EP1102585A2 - UTILISATION DE DERIVES DE CYCLOPENTABENZOFURANNE POUR LUTTER CONTRE DES MALADIES DEPENDANT DU NF-$g(k)B - Google Patents

UTILISATION DE DERIVES DE CYCLOPENTABENZOFURANNE POUR LUTTER CONTRE DES MALADIES DEPENDANT DU NF-$g(k)B

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Publication number
EP1102585A2
EP1102585A2 EP99944303A EP99944303A EP1102585A2 EP 1102585 A2 EP1102585 A2 EP 1102585A2 EP 99944303 A EP99944303 A EP 99944303A EP 99944303 A EP99944303 A EP 99944303A EP 1102585 A2 EP1102585 A2 EP 1102585A2
Authority
EP
European Patent Office
Prior art keywords
methoxy
represent
hydrogen
hydroxy
diseases
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99944303A
Other languages
German (de)
English (en)
Inventor
Matthias Gehling
Jörg Baumgarten
Axel Kretschmer
Horst-Peter Antonicek
Peter Proksch
Bambang W. Nugroho
Frank Bohnenstengel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer AG filed Critical Bayer AG
Publication of EP1102585A2 publication Critical patent/EP1102585A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to the use of cyclopentabenzofuran derivatives
  • Extracts from the Aglaia elliptifolia plant show anti-leukemic properties.
  • a dihydrocyclopenta- benzofuranol derivative called rocaglamide was identified as the first active compound (J. Chem. Soc, Chem. Commun. 1982, 1150; US
  • NF- ⁇ B Protein "Nuclear Factor kappa B", NF- ⁇ B for short, in the cell nucleus and the resulting stimulation of the expression of the genes, the products of which are responsible for inflammatory reactions (Trends Pharmacol. Sci. J_8, 46 (1997)).
  • the non-useful, excessive (non-self-limiting) production of these proteins is responsible for the enhancement and maintenance of the inflammatory process and the associated unpleasant to life-threatening symptoms of this disease.
  • glucocorticoids corresponding to the current state of the art has some disadvantages, NF- ⁇ B is seen as an imperative target for the development of new anti-inflammatory agents against asthma.
  • R 1 represents hydrogen
  • R 2 represents methoxy
  • R 3 represents hydrogen or
  • R and R together represent -OCH 2 O-
  • R 4 represents methoxy
  • R 5 represents hydroxy, OCHO or acetoxy
  • R 6 and R 7 each represent hydrogen or
  • R 5 and R 6 together represent oxygen (oxo) or hydroxyimino
  • R 8 represents -COOR 12 or -CONR 13 R ' 4 , wherein
  • R 12 and R 13 represent hydrogen or methyl
  • R 14 represents hydrogen, methyl, 4-hydroxybutyl or 2-tetrahydrofuryl
  • R 5 and R 8 together for a group of fo ⁇ neln (a) or (b)
  • R 9 represents phenyl
  • R 10 represents methoxy
  • R represents hydrogen, hydroxyl, methoxy or 2-rhamnosyl
  • R 10 and R are adjacent and together represent -OCH 2 O-, or
  • R 15 represents hydroxy, methoxy or ethoxy
  • R 16 represents hydrogen, hydroxy or methoxy
  • R 1 , R 3 and R 8 each represent hydrogen
  • R 2 and R 4 each represent methoxy
  • R 5 represents hydroxy
  • R 6 and R 7 each represent hydrogen or
  • R 5 and R 6 together represent oxygen (oxo group),
  • R 9 represents phenyl
  • R 10 represents methoxy
  • R represents 2-methoxy or 2-rhamnosyl, or R and R are adjacent and together represent -OCH 2 O-,
  • Suitable as inhibitors are the nuclear factor kappa B (NF- ⁇ B) -interrupted gene expression for the therapy of pathophysiological processes.
  • NF- ⁇ B nuclear factor kappa B
  • the substances that can be used according to the invention are from o.a. Literature known.
  • Examples of the substances of the formula (I) which can be used according to the invention are the compounds (1-1) to (1-45), which are listed below.
  • the substances which can be used according to the invention are low molecular weight inhibitors which selectively inhibit nuclear factor kappa B (NF- ⁇ B) -mediated pathophysiological processes.
  • NF- ⁇ B-mediated processes occur in inflammatory diseases, immunological diseases, septic shock, graft rejection, radiation damage, reperfusion injuries after ischemia, thrombosis or in complex, chronic inflammatory diseases such as arteriosclerosis.
  • Nuclear factor kappa B is a dimeric protein complex found in many tissue cells and especially in blood cells. NF- ⁇ B plays a special role in controlling the expression of genes which have an NF- ⁇ B binding sequence in their promoter sequence (5'-GGGPuNNPyPyCC-3 '). In this respect, NF-KB is a transcription factor.
  • the physiological activity of NF- ⁇ B to control gene expression is subject to a regulatory principle in which NF- ⁇ B is released from a complex with the protein I ⁇ B in order to translocate as a transcription factor into the cell nucleus for gene activation.
  • the regulatory principle for the release of active NF- ⁇ B from a complex with the protein I ⁇ B is not yet known in detail.
  • NF- ⁇ B acts as a dimeric transcription factor on gene activation.
  • the dimerization can take place under the structurally related transcription factors Rel A, Rel B, c-Rel, p50 or p52, which form a family of transcription factor proteins.
  • Rel A structurally related transcription factors
  • Rel B c-Rel
  • p50 or p52 which form a family of transcription factor proteins.
  • NF- ⁇ B there can already be a regulatory principle for controlling the genes described in more detail later, which is not yet known.
  • a key feature of NF- ⁇ B over other transcription factors is that NF- ⁇ B is a primary transcription factor. Primary transcription factors are already in the cell in an inactive (mostly complex-bound) form and are released after a corresponding stimulus in order to be able to develop their effects very quickly. Primary transcription factors are not only formed by activating the associated gene and subsequent transcription and translation.
  • NF- ⁇ B genes of the Rel family
  • I ⁇ B proteins genes for the formation of the I ⁇ B proteins
  • TNF- ⁇ Tumor necrosis factor- ⁇
  • PMA phorbol myristate acetate
  • NF- ⁇ B can primarily promote all pathophysiological processes in which genes are involved which have the NF- ⁇ B binding sequence in their promoter. These are genes that play a decisive causal role in immunological complications, inflammatory diseases, autoimmune diseases, septic shock, transplant rejection, thrombosis or even in chronic inflammatory diseases such as arteriosclerosis, arthritis, rheumatism and psoriasis.
  • NF- ⁇ B binding sequences contain e.g. the promoters of lymphoid cell receptors (T cell receptors), of MHCI and MHCII genes, of cell adhesion molecules (ELAM-1, VCAM-1, ICAM-1), of cytokines and growth factors (see also the table below). Furthermore, NF- ⁇ B binding sequences can be found in the promoters of acute phase proteins (angiotensinogen, complement factors, etc.).
  • cytokines of the inflammatory reaction TNF ⁇ , Interleukin-2, Interleukin-6, Interleukin-8 and others
  • ELAM-1, ICAM-1, VCAM-1 adhesion molecules
  • Inhibitors that prevent NF- ⁇ B-mediated gene expression intervene very early in the manifestation of pathophysiological changes in some diseases and can therefore be very represent effective therapeutic principle.
  • NF- ⁇ B inhibitors for diseases that are due to overexpression of acute phase proteins are also an example.
  • NF- ⁇ B strongly induces the serum amyloid A precursor protein in the liver by inducing acute phase proteins.
  • Interleukin-2 is a cytokine that i.a. as a hematopoietic growth factor plays a central role in various inflammatory processes (Annu. Rev. Immunol 1994, 12: 141-79).
  • the promoter of the interleukin-2 gene is dependent on NF- ⁇ B.
  • Inhibition of NF- ⁇ B stimulation thus opens up the possibility of preventing oversupply of 11-2 production and thus of treating inflammatory processes.
  • NF- ⁇ B-mediated gene expression can also represent a significant therapeutic advance.
  • NF- ⁇ B-controlled genes are induced by oxidation reactions that lead to oxidative stress after reperfusion of ischemic tissue.
  • an overexpression of cytokines and cell adhesion molecules in the ischemic tissue triggers an excessive recruitment of infiltrating lymphocytes.
  • the recruited lymphocytes cause tissue damage.
  • NF- ⁇ B-controlled gene expression in several neurodegenerative diseases is also evident.
  • the selective inhibition of genes with NF- ⁇ B binding sequence becomes therapeutic in particular in the case of nerve diseases in which the redox state of cells of the neuronal tissue is disturbed Attributed benefits.
  • a disrupted redox state of neuronal cells is assumed in amytrophic lateral sclerosis and in Down syndrome.
  • NF- ⁇ B is a common transcription factor in neuronal tissue and that NF- ⁇ B is a redox potential-controlled transcription factor in the brain (PA Bauerle, T. Henkel, Annu. Rev. Immunol. 12, 141-179, 1994 ).
  • a listing of the genes induced by NF- ⁇ B is given in Table 2.
  • T cell receptor ⁇ chain (human)
  • Vascular cell adhesion molecule 1 vascular cell adhesion molecule 1
  • Granulocyte / macrophage colony-stimulating factor (GM-CSF)
  • NF- ⁇ B NF- ⁇ B
  • lymphotropic viruses such as HIV, HTLV and Epstein-Barr virus
  • NF- ⁇ B has a positive effect on gene expression in the cytomegalovirus (CMV) and adenovirus.
  • CMV cytomegalovirus
  • adenovirus Antiviral effects with NF- ⁇ B inhibitors are also conceivable here.
  • TNF ⁇ tumor necrosis factor- ⁇
  • the promoter of the human TNF ⁇ gene contains three NF- ⁇ B binding sequences, which are designated as kl, k2 and k3.
  • Lipopolysaccharide or phorbol ester induce NF- ⁇ B release (M.J. Lenardo et al., Cell 58, 227-229, 1989).
  • Donor blood mononuclear cells are isolated using Vacutainer CPT (TM) tubes (Becton Dickinson and Company, Franklin Lakes, NJ. 07417-1885) according to the manufacturer's instructions.
  • the Vacutainer CPT tubes contain 1.0 ml of phosphate-buffered saline with 120 USP units of sodium heparin over 3.0 g of a polyester gel that covers 2.0 ml of a Ficoll solution. After centrifugation of the donor blood, the monocytes are taken from a zone above the polyester gel and ind with a cell density of 250 x 10 5 cells per well
  • the cells are kept in medium RPMI-1640 (Gibco BRL, Life
  • TNF ⁇ ELISA for concentration determination are e.g. from Sigma-Aldrich Chemie GmbH, Grünwalder Weg 30, 82039 Deisenhofen under the name Human TNF ⁇ ELISA Kit, order no .: CKH-200A. According to the manufacturer's instructions for use, the concentration of the TNF ⁇ formed in the culture supernatant of the monocyte culture after LPS stimulation with and without inhibitor substance is determined quantitatively.
  • the results of the TNF ⁇ concentration determination are plotted against each other in an x-y-axis diagram.
  • Inhibitors allows the inhibition of NF- ⁇ B-mediated TNF ⁇ synthesis to be read as a function of the concentration of the inhibitor substance.
  • the active substance concentration of the inhibitor added which, for example, inhibits TNF ⁇ synthesis by 50% can be read off from the diagram.
  • This active ingredient concentration, which causes 50% inhibition, is called the effective inhibitor concentration for 50% inhibition (IC 50 ).
  • the concentrations of the half-maximum TNF ⁇ synthesis inhibition (IC 50 ) of compound 1-2 are 0.3 ⁇ M, for compound 1-15 1.0 ⁇ M and 0.5 ⁇ m for connection 1-21.
  • the compounds thus represent potent inhibitors of NF- ⁇ B-mediated TNF ⁇ synthesis.
  • Tissue factor is a membrane-bound protein that is the primary initiator of the blood coagulation cascade and a key function in cardiovascular diseases such as unstable angina pectoris, acute implications after plaque
  • tissue factor gene is particularly induced in monocytes and endothelial cells by NF- ⁇ B activation.
  • the promoter of the human tissue factor gene contains an NF- ⁇ B binding site which contributes decisively to the activation of the promoter (P. Oeth et al. Arteriosclerosis, Thrombosis, and Vascular Biology 17, 365-374, 1997).
  • the promoter fragment of the human tissue factor gene which contains the NF- ⁇ B binding sequence, was with oligonucleotide primers of the sequence 5'-TCC CTC GAG ATC TCC CAG AGG CAA ACT GCC AGA T-3 '(5' primer of the position -925) and 5 '-TCC TCG AGC CAT GGC TAC CAG TTG GGC GGC GAG ATC-3' (3 'primer containing the ATG start codon of the coding sequence of the tissue factor gene) by the polymerase chain reaction (PCR) and fused by Ncol / Xhol cloning with the luciferase start codon in the plasmid pGL3-Basic Vector (Promega Corp.
  • RAW-A3 Refection of Mammalian Cells in Culture, L.G. Davis et al. Basic Methods in Molecular Biology, Elsevier Sei. Publishing Co., New York 1986. After selecting RAW clones that had the expression construct stably integrated into the genome, one of these transfectants, called RAW-A3, was selected for the test of the inhibitors.
  • RAW-A3 cells are sown in each well in 12-well microtiter plates.
  • the serum concentration in RPMI medium is gradually reduced from 10% fetal calf serum to 0.5% and 0.1% serum content in three days in order to minimize the serum-dependent tissue factor promoter activation.
  • the NF- ⁇ B inhibitor is added and then serum is added up to a concentration of 15% in the medium for promoter induction.
  • the culture supernatant is aspirated and the cells are used to measure the luciferase activity in accordance with the "Luciferase Assay System" (Technical Bulletin from Promega, 2800 Woods Hollow Road, Madison, WI 5371 1-5399 USA) E4030, E1483, E1501)
  • the cell lysate is incubated with the luciferase assay substrate and in a luminometer
  • a graph for f (x) results, in which the half-maximum y value of an inhibitor - concentration x is to be assigned, which corresponds to the inhibitory concentration IC 50 in this test.
  • the IC J0 value of compound 1-2 is 0.4 ⁇ M and compound 1-21 4.0 ⁇ M.
  • the NF- ⁇ B-mediated expression of luciferase by the inhibitors according to the invention with a concentration in the lower micromolar or in the submicromolar range indicates the high effectiveness of the
  • TNF ⁇ tumor necrosis factor- ⁇
  • NF- ⁇ B-mediated induction of TNF ⁇ synthesis is independent of the different stimuli used by LPS, opsonized zymosan or phorbol myristate acetate (PMA) for the activation of the TNF ⁇ promoter
  • Z4250 and P8139 are available. Zymosan is opsonized in human serum.
  • the NF- ⁇ B inhibitors according to the invention inhibit TNF ⁇ in a comparable manner regardless of the stimulus with IC 50 values in the submicromolar range Synthesis in human monocytes as shown in Example A.
  • the IC 50 value is 0.4 ⁇ M after PMA stimulus and 0.4 ⁇ M after zymosan stimulus.
  • the recruitment of leukocytes from the blood circulation into the extravascular space is essential for inflammatory responses and for the repair of
  • the process of leukocyte immigration involves several steps in series.
  • the initial interaction between leukocytes and the endothelium of the blood vessels is mediated by T ⁇ F and II-1-dependent expression of the adhesion protein ELAM-1 on the endothelium. It mediates the so-called rolling of the leukocytes along the blood vessel wall.
  • the transcriptional regulation of the ELAM-1 expression depends on the nuclear factor- ⁇ B (NF- ⁇ B) activation and binding to the ELAM-1 promoter as well as on the "AP-1 binding site.”
  • NF- ⁇ B nuclear factor- ⁇ B
  • ELAM-1 dependent neutrophil adhesion The influence of compound 1-2 on the expression of ELAM-1 was checked in two different test approaches.
  • the adhesion of human neutrophils to TNF- ⁇ stimulated HUVEC cells was measured in a functional approach.
  • the expression of ELAM-1 on the surface of the HEVECs was determined using a fluorescence-labeled ELAM-1-specific monoclonal antibody by means of FACS (cell sorting) analysis.
  • the neutrophils were isolated from human blood (100 ml). For this purpose, 3.5 ml of polyprep was placed in a centrifuge beaker and carefully overlaid with 5 ml of blood. After centrifuging at 2100 min -1 for 30 minutes, the neutrophil band was sucked off in the middle of the centrifuge cup. . After 1: 2 dilutions in Endothelial Cell Basal Medium (EBM) Fa Clonetics again for 20 minutes at 1000 has been min - centrifuged 1 ml and then taken up to a cell concentration of 10 6 cells /.
  • EBM Endothelial Cell Basal Medium
  • the umbilical cord endothelial cells were grown to confluence in 96-well microtiter plates in EBM + 10% FCS. At the start of the test, the medium was exchanged for EBM without FCS and the test substances were then used. After 20 minutes, the HUVECs were stimulated with 10 nM TNF- ⁇ . After 4 hours of incubation, 200 ⁇ l / well of the neutrophil suspension were exchanged. The neutrophils were previously labeled with a 25 ⁇ M BCESP fluorescent dye solution for 20 minutes. After 30 minutes of incubation, the BCECP neutrophil solution was drawn off with excess neutrophils and exchanged for 200 ⁇ l / well of 0.5% NaOH solution. The
  • Fluorescence of the adhering neutrophils was then measured in the fluorescence photometer.
  • Umbilical cord endothelial cells were cultured as described above and incubated for 4 hours in the presence or absence of 10 ng / ml TNF in the presence or absence of test substances.
  • the cells were extracted from the microtiter plates by incubation with 5 mM EDTA in PBS, centrifuged for 5 minutes at 1000 min -1 , and in 100 ⁇ l PBS plus 1% bovine serum albumin (BSA, Sigma-Aldrich GmbH, order no. A7906) in an anti-EL AM 1 antibody (monoclonal antibody, from Becton and Dickinson,
  • HUVECs stimulated with TNF for 4 hours showed significantly stronger fluorescence signals after incubation with anti-ELAM-1 antibodies than cells, on the other hand, which were not incubated with TMF.
  • Compound 1-2 was able to induce this induced expression of ELAM-1 in a concentration range between
  • a reporter gene cell line which contains the interleukin-2 promoter coupled to the luciferase gene.
  • the promoter contains the DNA sequence from -480 to +4.
  • the vector used is pGL3; the starting cell line into which the entire construct was stably transfected is SS-1.
  • the culture medium for this cell line was RPMI 1640 (Gibco, Rockille). It also contained: 100 ⁇ g / ml streptomycin, 100 U / ml penicillin, 2 mM L-glutamine, 10% heat-inactivated FBS and
  • the reporter gene test cell line was added to phenol red-free RPMI
  • LucLite TM solution Packard, Meriden, CT
  • Luminoskan Luminoskan, Labsystems

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Abstract

L'invention concerne l'utilisation de dérivés de cyclopentabenzofuranne pour la fabrication d'un médicament pour le traitement de maladies dépendant du facteur nucléaire λB.
EP99944303A 1998-08-05 1999-07-29 UTILISATION DE DERIVES DE CYCLOPENTABENZOFURANNE POUR LUTTER CONTRE DES MALADIES DEPENDANT DU NF-$g(k)B Withdrawn EP1102585A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19835325A DE19835325A1 (de) 1998-08-05 1998-08-05 Verwendung von Cyclopentabenzofuran-Derivaten zur Bekämpfung von NF-kB abhängigen Krankheiten
DE19835325 1998-08-05
PCT/EP1999/005426 WO2000007579A2 (fr) 1998-08-05 1999-07-29 UTILISATION DE DERIVES DE CYCLOPENTABENZOFURANNE POUR LUTTER CONTRE DES MALADIES DEPENDANT DU NF-λB

Publications (1)

Publication Number Publication Date
EP1102585A2 true EP1102585A2 (fr) 2001-05-30

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EP99944303A Withdrawn EP1102585A2 (fr) 1998-08-05 1999-07-29 UTILISATION DE DERIVES DE CYCLOPENTABENZOFURANNE POUR LUTTER CONTRE DES MALADIES DEPENDANT DU NF-$g(k)B

Country Status (5)

Country Link
US (1) US6518274B1 (fr)
EP (1) EP1102585A2 (fr)
AU (1) AU5729099A (fr)
DE (1) DE19835325A1 (fr)
WO (1) WO2000007579A2 (fr)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AUPQ866500A0 (en) 2000-07-05 2000-08-03 Exgenix Operations Pty Ltd Therapeutic compounds and methods
US20040086896A1 (en) * 2001-04-19 2004-05-06 Julie Carman Polynucleotides and polypeptides associated with the NF-kB pathway
DE10158561A1 (de) * 2001-11-29 2003-06-12 Bayer Ag Neue Verwendung von Cyclopentabenzofuranen
CA2504999A1 (fr) * 2002-11-08 2004-05-21 The Government Of The State Of Sarawak, Malaysia Composes et methodes therapeutiques
DE102004024504A1 (de) * 2004-05-18 2006-02-16 Bayer Healthcare Ag Neue Cylopenta[b]benzofuran-Derivate und ihre Verwendung
EP1693059A1 (fr) * 2005-02-22 2006-08-23 Deutsches Krebsforschungszentrum Utilisation des dérivés de rocaglamide en tant qu'inhibiteurs NF-À-spécifiques pour le traitement de certaines maladies inflammatoires
EP2189158A1 (fr) 2008-11-20 2010-05-26 DKFZ Deutsches Krebsforschungszentrum, Stiftung des Öffentlichen Rechts Combinaison de rocaglamide et de substances induisant l'apoptose pour le traitement du cancer
US20140255432A1 (en) * 2011-07-27 2014-09-11 Ohio State Innovation Foundation Silvestrol, silvestrol analogs and uses thereof
WO2015075165A1 (fr) 2013-11-22 2015-05-28 Deutsches Krebsforschungszentrum Inhibiteurs de translation en chimiothérapie à dose élevée et/ou radiothérapie à dose élevée
WO2020086562A1 (fr) * 2018-10-22 2020-04-30 Trustees Of Boston University Compositions et méthodes d'inhibition d'une infection virale
CA3181302A1 (fr) 2020-06-04 2021-12-09 Mahmoud Mohamed Abdrabo MOUSTAFA Analogues de cannabidiol rigide utilises en tant que modulateurs puissants de recepteurs cannabinoides et leurs utilisations
CN115073407A (zh) * 2021-03-10 2022-09-20 上海中医药大学 一种具有合成致死性的药用组合物及其应用

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Publication number Priority date Publication date Assignee Title
JPS59190956A (ja) 1983-04-15 1984-10-29 金　明儒 ロカグラマイド化合物
IL114758A0 (en) 1994-08-04 1995-11-27 Ciba Geigy Ag Insecticidal polycyclic compounds
WO1997008161A1 (fr) 1995-08-28 1997-03-06 Terumo Kabushiki Kaisha Agent deprimant une fonction oncogenique
JPH1112279A (ja) * 1997-06-27 1999-01-19 Microbial Chem Res Found Ｒａｓ蛋白の阻害活性を有する新規なアグライアスタチン立体異性体とそれらの製造法

Non-Patent Citations (1)

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Title
See references of WO0007579A2 *

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DE19835325A1 (de) 2000-02-10
AU5729099A (en) 2000-02-28
US6518274B1 (en) 2003-02-11
WO2000007579A3 (fr) 2000-09-08
WO2000007579A2 (fr) 2000-02-17

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