WO2012021692A1 - Analogues de la curcumine et procédés d'utilisation - Google Patents

Analogues de la curcumine et procédés d'utilisation Download PDF

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WO2012021692A1
WO2012021692A1 PCT/US2011/047403 US2011047403W WO2012021692A1 WO 2012021692 A1 WO2012021692 A1 WO 2012021692A1 US 2011047403 W US2011047403 W US 2011047403W WO 2012021692 A1 WO2012021692 A1 WO 2012021692A1
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curcumin
arom
compound
compounds
bis
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PCT/US2011/047403
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Allan H. Conney
Kun Zhang
Xingchuan Wei
Xi ZHENG
Zhi-yun DU
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Rutgers, The State University Of New Jersey
Guangdong University Of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to the field of oncology. Specifically, curcumin analogs and methods of use thereof are disclosed.
  • Curcumin a well-known diarylheptanoid, has been identified as a major constituent in turmeric. It is used as a spice to give a specific flavor and yellow color to curry, which is consumed daily by millions of people. Curcumin has been used in traditional medicine for liver disease (jaundice) , indigestion, urinary tract diseases, rheumatoid arthritis, and insect bites
  • curcumin is an attractive new
  • Curcumin has been evaluated in clinical trials for the treatment of liver disease, rheumatoid arthritis, infectious diseases, and cancers (Hsu et al . (2007) Adv. Exp. Med. Biol., 595:471-480). Despite its efficacy and safety, the clinical usefulness of curcumin is
  • curcumin The weakness of the pharmacokinetic profile of curcumin in vivo significantly inhibits its clinical application. Accordingly, superior analogs of curcumin are greatly desired.
  • curcumin analogs are provided.
  • Compositions comprising the curcumin analog and at least one pharmaceutically acceptable carrier are also provided.
  • the method comprises administering at least one curcumin analog of the instant invention to the subject.
  • the inflammation disorder is a
  • neurodegenerative disease such as Alzheimer's disease or Parkinson's disease.
  • Figure 1 provides a schematic of the synthesis of group A to group F compounds .
  • Figure 2 provides a schematic of the synthesis of group AN, BN, EN and FN compounds.
  • Figure 3 provides a schematic of the synthesis of the AS, BS, ES and FS compounds.
  • Figure 4 provides structures of curcumin and certain highly active anticancer analogs of curcumin.
  • Figure 5 provides a graph showing the stimulatory effect of E10, F10, FN1 and FN2 on apoptosis in cultured PC-3 cells.
  • Various concentrations of E10, F10, FNl and FN2 were incubated with PC-3 cells for 96 hours.
  • Apoptosis was determined by morphology.
  • curcumin analogs such as cyclohexanone analogs were found to have enhanced activity and stability in biological medium compared to curcumin (Liang et al . (2009) Bioorg. Med. Chem., 17:2623-2631). Of the many curcumin analogs that were synthesized, a few were found to have strong anticancer activity when tested on cultured cancer cells (10- to 60-fold more potent than curcumin).
  • the 1,5- diaryIpentadienones G0-Y016, GO-YO30 and GO-Y031 were as much as 60-fold more active than curcumin in certain cancer cell lines (Ohori et al . (2006) Mol. Cancer
  • Curcumin analogs of the instant invention include the compounds set forth hereinbelow (e.g., compounds of formulas I-IV) and pharmaceutically acceptable salts thereof, with the proviso that the curcumin analog is not curcumin or a curcumin analog described in Du et al . (Eur. J. Med. Chem. (2006) 41:213) (particularly, Ai, A 3 , A 5 , A 6 , Bi, B 3 , B 5 , B 6 , Ci, C 2 , C 3 , C 5 , C 6 , Di) or provided in Figure 6.
  • the curcumin analogs may be isolated.
  • the curcumin analog has the structure of formula I:
  • n is 2 or 3.
  • the carbon chain optionally comprises one heteroatom (e.g., 0, S, or NH) .
  • Y and Z can be the same or different.
  • Y and/or Z is selected from the group consisting
  • R p is absent, H , CH 3 , alkyl, or lower alkyl, particularly absent, H, CH 3 , or C 2 H 5 ;
  • Ri and R5 are H.
  • the curcumin analog has the structure of formula II:
  • Y and Z are as defined above for formula I and wherein X is 0, S, NH, or NR n nw wherein R n and R m are each independently H, CH 3 , alkyl, or lower alkyl, particularly H, CH 3i C 2 H 5 , C 3 H 7 , C 4 H9, C 5 Hn, or C 6 Hi 3 .
  • the curcumin analog has the struc re of formula III:
  • n is as defined above for formula I and wherein Ri ' , R 2 ' , R 3 ' , R4 ' , R 5 ' , Ri , R 2 , R 3 , R 4 , and R 5 are each independently H, OH, halo, 0CH 3 , or 0-alkyl,
  • Ri, R5, Ri' and R 5 ' are H.
  • the curcumin analog has the struc re of formula IV:
  • the curcumin analog is selected from the group consisting of:
  • the curcumin analog is selected from the group consisting of:
  • compositions comprising the curcumin analogs of the instant invention are also encompassed herein.
  • the composition comprises at least one curcumin analog of the instant invention
  • compositions may further comprise at least one other chemotherapeutic agent.
  • the composition may further comprise at least one other anti-inflammatory agent (e.g., steroids (e.g., glucocorticoids) or NSAIDs) .
  • the composition may further comprise curcumin or at least one other curcumin analog (e.g., those described in Du et al. (2006) Eur. J .Med. Chem. , 41:213).
  • the compositions may also comprise an enhancer compound which works synergistically with the curcumin analog. Enhancer compounds which work synergistically with the curcumin analogs include, without limitation, all-trans retinoic acid, 1 , 25-dihydroxyvitamin D3 , sodium
  • compositions comprising the curcumin analogs of the instant invention may also be separate from
  • compositions comprising the agents described above
  • kits comprising a first composition comprising at least one curcumin analog of the instant invention and at least one
  • composition comprising a chemotherapeutic agent, enhancer, and/or curcumin or other curcumin analog and a pharmaceutically acceptable carrier.
  • curcumin analogs of the instant invention can be administered to a patient in need thereof, as
  • curcumin analogs may be delivered to a subject to inhibit or treat cancer.
  • Cancers that may be treated using the present protocol include, but are not limited to: cancers of the
  • prostate colorectum
  • pancreas pancreas
  • cervix stomach
  • the cancer is prostate, pancreatic, or colon cancer.
  • the curcumin analogs are co-administered with chemotherapy (e.g., radiation) .
  • the curcumin analog of the instant invention is administered with at least one chemotherapeutic agent, enhancer, and/or curcumin or other curcumin analog.
  • the curcumin analog of the instant invention may be administered before, after, and/or simultaneously with the other agents or therapy .
  • the curcumin analogs of the instant invention may also be delivered to a subject to inhibit or treat inflammation in a patient, particularly an inflammation related neurodegenerative disease or neuroinflammatory diseases, such as amyotrophic lateral sclerosis (ALS) , Alzheimer's disease, and Parkinson's disease.
  • an inflammation related neurodegenerative disease or neuroinflammatory diseases such as amyotrophic lateral sclerosis (ALS) , Alzheimer's disease, and Parkinson's disease.
  • ALS amyotrophic lateral sclerosis
  • Alzheimer's disease Alzheimer's disease
  • Parkinson's disease Parkinson's disease.
  • the curcumin analogs of the instant invention may be any inflammation related neurodegenerative disease or neuroinflammatory diseases, such as amyotrophic lateral sclerosis (ALS) , Alzheimer's disease, and Parkinson's disease.
  • ALS amyotrophic lateral sclerosis
  • the curcumin analogs of the instant invention may be
  • the curcumin analog of the instant invention is administered with at least one anti-inflammatory or other neurodegenerative disease therapies or therapeutic agents.
  • the curcumin analog of the instant invention is administered with at least one anti-inflammatory, enhancer and/or curcumin or other curcumin analog.
  • the curcumin analog of the instant invention may be administered before, after, and/or simultaneously with the other agents or therapy.
  • curcumin analog as described herein will generally be administered to a patient as a
  • patient refers to human or animal subjects.
  • curcumin analogs may be employed therapeutically, under the guidance of a physician for the treatment of malignant tumors, metastatic disease, and inflammatory- disorders .
  • the pharmaceutical preparation comprising at least one curcumin analog of the invention may be conveniently formulated for administration with at least one
  • curcumin analog in the chosen medium will depend on the hydrophobic or hydrophilic nature of the medium, as well as the size and other properties of the curcumin analog. Solubility limits may be easily determined by one skilled in the art.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media and the like which may be appropriate for the desired route of administration of the pharmaceutical
  • administration to a particular patient may be determined by a physician considering the patient's age, sex, weight, general medical condition, and the specific condition and severity thereof for which the antibody is being administered.
  • the physician may also consider the route of administration of the curcumin analog, the pharmaceutical carrier with which the antibody may be combined, and the curcumin analog's biological activity.
  • curcumin analog of the invention may be administered by direct injection into any cancerous tissue or into the area surrounding the cancer or to the site of inflammation/neurodegeneration .
  • the curcumin analog of the invention may be administered by direct injection into any cancerous tissue or into the area surrounding the cancer or to the site of inflammation/neurodegeneration .
  • a pharmaceutical preparation comprises the antibody molecules dispersed in a medium that is
  • curcumin analog may also be any curcumin analog compatible with the cancerous tissue or the damaged nerve tissue.
  • curcumin analog may also be any curcumin analog
  • curcumin analogs may also be administered parenterally by intravenous injection into the blood stream, or by subcutaneous, intramuscular, intrathecal, or intraperitoneal injection.
  • parenteral injection preparations for parenteral injection are known in the art. If parenteral injection is selected as a method for administering the curcumin analogs, steps should be taken to ensure that sufficient amounts of the molecules reach their target cells to exert a biological effect.
  • curcumin analogs may be delivered in a cell-targeting carrier so that sufficient numbers of molecules will reach the target cells.
  • compositions containing a compound of the present invention as the active ingredient in intimate admixture with a pharmaceutical carrier can be prepared according to conventional pharmaceutical compounding techniques .
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., intravenous, oral or parenteral .
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid
  • preparations such as, for example, suspensions, elixirs and solutions
  • carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations (such as, for example, powders, capsules and tablets) . Because of their ease in
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar-coated or enteric-coated by standard techniques.
  • the carrier will usually comprise sterile water, though other ingredients, for example, to aid solubility or for preservative purposes, may be included. Injectable suspensions may also be prepared, in which case
  • liquid carriers such as liquid carriers, suspending agents and the like may be employed.
  • a pharmaceutical preparation of the invention may be formulated in dosage unit form for ease of
  • Dosage unit form refers to a physically discrete unit of the pharmaceutical preparation appropriate for the patient undergoing treatment. Each dosage should contain a quantity of active ingredient calculated to produce the desired effect in association with the selected pharmaceutical carrier. Procedures for determining the appropriate dosage unit are well known to those skilled in the art.
  • Dosage units may be proportionately increased or decreased based on the weight of the patient.
  • particular pathological condition may be determined by dosage concentration curve calculations, as known in the art .
  • the appropriate dosage unit for the administration of curcumin analogs may be determined by evaluating the toxicity of the curcumin analogs in animal models.
  • the minimal and maximal dosages may be determined based on the results of significant reduction of tumor size or inflammation and side effects as a result of the treatment.
  • Appropriate dosage unit may also be determined by assessing the efficacy of the treatment in combination with other standard anti-cancer or anti-inflammation drugs.
  • the pharmaceutical preparation comprising the curcumin analogs may be administered at appropriate intervals, for example, at least twice a day or more until the pathological symptoms are reduced or
  • the dosage may be reduced to a maintenance level .
  • the appropriate interval in a particular case would normally depend on the condition of the patient.
  • isolated is not meant to exclude artificial or synthetic mixtures with other compounds or materials, or the presence of impurities that do not interfere with the fundamental activity, and that may be present, for example, due to incomplete purification, addition of stabilizers, or compounding into, for example, pharmaceutically acceptable preparations.
  • Chemotherapeutic agents are compounds that exhibit anticancer activity and/or are detrimental to a cell (e.g., a toxin). Suitable chemotherapeutic agents include, but are not limited to: toxins (e.g., saporin, ricin, abrin, ethidium bromide, diptheria toxin,
  • toxins e.g., saporin, ricin, abrin, ethidium bromide, diptheria toxin
  • alkylating agents e.g., nitrogen mustards such as chlorambucil, cyclophosphamide, isofamide, mechlorethamine, melphalan, and uracil mustard;
  • aziridines such as thiotepa; methanesulphonate esters such as busulfan; nitroso ureas such as carmustine, lomustine, and streptozocin; platinum complexes such as cisplatin and carboplatin; bioreductive alkylators such as mitomycin, procarbazine, dacarbazine and
  • DNA strand-breakage agents e.g.,
  • topoisomerase II inhibitors e.g., glycyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-N-(2-aminoethyl)-2-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-amino
  • DNA minor groove binding agents e.g., plicamydin
  • antimetabolites e.g., folate antagonists such as methotrexate and trimetrexate; pyrimidine antagonists such as fluorouracil, fluorodeoxyuridine, CB3717, azacitidine, cytarabine, and floxuridine; purine antagonists such as mercaptopurine, 6-thioguanine, fludarabine, pentostatin; asparginase; and
  • tubulin interactive agents e.g., ribonucleotide reductase inhibitors such as hydroxyurea
  • tubulin interactive agents e.g., ribonucleotide reductase inhibitors such as hydroxyurea
  • hormonal agents e.g., estrogens; conjugated estrogens; ethinyl estradiol; diethylstilbesterol ; chlortrianisen; idenestrol; progestins such as hydroxyprogesterone caproate, medroxyprogesterone, and megestrol; and androgens such as testosterone, testosterone propionate, fluoxymesterone, and methyltestosterone) ; adrenal corticosteroids (e.g., prednisone, dexamethasone, methylprednisolone, and prednisolone) ; leutinizing hormone releasing agents or gonadotropin-releasing hormone antagonists (e.g., leuprolide acetate and goserelin acetate); and antihormonal antigens (e.g., tamoxifen, antiandrogen agents such as flutamide; and antiadrenal agents such as mitotane and
  • alkyl includes both straight and branched chain hydrocarbons containing about 1 to 20 carbons or about 1 to 10 carbons in the normal chain.
  • the hydrocarbon chain of the alkyl groups may be interrupted with at least one heteroatom (e.g., oxygen, nitrogen, or sulfur atoms) .
  • alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4 dimethylpentyl , octyl, 2,2,4 trimethylpentyl , nonyl, decyl, the various branched chain isomers thereof, and the like.
  • substituent e.g., about 1 to 4
  • substituent e.g., about 1 to 4
  • aryl refers to monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion.
  • aryl groups include, without limitation, phenyl, naphthyl, such as 1-naphthyl and 2-naphthyl, indolyl, and pyridyl, such as 3-pyridyl and 4-pyridyl.
  • Aryl groups may be optionally substituted through available carbon atoms with 1 to about 4 groups. Exemplary substituents include those provided above for alkyl.
  • the aromatic groups may be heteroaryl .
  • Heteroaryl refers to an optionally substituted aromatic ring system that includes at least one, particularly from 1 to about 4 sulfur, oxygen, or nitrogen heteroatom ring members.
  • PC-3, Panc-1 and HT-29 cells were obtained from the American Type Culture Collection (ATCC, Rockville, MD, USA) .
  • RPMI-1640 and DMEM tissue culture medium, penicillin-streptomycin, L-glutamine and fetal bovine serum (FBS) were from Gibco (Grand Island, NY) .
  • PC-3 cells were maintained in RPMI-1640 culture medium, and Panc-1 and HT-29 cells were maintained in DMEM medium. Both RPMI-1640 and DMEM media were supplemented with 10% FBS, penicillin (100 units/ml) -streptomycin (100 pg/ml) and L-glutamine (300 ug/ml) .
  • Cultured cells were grown at 37°C in a humidified atmosphere of 5% C0 2 and were passaged twice a week. Different curcumin analogs were dissolved in DMSO and the final concentration of DMSO in all experiments was 0.1%.
  • PC-3, Panc-1 and HT-29 cells were seeded at a density of 0.2 x 10 5 cells/ml of medium in 96-well plates (0.2 ml/well) and incubated for 24 hours. The cells were then treated with various concentrations (0.05-30 ⁇ ) of the different curcumin analogs for 72 hours.
  • DMSO dimethyl methacrylate
  • concentration of DMSO as a solvent for the different curcumin analogs was 0.1% in the culture medium used and was without any effect on cell growth.
  • Apoptosis was determined by a morphological assay as described (Zheng et al. (2008) Int. J. Oncol., 32:257- 264; Zheng et al . (2010) Cancer Prev. Res., 3:114-124; Motyl et al. (1998) Eur. J. Cell. Biol., 75:367-374).
  • curcumin The inhibitory effects of sixty-one curcumin analogs on the growth of cultured human prostate cancer cells (PC-3), pancreatic cancer cells (Panc-1) and colon cancer cells (HT-29) were determined by using the MTT assay. For each incubation, curcumin was evaluated as a positive control. The inhibitory effect of curcumin did not vary significantly between the different curcumin analogs.
  • Heteroatoms such as nitrogen, oxygen or sulfur in the 4-position of the central six-carbon ring increased the inhibitory effect of these compounds on tumor cell growth . 1
  • Table I t Inhibitory ef fects of groups A to F compounds on the growth of human prostate cancer PC-3 , pancreas cancer Panc-1 and colon cancer HT-29 cells .
  • PC-3 , Panc- 1 and HT-29 cells were seeded at a density of 0 . 2 x 10 5 cells /ml of medium in 96-well plates ( 0 . 2 ml /well ) and incubated for 24 hours . The cells were then treated with various concentrations ( 0 . 05-30 uM) of the
  • Table 2 Inhibitory effects of groups AN, BN, EN, FN compounds on the growth of human prostate cancer PC-3, pancreas cancer Panc-1 and colon cancer HT-29 cells.
  • PC-3, Panc-1 and HT-29 cells were seeded at a density of 0.2 x 10 5 cells/ml of medium in 96-well plates (0.2 ml/well) and incubated for 24 hours. The cells were then treated with various concentrations (0.05-30 ⁇ ) of the different compounds for 72 hours. Effects of the different compounds on the growth of PC-3, Panc-1 and HT-29 cells were determined by the MTT assay. 5 ⁇ ( ⁇ )
  • Table 3 Inhibitory effects of AS, BS, ES and FS on the growth of human prostate cancer PC-3, pancreas cancer Panc-1 and colon cancer HT-29 cells.
  • PC-3, Panc-1 and HT-29 cells were seeded at a density of 0.2 x 10 5 cells/ml of medium in 96-well plates (0.2 ml/well) and incubated for 24 hours. The cells were then treated with various concentrations (0.1-30 ⁇ ) of different compounds for 72 hours. Effects of the different compounds on the growth of PC-3, Panc-1 and HT-29 cells were determined by the MTT assay.
  • ElO was 72-, 46- and 117-fold more active than curcumin (IC 50 ) for inhibiting the growth of PC-3, Panc-1 and HT-29 cells, respectively (Table 1), whereas FlO was 69-, 34- and 72-fold more potent than curcumin for inhibiting the growth of PC-3, Panc-1 and HT-29 cells, respectively (Table 1) .
  • FNl and FN2 had about the same inhibitory effect as ElO and FlO towards Panc-1 cells but were less active than ElO and FlO towards PC-3 and HT-29 cells (Tables 1 and 2) .
  • the structures of ElO, FlO, FNl, FN2 and curcumin are shown in Figure 4.
  • piperidin-4-one (group D) had moderate activity whereas compounds with cyclohexanone (group A) , acetone (group C) or cyclopentanone (group B) linker were less active.
  • the activities of compounds with a heteroatom linker were better than those without a heteroatom linker (groups A, B and C) , which indicates that a flexible cycle linker could exhibit stronger activity than that of a small and highly rigid linker.
  • Some curcumin analogs with piperidin-4-one possess potent anticancer activity, such as compound 14 (Adams et al . (2004) Bioorg. Med. Chem.
  • inhibitory effect of certain analogs with a sulfur or oxygen heterocyclic ketone linker and distal benzene rings e.g. compounds E10 and F10
  • tumor cell growth were slightly more potent than that of analogs with a sulfur or oxygen heterocyclic ketone linker and distal nitrogen heterocyclic rings (e.g. compounds FNl and FN2) described herein.
  • halogen at R3 in group A, B or C compounds did not result in strongly active compounds (compounds Al, A2, A3, Bl, B2 , B3 , CI, C2 and C3) whereas introduction of halogen at R3 in the D series (compounds Dl, D2 and D3) resulted in compounds that had substantially more activity than curcumin.
  • mice were injected subcutaneously with human prostate cancer PC-3 or human pancreatic cancer Panc-1 cells (2xl0 6 cells/mouse) .
  • PC-3 or Panc-1 tumors received i.p. injections of vehicle, curcumin, or E10 once a day for 28 days.
  • Tumor size length x width; cm 2
  • body weight g
  • curcumin analogs were synthesized and evaluated for anticancer activity using cultured human prostate, pancreas and colon cancer cells. Curcumin analogs with a tetrahydropyran-4-one

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Abstract

L'invention concerne des analogues de la curcumine ainsi que des procédés d'utilisation correspondants.
PCT/US2011/047403 2010-08-11 2011-08-11 Analogues de la curcumine et procédés d'utilisation WO2012021692A1 (fr)

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WO2014022660A1 (fr) * 2012-08-03 2014-02-06 Georgia State University Research Foundation, Inc. Analogues de curcumine et procédés de fabrication et d'utilisation de ceux-ci
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WO2014082581A1 (fr) * 2012-11-28 2014-06-05 无锡药兴医药科技有限公司 Hydrocarbure cyclique de α-(3,5-diméthoxy benzylidène)-α'-méthylène avec cétones et son procédé de préparation
WO2014160339A1 (fr) * 2013-03-13 2014-10-02 Board Of Regents, The University Of Texas System Composés pour traiter des maladies inflammatoires et hyperprolifératives
WO2015131848A1 (fr) * 2014-03-06 2015-09-11 Hong Kong Baptist University Activateur du gène tfeb indépendant de mtor pour l'amélioration de l'autophagie et utilisations associées
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CN109820843A (zh) * 2019-02-25 2019-05-31 天津国际生物医药联合研究院 双不饱和酮类化合物在制备抗流感药物中的应用
US10875841B2 (en) 2018-08-29 2020-12-29 Baylor College Of Medicine Small molecule stimulators of steroid receptor coactivator-3 and methods of their use as cardioprotective and/or vascular regenerative agents
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CN114671779A (zh) * 2022-03-15 2022-06-28 温州医科大学 含环戊酮片段的化合物及其作为抗肿瘤药物的应用
RU2781790C1 (ru) * 2021-12-09 2022-10-18 Федеральное государственное учреждение "Федеральный научно-исследовательский центр "Кристаллография и фотоника" Российской академии наук" Бис-N-метилазакраунсодержащие диеноны в качестве оптических молекулярных сенсоров для определения катионов щелочных, щелочноземельных металлов, аммония и способ их получения

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