heated with iodine of catalytic amount while refluxing with an organic solvent such as heptane to be transformed into E-isomer(7).
  • step (4) the reaction mixture is diluted with an organic solvent such as diethylether, and washed with saturated aqueous sodium bisulfite and distilled water to remove the iodine from the produced stilbene derivatives.
  • stilbene moiety can be formed by Wittig reaction between aromatic aldehyde and aromatic phosphonium ylide.
  • semi-stabilized ylide such as benzyl ylide produces triphenylphosphine oxide as an inevitable byproduct as well as Z and E-isomer mixture as the target products.
  • the preferable stilbene derivative according to the present invention includes a compound of chemical formula 6 in which Ri represents hydrogen, hydroxy or methoxy group, and M of chemical formula 1 is an hetero aromatic compound(Ar) such as 2-thiophenyl, 3-thiophenyl, 2-furanyl, 3-furanyl, 2-pyrrole, 3-pyrrole, 2-pyridyl, 3-pyridyl or 4-pyridyl; and a compound of chemical formula 7 in which Ri represents hydrogen, hydroxy or methoxy group, and M of chemical formula 1 is a phenyl ring of chemical formula I -1.
  • Ri represents hydrogen, hydroxy or methoxy group
  • Ar represents 2-thiophenyl, 3-thiophenyl, 2-furyl, 3-furyl, 2-pyrrole, 3-pyrrole, 2-pyridyl, 3-pyridyl or 4-pyridyl.
  • Ri represents hydrogen, hydroxy or methoxy group
  • R 2 and R 3 independently represents hydrogen, hydroxy or C 1 - 3 alkoxy group.
  • the more preferable stilbene derivative according to the present invention includes 2,4-dimethoxyphenyl (chemical formula 8), 3,4,5-trimethoxyphenyl
  • the stilbene derivative of chemical formula 1 according to the present invention can be provided in the form of a pharmaceutically acceptable salt or solution composition.
  • the salt acid addition salt formed with a pharmaceutically acceptable free acid is preferable.
  • the acid addition salt can be prepared by conventional methods, for example, by dissolving the compound with excess acid aqueous solution, and precipitating the salt using water miscible organic solvent such as methanol, ethanol, acetone and acetonitrile. Alternatively, acid or alcohol (ex. glycolmonomethylether), the active ingredient and water solution can be heated, evaporated and dried, or the precipitated salt can be filtered.
  • the free acid organic acid or inorganic acid can be used.
  • Examples of the inorganic acid include hydrochloric acid, phosphoric acid, hydro idodic acid, sulfuric acid, and nitric acid
  • examples of the organic acid include methane sulfonic acid, p-toluene sulfonic acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, phenylglycolic acid, propionic acid, lactic acid, glycollic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid, and vanillic acid.
  • pharmaceutically acceptable metal salt can be prepared with
  • Alkali metal or alkaline earth metal salt can be prepared by conventional methods, for example, by dissolving the compound with excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering insoluble salt, and evaporating or drying the residue solvent.
  • the pharmaceutically preferable metal salts include sodium, potassium and calcium salts.
  • .0 silver salt is produced by reacting a proper silver salt (ex.: silvernitrate) with alkali metal or alkaline earth metal salt.
  • the present invention also provides pharmaceutical composition including the stilbene derivative having inhibitory effects of
  • cytochrome P450 1 B1 L5 cytochrome P450 1 B1 or the pharmaceutically acceptable salt thereof as active ingredient.
  • the stilbene derivative newly synthesized in this present invention shows significantly higher inhibitory activity on cytochrome P450 1 enzymes compared with the conventional_oxyresveratrol, 0 its amine or imine derivatives.
  • the most selective inhibitor of cytochrome P450 1B1 is 2',3,4 ⁇ 5- tetramethoxystilbene(chemical formula 8), and the strongest inhibitor of cytochrome P450 1B1 is 3,5-dimethoxyphenyl-vinyl-thiophene (chemical formula 17).
  • the active trans stilbene derivatives, 2', 3,4', 5- tetramethoxystilbene(chemical formula 8) of the present invention can be used as a chemical probe to characterize the properties of cytochrome P450 1B1 , and can be used as chemopreventive agent or therapeutic agent for chemical carcinogenesis by protecting the metabolism of 17 ⁇ -estradiol by cytochrome P450 1 B1.
  • the compound of the chemical formula 1 can be administrated orally and parenterally for clinical inoculation, and can be used in the form of conventional drug preparations.
  • the compound of the chemical formula 1 according to the present invention can be administered in various forms of oral or parenteral preparation.
  • conventional diluents or vehicles such as filler, expander, bonding agent, wetting agent, releasing agent, and surfactant can be used.
  • the solid preparation for oral administration can include tablet, pilula, pulvis, granulum, and capsule, and can be produced by mixing the compound of the chemical formula 1 with at least one vehicle, for example, starch, calcium carbonate, sucrose, lactose, or gelatin.
  • the liquid preparation for oral administration can include suspension, liquid drug, emulsion, and syrup, and can include water as a conventional diluent, and various vehicles such as wetting agent, sweetening agent, odorant, preservative and liquid paraffin.
  • the preparation for parenteral administration can include sterilized aqueous solution, non-aqueous solution, suspension, emulsion, lyophilization, and suppository.
  • solvent for the non-aqueous solution or suspension include propylene glycol, polyethyleneglycol, vegetable oil such as olive oil, injectable ester such as ethylolate.
  • the basement for suppository includes witepsol, macrogol, tween 61 , cacao, laurine, glycerogelatin, etc.
  • the effective amount of the compounds of the chemical formula 1 according to the present invention is 0.1 - 100 mg/kg, preferably 0.1 - 10 mg/kg, and the compounds of the chemical formula 1 may be administered 1 - 3 times a day.
  • the effective amount can be varied according to the individual constitution of the subject, specificity, weight, type and seriousness of the disease, characteristics of preparation, administration method of drug, administration period and interval.
  • the melting point was measured with Buchi melting point B-540 apparatus, and was not corrected.
  • NMR spectrum was obtained with Varian Gemini 2000 spectrophotometer at 300MHz with tetramethylsilane as an internal standard.
  • Electron impact mass spectrum was obtained with HP 5989B mass spectrometer at 70eV with using electrospray(ES) ionizing technology.
  • the elemental analysis was carried out on an EA1110 elemental analyzer. The 5 results were within 0.4% of the calculated values. Reaction was monitored by
  • Example 3 Biological analysis of stilbene derivatives.
  • ethoxyresorufin O- deethylation reaction was performed to measure the activity of cytochrome P450 1 enzymes.
  • Examples 1 and 2 (chemical formulas 8-17) according to the present invention, and oxyresveratrol were used.
  • reaction mixtures were preincubated at 37 ° C for 3 minutes, and NADPH-generating systems consisting of 5mM of glucose 6-phosphate, 0.5 mM NADP+ and 0.5 unit glucose 6-phosphate dehydrogenase were added to initiate the reaction.
  • NADPH-generating systems consisting of 5mM of glucose 6-phosphate, 0.5 mM NADP+ and 0.5 unit glucose 6-phosphate dehydrogenase were added to initiate the reaction.
  • the reaction mixtures were incubated for 10 minutes at 37 ° C, and 1 ml of methanol was added to terminate the reaction.
  • resorufin was determined fluorometrically using Perkin- Elmer LS5 spectrofluorometer at the excitation and emission wavelengths of 550 nm and 585 nm, respectively. The results are shown in Table 1.
  • IC 50 values of stilbene derivatives according to the present invention with respect to the activities of cytochrome P450 1A1, cytochrome P450 1A2, or cytochrome P450 1B1 are depicted in Fig.
  • IC 50 values(1A1/1B1 or 1A2/1B1) of stilbene derivatives according to the present invention with respect to the activities of cytochrome P450 1A1 , cytochrome P450 1A2, or cytochrome P450 1B1 are depicted in Fig. 2.
  • Figs 1 and 2 2,3',4,5'-tetramethoxystilbene (Chemical formula 8) is found out to be the most potently selective inhibitor of cytochrome P450 1B1 from the stilbene derivatives tested.
  • the compound of chemical formula 8 is a methylated derivative of naturally occurring oxyresveratrol.
  • the oxyresveratrol inhibits cytochrome P450 1 with IC 50 values of 15 ⁇ M, 150 ⁇ M and 34 ⁇ M with respect to 1A1 , 1A2 and 1 B1 , respectively (Chun, Y. J., Ryu, S. Y., Jeong, T. C, Kim, M. Y., Drug Metab.
  • the modification of phenyl ring by addition, deletion or change in the position of methoxy groups results in the reduced efficiency and selectivity.
  • the test results suggest that the position of methoxy group is very important in selectivity.
  • the compound of chemical formula 12 is structurally different in methoxy group at 2-position.
  • the inhibitory activities of the compound of chemical formula 12 on 1A1 and 1A2 are a little less than those of the compound of chemical formula 8.
  • the compound of chemical formula 13 or 14 in which 2-methoxy group is substituted with F or OH has more selective inhibitory activity on 1 B1 rather than 1A1 and 1A2, and has more improved characteristics than the compound of chemical formula 12.
  • the inhibitory activity and selectivity thereof are less than those of the compound of chemical formula 8.
  • the compounds of chemical formulas 15 to 17 in which phenyl groups are substituted with 4-pyridyl, 2-thiophenyl, or 3-puranyl ring do not show any selectivity similar to the compound of chemical formula 8.
  • the compound of chemical formula 17 having 2-thiophenyl ring inhibits cytochrome P450 1 with IC 50 values of 61 nM, 11 nM, or 2 nM for 1 A1 , 1A2 and 1B1 , respectively.
  • Example 4 Acute toxicity test of oral administration in rats. To test in vivo toxicity of the compound of chemical formula 8, the acute toxicity test was carried out with SPF(Specific Pathogen Free) SD rat of 6-weeks old. The stilbene derivative compounds of chemical formulas 8 - 17 were suspended with corn oil, and orally administered to 5 animals per group with the amount of 0.5 g/kg . After administration, the survival of animal, clinical manifestation, and changes in weight were investigated, and hematological and hemato-biological examinations were also carried out. In addition, the abdominal and thoracic organs were examined with naked eye after autopsy.
  • the tested compounds do not induce any change due to toxicity within the administration amount of 0.5 g/kg for rat, and can be considered as safe, and the minimum lethal dose (LD50) for oral administration is more than 0.5 g/kg.
  • stilbene derivatives according to the present invention have the inhibitory activity on human cytochrome P450 family, i.e., cytochrome P450 1A1 , 1A2 and 1 B1.
  • 2,3',4,5'-tetramethoxystilbene compound has the strongest inhibitory activity on and most selective to cytochrome P450 1B1.
  • stilbene derivatives according to the present invention is useful in evaluating the relation between the structure of stilbene as the inhibitor of cytochrome P450 1 and its activity, and in preparing stilbene derivatives having the strong and selective activity.
  • 2,3',4,5'-tetramethoxystilbene according to the present invention is useful not only as the strong and selective inhibitor of cytochrome P450 1B1 , but also as a compound for studying the enzymatic properties of cytochrome P450 1 B1.
  • Stilbene derivatives according to the present invention can be used as chemopreventive or therapeutic agent for inhibiting carcinogenesis in mammals, in particular the development of breast cancer.

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Abstract

Dérivé de stilbène ayant une activité inhibitrice du cytochrome P450 1B1, sel pharmaceutiquement acceptable dudit dérivé, méthode de préparation de ce dérivé et composition le contenant. Ce dérivé de stilbène est un inhibiteur puissant et sélectif du cytochrome P450 1B1 qui permet de réduire ou de prévenir la carcinogenèse chimique chez les mammifères, en particulier le développement du cancer du sein. Il peut également être utilisé en tant qu'outil pharmaceutique pour élucider la fonction du cytochrome P450.
PCT/KR2002/000977 2001-08-31 2002-05-23 Derives de stilbene ayant une activite inhibitrice du cytochrome p450 1b1, sel pharmaceutiquement acceptable de ces derives, methode de preparation desdits derives et composition les contenant Ceased WO2003018013A1 (fr)

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KR2001/53363 2001-08-31
KR1020010053363A KR20030018800A (ko) 2001-08-31 2001-08-31 시토크롬 피450 1비1 억제활성을 갖는 페닐환 유도체 및약학적으로 허용가능한 그의 염, 그의 제조방법 및 이를함유하는 조성물

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CN1331856C (zh) * 2005-08-05 2007-08-15 大连理工大学 多羟基茋类化合物的制备和抑制sars病毒药物的用途
WO2009001046A3 (fr) * 2007-06-22 2009-02-26 Univ Aberdeen 2,3',4,5'-tétraméthylstilbène (tms) radiomarqué par [11c]méthoxy et ses préparation et utilisation
WO2013147630A1 (fr) * 2012-03-30 2013-10-03 Uniwersytet Medyczny Im. Karola Marcinkowskiego Dérivés de méthoxy et de méthylthio de trans-stilbène et leur utilisation
WO2015039036A3 (fr) * 2013-09-13 2015-05-21 Cortendo Ab(Publ) Nouveaux inhibiteurs du cytochrome p450 et leur méthode d'utilisation
JP2023507851A (ja) * 2019-12-23 2023-02-27 カイナン デューク アイピー，エルエルシー 置換ヒドロキシスチルベン化合物および誘導体、合成ならびにそれらの使用

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Cited By (9)

* Cited by examiner, † Cited by third party
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CN1331856C (zh) * 2005-08-05 2007-08-15 大连理工大学 多羟基茋类化合物的制备和抑制sars病毒药物的用途
WO2009001046A3 (fr) * 2007-06-22 2009-02-26 Univ Aberdeen 2,3',4,5'-tétraméthylstilbène (tms) radiomarqué par [11c]méthoxy et ses préparation et utilisation
GB2463436A (en) * 2007-06-22 2010-03-17 Univ Aberdeen (11C)methoxy-radiolabelled 2,3',4,5'-tetramethylstilbene (TMS) and its preparation and use
WO2013147630A1 (fr) * 2012-03-30 2013-10-03 Uniwersytet Medyczny Im. Karola Marcinkowskiego Dérivés de méthoxy et de méthylthio de trans-stilbène et leur utilisation
WO2015039036A3 (fr) * 2013-09-13 2015-05-21 Cortendo Ab(Publ) Nouveaux inhibiteurs du cytochrome p450 et leur méthode d'utilisation
US9725436B2 (en) 2013-09-13 2017-08-08 Cortendo Ab (Publ) Cytochrome P450 inhibitors and their method of use
JP2023507851A (ja) * 2019-12-23 2023-02-27 カイナン デューク アイピー，エルエルシー 置換ヒドロキシスチルベン化合物および誘導体、合成ならびにそれらの使用
JP7679090B2 (ja) 2019-12-23 2025-05-19 カイナン デューク アイピー，エルエルシー 置換ヒドロキシスチルベン化合物および誘導体、合成ならびにそれらの使用
US12459883B2 (en) 2019-12-23 2025-11-04 Kynan Duke IP, LLC Substituted hydroxystilbene compounds and derivatives synthesis and uses thereof

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