WO2005072723A1 - Composition pharmaceutique comportant des derives d'hydroxyphenyle de l'acide rosmarinique pour le traitement contre le cancer - Google Patents

Composition pharmaceutique comportant des derives d'hydroxyphenyle de l'acide rosmarinique pour le traitement contre le cancer Download PDF

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WO2005072723A1
WO2005072723A1 PCT/KR2004/001597 KR2004001597W WO2005072723A1 WO 2005072723 A1 WO2005072723 A1 WO 2005072723A1 KR 2004001597 W KR2004001597 W KR 2004001597W WO 2005072723 A1 WO2005072723 A1 WO 2005072723A1
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phenyl
dihydroxy
trans
propionic acid
ester
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PCT/KR2004/001597
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English (en)
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Jonghwa Won
Yun-Gyoung Hur
Sung-Joo Kim
See-Hyoung Park
Doohong Park
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Mogam Biotechnology Research Institute
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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate

Definitions

  • the present invention relates to a pharmaceutical composition for anticancer containing hydroxylphenyl derivatives of rosmarinic acid as an effective ingredient.
  • Cancer is the second leading cause of disease-induced death, next to cardiovascular diseases, world- wide, regardless of men and women. Cancer is generally known to be the result of abnormal cell growth and proliferation due to various reasons. Inherent gene abnormality and gene alterations by exposures to the chemical carcinogens or by infection with viruses are examples of those reasons.
  • Proto- oncogene is basically essential for cell growth and differentiation by stimulating protein synthesis and intracellular signal transduction. However, once mutated, it induces over-proliferation of a cell, leading cells more prone to timorigenesis. In the meantime, tumor suppressor inhibits excessive cell growth by regulating cell cycles and repairing genetic defects. Nevertheless, cancer can be developed by loss- of-function mutation of tumor suppressor genes or gain-of-function mutation of proto- oncogenes.
  • Cells with mutated proto-oncogenes or tumor suppressor genes generally go through apoptosis process by apoptosis-regulating genes.
  • oncogene, tumor suppressor gene and apoptosis-regulating gene there are many other protective mechanisms with functions of gene repair, signal transmission, etc., to keep cells healthy.
  • cancer can be developed when cells are continuously and excessively exposed to carcinogens and genetic defects occur to the genes.
  • Chemotherapy has been popular after choriocarcinoma was completely cured by using methotrexate, and more than 50 chemotherapeutic agents are now in use.
  • cancers such as choriocarcinoma, leukemia, Wilms' timor, Ewing's s arcana, rhabdcr ⁇ joma, retinoblastoma, lymphoma and testis t nors are generally well-treated with chemotherapeutic agents.
  • chemotherapeutic agents inhibit the synthesis of nucleic acid or polymerization of nucleic acids.
  • those chemotherapeutic agents not only work for cancer cells but also damage normal cells, especially actively proliferating cells, resulting in serious side effects such as dysfunction of bone marrow, injury of gastrointestinal mucosa, depilation, etc.
  • the biggest problem of chemotherapeutic agents is non-specificity, i.e., they damage normal cells showing active cell division, for example, bone marrow cells, gastrointestinal epithelial cells, hair follicle cells, etc.
  • most of patients under chemotherapy suffer side effects such as dysfunction of bone marrow, gastrointestinal disorder, depilation, etc.
  • the only difference in the effect of chemotherapy between normal cells and cancer cells is not in quality but in quantity. The only reason why cancer cells are destroyed more than normal cells is because they are more sensitive than normal cells and regeneration of normal cells are faster.
  • Apoptosis induction by finding or improving a prominent candidate which is able to induce apoptosis of cancer cells.
  • Apoptosis is a kind of active mechanism causing cell death, which functions not only in normal physiological circumstances such as development and differentiation but also in pathological environments such as cell defect or infection with a microorganism.
  • External apoptosis-inducing factors are UV, g-ray irradiation, heat shock, ceramide, anticancer drugs, reactive oxygen species, virus infection and elimination of a growth factor, etc, and those are divided into two groups according to their action mechanism; 1) factors acting through a death receptor and 2) apoptosis-inducers working other pathways.
  • Apoptosis-inducers working through a death receptor usually induce the expression of death receptors, i.e., Fas, tumor necrotizing factor receptor 1 (TNFR1), TNF-related apoptosis-inducing ligand (TRAIL), TNF-receptor-related apoptosis ⁇ nediated protein (TRAMP), nerve growth factor (NGF), etc.
  • Apoptosis- inducers that do not use the death receptors generally induce the expression of bax, a pro-apoptotic protein of bcl-2 family inducing apoptosis, leading to caspase activation, and a breakdown of mitochondrial membrane potential.
  • the primary goal of most anticancer agents is to induce apoptosis of cancer cells.
  • the conventional anticancer agents induce apoptosis, but cannot control specific apoptosis-regulating genes.
  • G-3139 developed by another company (Genta, Lexington, MA, USA), is a substance lowering the amount of bcl-2 protein in a cancer cell by inhibiting the synthesis of mRNA of bcl-2 gene.
  • G-3139 might be used in conjunction with other anticancer agents such as docetaxel, irinotecan or paclitaxel.
  • Lck expression is generally restricted to T-lymphocytes and NK cells.
  • over-expression of Lck was also reported in a blood cancer patient, in particular B cell neoplasia.
  • B cell neoplasia is exemplified by Burkitt lymphoma (Cheung RK & Dosch M. 1991, J. Biol. Chem. 266:8667-8670; Jucker M et al. 1991. Leukemia 5:528-530; Knethen AV et al. 1997. Leukemia & Lymphoma 26:551-562), which is a B- transformed cell line, non-Hodgkin B-cell lymphoma (Rouer et al. 1993.
  • Leukemia 7:246-250 B-lymphoblastoid cells, chronic B-lymphocytic leukemia (Knethen AV et al. 1997. Leukemia & Lymphoma 26:551-562; Majolini MB et al. 1998. Blood 91:3390-3396), etc.
  • abnormal expression of Lck was also observed in a lung cancer, colon cancer cell line (Veillette et al. 1987. Oncogene Res. 1:357-374), colorectal cancer tissue (Nakamura K et al. 1996. Eur. J. Cancer 32 1401- 1407) and in breast cancer tissues (Koster A et al. 1991. Anticancer Res. 11:193-201).
  • Leukemia a malignant tumor generated in bone marrow and blood, is resulted from abnormal proliferation of blood cells.
  • Leukemia is classified into four groups; acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, and chronic lymphoblastic leukemia.
  • Myelogenous leukemia is caused by abnormality of myeloid cells, erythrocytes or megakaryocytes in bone marrow
  • Lymphoblastic leukemia is caused by abnormality of lymphoblastic cells such as T-cells or B-cells.
  • Radiotherapy, bone marrow transplantation and chemotherapy are used for the treatment of leukemia.
  • bone marrow transplantation is the most fundamental treatment for leukemia among many methods, it is limited in use because of difficulty in securing a donor. Thus, chemotherapy is taking the place of it.
  • more than two anticancer agents are c ⁇ nbinatorially used for leukemia. In fact, about 40 anticancer agents are administered either singly or c ⁇ nbinatorially.
  • Most chemotherapeutic agents are DNA synthesis inhibitors or cell growth inhibitors, and since they target actively-proliferating cells no matter it is normal or cancerous, side effects are inevitable.
  • leukemia patients are not completely recovered and, in sane patients, chemotherapy merely extend the survival period.
  • Rosmarinic acid has been known to have various activities in vivo. In particular, it has anti-viral, anti-bacterial, anti-oxidant activities and inhibitory activities on the synthesis of tumor necrosis factor. Rosmarinic acid also has anti-5-lipoxygenase, anti- cyclooxygenase, anti-c ⁇ nplement and anti-inflammatory activities.
  • the present inventors have eagerly studied to find a substance being able to kill cancer cells only without damaging normal cells. At last, the present inventors have completed this invention by confirming that apoptotic effect of hydroxylphenyl derivatives of rosmarinic acid is mostly restricted to cancer cells only.
  • FIG. 1 is a graph showing the apoptotic effect of hydroxylphenyl derivatives of rosmarinic acid on various leukemia cell lines
  • FIG. 2 is a graph showing the apoptotic effect of hydroxylphenyl derivatives of rosmarinic acid on various leukemia cell lines according to the concentration of the same,
  • FIG. 3 is a graph showing the apoptotic effect of hydroxylphenyl derivatives of rosmarinic acid on peripheral blood mononuclear cells of a healthy donor
  • FIG. 4 is a graph showing the apoptotic effect hydroxylphenyl derivatives of rosmarinic acid on peripheral blood mononuclear cells of a patient with B-cell chronic lymphoblastic leukemia.
  • the present invention provides a pharmaceutical c ⁇ nposition for anticancer containing hydroxylphenyl derivatives of rosmarinic acid represented by the following ⁇ formula 1> as an effective ingredient.
  • R , R , R , R and R are independent each other, at least one of them is hydroxy, 1 2 3 4 5 and the others are selected fr ⁇ n a group consisting of H, halogen at ⁇ n, C ⁇ C alkoxy, 1 3 aldehyde, carboxyl, amino, trif uormethyl, and nitro;
  • R , R , R , R and R are independent each other, at least one of them is hydroxy, 6 7 8 9 10 and the others are selected fr ⁇ n a group consisting of H, halogen at ⁇ n, C ⁇ C alkoxy, 1 3 aldehyde, carboxyl, amino, trifluormethyl, and nitro;
  • A is H, C ⁇ C straight or branched alkyl, thiol, phenyl, 2 m 1 1 4 cyano, or C ⁇ C alkoxycarbonyl;
  • A is H, or C ⁇ C straight or branched alkyl; n is 0, 1 1 3 2 1 4 or 2; m is 0, 1 or 2;
  • Y is not existed or -NZ Z , -O-Z , or -S-Z ; 2 11 12 2 2
  • Z or Z is independent each other, H, amine substituted with t-butoxycarbonyl or 11 12 not, C ⁇ C straight or branched alkyl, aryl, cycloalkyl, or heteroalkyl; 1 12
  • Z is H, C ⁇ C straight or branched alkyl, aryl, cycloalkyl, or heteroalkyl; 2 1 12
  • [41] B is H or alkyl
  • [42] * represents a chiral carbon.
  • the c ⁇ npounds of ⁇ Formula 1> are optical is ⁇ ners of R or S. In the present invention, all the optical is ⁇ ners and racemic mixtures thereof are included.
  • R , R and R are H; R and R are hydroxy; R , R and R are H; R and 1 5 2 3 6 7 10 8 R are hydroxy;
  • X is O, S, -NH- or -N(CH )-;
  • Y is O or not;
  • Y is C ⁇ C alkoxy, -NH or hydroxy;
  • B is Q 1 2 1 4 2
  • the compounds of hydroxylphenyl derivatives of rosmarinic acid comprise: [48] 1) 3-(3,4-dihydroxy-phenyl)-(R)-2-[3-trans-(3,4-dihydroxy-phenyl)-acryloylamino] -propionic acid methyl ester; [49] 2) 3-(3,4-dihydroxy-phenyl)-(R)-2-[3-trans-(3,4-dihydroxy-phenyl)-acryloylamino] -propionic acid; [50] 3) 3-(3,4-dihydroxy-phenyl)-(R)-2-[3-trans-(3,4-dihydroxy-phenyl)-acryloylamino] -propionic acid ethyl ester; [51] 4) 3-(3,4-dihydroxy-phenyl)-(R)-2-[3-trans-(3,4-dihydroxy-phenyl)-acryloylamino] -propionic acid eth
  • hydroxylphenyl derivatives of rosmarinic acid of the present invention can be prepared by the preparation method disclosed in WO 03/089405.
  • Hydroxylphenyl derivatives of rosmarinic acid of the present invention induce apoptosis of various leukemia cell lines. Particularly, Jurkat and LBRM-33, derived from T-cells expressing Lck, and BCL-1, derived from B-cells not expressing Lck until tumorigenesis, are killed by the derivatives effectively. On the other hand, J.CaM1.6, Raji and mononuclear (THP-1, U937) cell lines, not expressing Lck, are not affected by the hydroxylphenyl derivatives of rosmarinic acid.
  • Hydroxylphenyl derivatives of rosmarinic acid of the present invention loses apoptotic effect when hydroxyl groups in the phenyl groups located in both ends of the derivatives are either eliminated or masked.
  • hydroxyl groups of phenyl groups located in both ends of the derivatives play very important role in apoptosis.
  • Hydroxylphenyl derivatives of rosmarinic acid of the present invention do not destroy peripheral blood mononuclear cells of a healthy donor but kill peripheral blood mononuclear cells of a leukemia patient, more particularly, B-cell leukemia cells taking 80% of mononuclear lymphocytes of a leukemia patient.
  • hydroxylphenyl derivatives of rosmarinic acid of the present invention can be effectively used for preventing or treating cancers by inducing apoptosis in cancer cells only without damaging normal cells.
  • the c ⁇ nposition of the present invention can be prepared by c ⁇ nprising one or more pharmaceutically acceptable carrier additionally in addition to above mentioned effective ingredients for administration.
  • a pharmaceutically acceptable carrier can use by mixing saline, sterilized aqueous solution, linger solution, buffer saline, dextrose solution, malto-dextrin solution, glycerol, ethanol and one or more ingredient of them, and as occasion demands, it can use by adding other conventional additives such as an- tioxidant, buffer solution, fungistats etc.
  • parenteral formulation such as aqueous solution, suspension, emulsion, or pellet, capsule, granule, or tablets by addition diluent, dispersion agent, surfactant, binding agent and lubricant additionally.
  • the c ⁇ nposition can further be prepared in suitable forms for each diseases or according to ingredients by following a method represented in Remington's Pharmaceutical Science (the newest edition), Mack Publishing C ⁇ npany, Easton PA
  • the c ⁇ nposition of the present invention can be administered orally or parenterally by objective method (for example, intravenous, hypodermic, local or peritoneal injection).
  • the effective dosage of the c ⁇ nposition can be determined according to weight, age, gender, health condition, diet, administration frequency, administration method, excretion and severity of a disease.
  • the dosage of hydroxylphenyl derivatives of rosmarinic acid is 0.05-500 mg/kg per day when they are administered by intramuscular injection and 1-5 g/kg per day when they are orally administered, and administration frequency is once a day or preferably a few times a day.
  • a composition of the present invention can be used singly or together with other treatments such as surgical operation, hormone treatment, pharmacologic treatment, biological regulators, etc., for preventing and treating cancers.
  • Anticancer agents available for co-use with the c ⁇ nposition of the present invention are cell growth inhibitors such as zinostatin, pirarubicin, idarubicin, el- liptinhm acetate, streptozocin and zinostatin stimalamer, antibodies such as lentinan, procodazol, TheraCys, OncoVAX-CL, ukrain, BCG vaccine and sizofilan, hormones such as aminoglutethimide, fadrozole, formestane and trilostane, and others such as razoxane, etoposide phosphate, vindesine, nitracrine, tretinoin, amsacrine, vinorelbine and sobuzoxane.
  • cell growth inhibitors such as zinostatin, pirarubicin, idarubicin, el- liptinhm acetate, streptozocin and zinostat
  • Cytarabine doxorubicin, daunorubicin, mitoxantrone, thioguanine, mercaptopurine, prednisone, etoposide, asparaginase, vincristin, cyclophosphamide, 5-FU and paclitaxel can be also included in the above drug category.
  • Example 1 Apoptotic effect of hydroxylphenyl derivatives of rosmarinic acid on various leukemia cell lines
  • Cell lines derived fr ⁇ n T lymphocytes, B-lymphocytes and monocytes such as Jurkat (human acute T-cell leukemia cell line), J.CaMl.6 (human acute T-cell leukemia cell line not expressing Lck), LBRM-33 (mouse T-cell lymphoma cell line), BCL-1 (mouse B-cell leukemia cell line), Raji (human Burkitt's lymphoma cell line), THP-1 (himan monocyte cell line), U937 (h nan monocyte cell line), etc were used. All the cell lines were purchased fr ⁇ n ATCC (American Type Culture Collection).
  • Each cell line was maintained in RPMI 1640 mediim containing 10% FBS, 2mM L-glutamine, 100 XJM of penicillin and 100 ⁇ gM of streptomycin.
  • hydroxylphenyl derivative of rosmarinic acid [3-(3,4-dihydroxy-phenyl)-(R)-2-[3-trans-(3,4-dihydroxy-phenyl)-acryloylamino]-prop ionic acid methyl ester] destroyed 40-50% Jurkat, LBRM-33 (both are T-cell derived leukemia cell lines expressing Lck) and BCL-1 (B-cell leukemia cell line) cells for 16 hours and 100% of them all after 40 hours, indicating that apoptotic effect of the hydroxylphenyl derivative of rosmarinic acid was time-dependent.
  • apoptotic effect of the derivative was not detected in those cell lines not expressing Lck such as Jurkat T-lymphocyte derived J.CaMl.6, B-cell derived Raji, monocyte cell line THP-1, U937, etc.
  • the cell density of BCL-1 for culture was 1x10 cells/m ⁇ . Hydroxylphenyl de rivatives of rosmarinic acid (compounds 1-58) were added at the concentrations of 100, 50, 25, 12.5, 6.25, 3.125 uM each and cultured for 40 hours. The cells were stained with annexin V-FITC to measure apoptotic effects of them by FACS.
  • R ⁇ R of hydroxylphenyl derivatives of rosmarinic acid, represented by Formula 1 should be independent each other and at least one of them must be a hydroxyl group. And, R ⁇ R of the derivatives should be independent each other and 6 10 at least one of them must be a hydroxyl group.
  • R ⁇ R of the derivatives are not necessarily hydroxyl groups but can be substituted with other groups having similar characteristics to hydroxyl groups.
  • Example 2 Apoptotic effect of hydroxylphenyl derivatives of rosmarinic acid on various leukemia cell lines
  • the present inventors have performed following experiments to investigate apoptotic effect of hydroxylphenyl derivatives of rosmarinic acid of the present invention on various leukemia cell lines.
  • Cell lines derived fr ⁇ n T lymphocytes, B-lymphocytes and monocytes such as Jurkat (human acute T-cell leukemia cell line), H9 (human T cell leukemia cell line), CCRF-CEM (human acute T cell leukemia cell line), BCL-1 (mouse B-cell leukemia cell line expressing Lck), J.CaMl.6 (human acute T-cell leukemia cell line not expressing Lck), EL4 (mouse T cell leukemia cell line), LBRM-33 (mouse T-cell lymph ⁇ na cell line), WEHI-3 (mouse leukemia cell line), K-562 (mouse myelogenous leukemia cell line), etc were used. All the cell lines were purchased fr ⁇ n ATCC (American Type Culture Collection).
  • Each cell line was maintained in a medi n according to the instructions provided by ATCC.
  • Cell density was 1x10 cells/m ⁇ and hydroxylphenyl derivatives of rosmarinic acid were added at the concentrations of 5, 10, 20, 30 and 50 uM, respectively.
  • Culture was continued for 24-48 hours. Then, the cells were stained with annexin V-FITC to measure apoptotic effects of them by FACS.
  • hydroxylphenyl derivatives of rosmarinic acid effectively destroyed T-cell leukemia cell lines (Jurkat, H9, CCRF-CEM) and B-cell leukemia cell line, BCL-1, expressing Lck abnormally, showing ED of 12 uM.
  • Hydroxylphenyl derivatives of rosmarinic acid also killed other leukemia cell lines not expressing Lck (J.CaMl.6, EL-4, WEHI, K-562, etc), which was, though, not significant (showing ED at 25-40 uM). 50
  • Hydroxylphenyl derivatives of rosmarinic acid of the present invention can destroy cancer cell lines not expressing Lck with the concentrations over 50 uM, meaning that their apoptotic effects were not limited to cancer cell lines expressing Lck.
  • hydroxylphenyl derivatives of the present invention are expected to induce apoptosis of leukemia cell lines even originated from B-lymphocytes showing abnormal Lck expression, for example blood cancer cell lines, lung cancer cell lines, large intestine cancer cell lines, colon carcinoma cell lines and breast cancer cell lines.
  • Example 3 Apoptotic effect of hydroxylphenyl derivatives of rosmarinic acid on peripheral blood mononuclear cells of healthy donors
  • the present inventors have performed following experiments to investigate apoptotic effect of hydroxylphenyl derivatives of rosmarinic acid on peripheral blood mononuclear cells of a healthy donor.
  • hPBMC Human Peripheral Blood Mmonuclear Cells
  • Mmonuclear cells (1x10 cellsM) were treated with various concentrations (12.5 - 50 uM) of hydroxyl phenyl derivatives of rosmarinic acid in the absence of any stimulators for 24-48 hours. Then, the mononuclear cells were stained with annexin V-FITC to measure apoptotic effect by FACS.
  • Example 4 Apoptotic effect of hydroxylphenyl derivatives of rosmarinic acid on peripheral blood mononuclear cells from B-cell chronic lymphocytic leukemia patients
  • the present inventors performed following experiments to investigate apoptotic effect of hydroxylphenyl derivatives of rosmarinic acid of the present invention on mononuclear cells from leukemia patients.
  • mononuclear cells were stained with anti-CD3-Cy-chr ⁇ ne and anti-CD 19-PE, followed by FACS analysis. Around 80% of mononuclear cells were CD19-positive (B cell marker) in B-cell chronic lymphocytic leukemia patients, which were greatly increased percentages of B cells compared to a normal range of B cell percentage (more or less than 5%).
  • hydroxylphenyl derivative of rosmarinic acid induced apoptosis more than 50% of mononuclear cells from B-cell chronic lymphocytic leukemia patients at the concentration of 12.5 uM.
  • Peripheral blood mononuclear cells from leukemia patients are almost homogeneous to B -lymphocyte populations because leukemic B -lymphocytes take more than 80% of total peripheral blood mononuclear cells fr ⁇ n B-cell leukemia patients.
  • the present inventors prepared injectable solutions containing lOmg of hydroxylphenyl derivatives of rosmarinic acid as an effective ingredient as follows.
  • the hydroxylphenyl derivatives of rosmarinic acid of the present invention have excellent apoptotic effect on both T-cell originated leukemia cells and B-cell originated leukemia cells expressing Lck abnormally.
  • hydroxylphenyl derivatives of rosmarinic acid of the present invention do not induce apoptosis of B-cells and monocytes, which do not express Lck.
  • Hydroxylphenyl derivatives of the present invention do not induce apoptosis of peripheral blood mononuclear cells fr ⁇ n healthy donors, but induce apoptosis of peripheral blood mononuclear cells fr ⁇ n leukemia patients. Therefore, hydroxylphenyl derivatives of rosmarinic acid of the present invention can be effectively used for preventing and treating cancers since they induce apoptosis of cancer cells but not normal cells.

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Abstract

La présente invention a trait à une composition pharmaceutique pour le traitement contre le cancer contenant des dérivés d'hydroxyphényle de l'acide rosmarinique comme principe actif. Les dérivés d'hydroxyphényle de l'acide rosmarinique de la présente invention réalisent une forte induction de l'apoptose de cellules leucémiques dérivées de lymphocytes T et même des cellules leucémiques dérivées de cellules B d'expression anormale de Lck. Cependant, ils ne déclenchent pas l'apoptose d'autres lignées cellulaires tirant leur origine des cellules B et de monocytes, qui n'expriment pas le Lck normalement. Alors que les dérivés d'hydroxyphényle de l'acide rosmarinique de la présente invention n'induisent pas l'apoptose des cellules mononucléaires sanguines périphériques en provenance de donneurs sains, ils induisent l'apoptose des cellules mononucléaires sanguines périphériques en provenance des patients atteints de la leucémie. Lors de l'élimination ou du masquage des groupes hydroxyles dans les noyaux phényliques de l'acide rosmarinique, l'activité apoptotique est éliminée, indiquant que les groupes hydroxyles des noyaux phényliques se trouvant aux deux extrémités de l'acide rosmarinique sont indispensables à l'apoptose. Les dérivés hydroxyphényles de l'acide rosmarinique de la présente invention induisent l'apoptose des cellules cancéreuses mais pas des cellules normales, de sorte qu'ils peuvent être utilisés de manière efficace pour la prévention et le traitement des cancers.
PCT/KR2004/001597 2004-02-02 2004-06-30 Composition pharmaceutique comportant des derives d'hydroxyphenyle de l'acide rosmarinique pour le traitement contre le cancer WO2005072723A1 (fr)

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WO2008009655A3 (fr) * 2006-07-17 2008-05-29 Univ Muenster Wilhelms Utilisation médicale de dérivés d'acides n-phénylpropénoyl-aminés et de composés apparentés
WO2010032771A1 (fr) * 2008-09-18 2010-03-25 日本臓器製薬株式会社 Dérivé d'acide aminé
CN101157668B (zh) * 2007-10-31 2011-08-31 温州医学院 具有肿瘤细胞毒活性的取代桂皮酸类含氮衍生物
JP2011213718A (ja) * 2010-03-17 2011-10-27 Nippon Zoki Pharmaceut Co Ltd アミノ酸誘導体を含有する医薬及び該誘導体の製造方法
WO2017123935A1 (fr) * 2016-01-13 2017-07-20 Cardelli James Allen Procédés de traitement des cancers dépendant de c-met
CN108484431A (zh) * 2018-03-26 2018-09-04 中国药科大学 一种肉桂酰氨基酸类化合物及其用途

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KR102106851B1 (ko) * 2018-07-20 2020-05-06 성균관대학교산학협력단 새로운 s6k1 억제제를 유효성분으로 포함하는 자궁경부암 또는 두경부암의 예방 또는 치료용 약학적 조성물
US20210395181A1 (en) * 2020-04-06 2021-12-23 Korea Advanced Institute Of Science And Technology Rosmarinic acid derivative, rosmarinic acid-derived particles, composition containing same for treating inflammatory disease

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008009655A3 (fr) * 2006-07-17 2008-05-29 Univ Muenster Wilhelms Utilisation médicale de dérivés d'acides n-phénylpropénoyl-aminés et de composés apparentés
CN101157668B (zh) * 2007-10-31 2011-08-31 温州医学院 具有肿瘤细胞毒活性的取代桂皮酸类含氮衍生物
EP2345635A4 (fr) * 2008-09-18 2012-05-30 Nippon Zoki Pharmaceutical Co Dérivé d'acide aminé
EP2345635A1 (fr) * 2008-09-18 2011-07-20 Nippon Zoki Pharmaceutical Co., Ltd. Dérivé d'acide aminé
CN102216260A (zh) * 2008-09-18 2011-10-12 日本脏器制药株式会社 氨基酸衍生物
WO2010032771A1 (fr) * 2008-09-18 2010-03-25 日本臓器製薬株式会社 Dérivé d'acide aminé
JP5213961B2 (ja) * 2008-09-18 2013-06-19 日本臓器製薬株式会社 アミノ酸誘導体
AU2009293750B2 (en) * 2008-09-18 2014-05-22 Nippon Zoki Pharmaceutical Co., Ltd. Amino acid derivative
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