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WO2007116114A1 - Utilisation d'agonistes du récepteur opioïde delta dans l'élaboration de compositions pharmaceutiques qui les contiennent et leurs applications dans le traitement des tumeurs - Google Patents

Utilisation d'agonistes du récepteur opioïde delta dans l'élaboration de compositions pharmaceutiques qui les contiennent et leurs applications dans le traitement des tumeurs Download PDF

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Publication number
WO2007116114A1
WO2007116114A1 PCT/ES2007/070074 ES2007070074W WO2007116114A1 WO 2007116114 A1 WO2007116114 A1 WO 2007116114A1 ES 2007070074 W ES2007070074 W ES 2007070074W WO 2007116114 A1 WO2007116114 A1 WO 2007116114A1
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dpdpe
compound
agonist
cells
cancer
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PCT/ES2007/070074
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English (en)
Spanish (es)
Inventor
Carlos Martinez Alonso
Beatrice Duthey
Wolf-Henning Boehncke
Jens Gille
Ralf Ludwig
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Consejo Superior De Investigaciones Científicas
Johann Wolfgang Goethe University
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Publication of WO2007116114A1 publication Critical patent/WO2007116114A1/fr

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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/33—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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention falls within the biomedical sector, specifically in the field of the development of pharmaceutical compositions for the treatment of tumor diseases, and more specifically, in the use of opioid receptor delta agonists (for example, DPDPE, D-Pen-D -Pen-encephalin), as new antitumor agents that specifically reduce tumor progression and the appearance of metastases by blood dissemination.
  • opioid receptor delta agonists for example, DPDPE, D-Pen-D -Pen-encephalin
  • the CXCR4 chemokine receptor is involved in the establishment of metastases by promoting the migration and adhesion of tumor cells to lymph nodes, lungs and liver, when its ligand, CXCL12, is overexpressed in these locations (Benovic, JL and Marchese , A. 2004 .; Muller, A. et al, 2001; Balkwill, F., 2004).
  • CXCR4 is overexpressed in numerous types of tumor cells and its presence anticipates unsatisfactory clinical results (Kang H et al. 2005; Salvucci O et al. 2005; Wang N et al. 2005).
  • CXCR4 antagonists such as AMD 3100
  • blocking antibodies or interfering RNA strategies reduce metastases in several murine models (Liang, Z. et al, 2004; Lapteva, N. et al, 2005 ; Takenaga, M. et al, 2004).
  • CXCL12 is released in large quantities at the level of lymph nodes, lungs and livers, organs where metastases tend to appear.
  • CXCR4 belongs to the superfamily of G protein-coupled receptors (GPCR). Opioid receptors are also part of this family. Endogenous opioids (endorphins) are small peptide molecules, initially discovered in brain tissues, which reduce the sensation of pain. Opioids bind to mu, delta and kappa GPCRs (Kirk-Othmer, 1996; Kieffer BL, 2000). Although they are expressed at high levels in the brain, opiates have also been detected in cells of the immune system and in some types of malignant cells, such as melanoma, prostate and lung tumors (Fichna, J. and Janecka, A 2004), where his role is still unknown.
  • GPCR G protein-coupled receptors
  • Heterologous desensitization is a well-studied mechanism in this superfamily of receptors: a GPCR is activated by an agonist, initiating a signaling process that leads to the inactivation of another GPCR, thus producing a cross modulation.
  • Tumor metastases are the cause of determining mortality in most malignant cancers. Taking into account the cross-interaction that can be established between opioids and receptors related to tumor cell migration, this invention discovers that delta receptor agonist opiates can act as effective antitumor agents in reducing metastases. DESCRIPTION Brief Description
  • An object of the present invention is the use of opioid delta receptor agonists, hereinafter used a compound of the present invention, in the preparation of pharmaceuticals or pharmaceutical compositions for the prevention and / or treatment of cancer.
  • a particular object of the present invention is the use of a compound of the invention in which the agonist compound belongs to the following group, whether peptide structure or not: diarylmethylpiperazine compounds (US Pat 20060004016, Chang; Kwen-Jen 2006 , Enantiomerically pureed opioid diarylmethylpiperazine as a cardioprotection agent), TAN-67
  • a particular embodiment of the present invention is the use of a compound of the invention in which the agonist compound is the D-Pen-D-Pen-encephalin agonist (DPDPE).
  • DPDPE D-Pen-D-Pen-encephalin agonist
  • Another object of the present invention is a pharmaceutical composition, hereinafter pharmaceutical composition of the present invention, which comprises a therapeutically effective amount of a compound or agonist agent of the delta opioid receptor, together with, optionally, one or more adjuvants and / or pharmaceutically acceptable vehicles.
  • Another particular object of the present invention is the pharmaceutical composition of the invention in which the agonist compound belongs to the following group, whether peptide structure or not: diarylmethylpiperazine compounds, TAN-67, tetracyclic derivatives of pyridine and pyrazine, pyrrolooctahydroisoquinolones , compound BW373U86, compound SNC 80, DPDPE, deltorfina I and II, biphalin, the DADLE peptide and methadone.
  • the agonist compound belongs to the following group, whether peptide structure or not: diarylmethylpiperazine compounds, TAN-67, tetracyclic derivatives of pyridine and pyrazine, pyrrolooctahydroisoquinolones , compound BW373U86, compound SNC 80, DPDPE, deltorfina I and II, biphalin, the DADLE peptide and methadone.
  • Another particular object of the present invention is the pharmaceutical composition of the invention in which the compound is the D-Pen-D-Pen-encephalin agonist (DPDPE).
  • DPDPE D-Pen-D-Pen-encephalin agonist
  • Another object of the present invention is the use of the pharmaceutical composition of the invention in the treatment of a mammal, preferably a human being, affected by cancer, hereinafter use of the composition
  • Pharmaceutical of the present invention consisting of the administration of said therapeutic composition that reduces tumor progression, for example, the migration, extravasation and settlement of tumor cells in locations other than the original (metastasis).
  • the present invention offers a new therapeutic strategy for the prophylaxis and / or treatment of human tumor diseases.
  • the invention is based on the fact that the inventors have identified the inactivating effect of the DPDPE compound, delta opioid receptor agonist, on the pair-induced molecular event cascade, ligand-receptor, CXCL12-CXR4 that induces tumor progression, for example to the establishment of metastases.
  • This inactivating effect occurs after its binding to the opioid delta receptor and by a cross-modulation process between GPCR receptors
  • Example 1 The inventors have discovered that DPDPE could exert heterologous desensitization on CLCX12-CXR4, reducing cell adhesion, cell migration, extravasation and anchoring in distant organs of tumor cells (Example 2). Thus, treatment with DPDPE in animals that have been injected with melanone cells reduced the appearance of foci of metastasis in the lung (Example 2).
  • DPDPE in the treatment of tumors offers the following advantages: 1) it could help to remit metastases from numerous tumors (lung, liver, nodules, breast, prostate) in whose cells DPDPE and CXCR4 agonist receptors appear; in addition, 2) it could represent a less aggressive alternative to current chemotherapy and radiotherapy treatments; 3) considering the analgesic effect, it has been observed that in rats DPDPE causes less unwanted effects than morphine, an opioid is administered to critically ill cancer patients (Cheng, et al, 1993); 3) Finally, opiates are currently being sought that do not cross the blood brain barrier and remain in the periphery.
  • an object of the present invention is the use of opioid delta receptor agonists, hereinafter used a compound of the present invention, in the preparation of pharmaceuticals or pharmaceutical compositions for the prevention and / or treatment of human tumor diseases and animals.
  • opioid delta receptor agonist is a compound that binds or interacts with the opioid delta receptor and whose interaction induces its therapeutic effects, that is, analgesic and / or antitumor.
  • a particular object of the present invention is the use of a compound of the invention in which the agonist compound belongs to the following group, whether peptide or not: diarylmethylpiperazine compounds (US Pat 20060004016, Chang; Kwen-Jen 2006, Enantiomerically pure opioid diarylmethylpiperazine as a cardioprotection agent), TAN-67 (Fryer et al. In 274 J. Biol. Chem. 451-457, 2000), tetracyclic derivatives of pyridine and pyrazine (WO 99/04795, Toray Industries Inc .), pyrrolooctahydroisoquinolones (Dondio, G. et al.
  • biphalin Crystal structure of biphalin sulfate: a multireceptor opioid peptide.
  • DADLE Alzheimer's disease
  • a particular embodiment of the present invention is the use of a compound of the invention in which the agonist compound is the D-Pen-D-Pen-encephalin agonist (DPDPE).
  • DPDPE D-Pen-D-Pen-encephalin agonist
  • the term "the use of an agonist compound” further includes the use of its isomeric forms, pharmaceutically acceptable salts, derivatives, solvates, amides, esters and ethers of the original compounds.
  • the agonist compounds of the present invention used may be isomers, including optical isomers or enantiomers. The use of their individual isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention. The Single enantiomers or diastereoisomers, as well as mixtures thereof, can be separated by conventional techniques.
  • prodrugs of the agonist compounds of the invention include any compound derived from an agonist compound of the invention, for example, esters, including carboxylic acid esters, amino acid esters, phosphate esters, metal salt sulphonate esters, etc. ., carbamates, amides, etc., which, when administered to an individual, is capable of providing, directly or indirectly, said agonist compound of the invention in said individual.
  • said derivative is a compound that increases the bioavailability of the agonist compound when administered to an individual or that enhances the release thereof in a biological compartment.
  • the preparation of said prodrug can be carried out by conventional methods known to those skilled in the art.
  • tumor diseases refers to pathologies created by the growth of human or animal tumor cells, and more specifically we refer to, by way of illustration and without limiting the scope of the invention, to melanoma, breast cancer, lung cancer, prostate cancer, central nervous system cancer and sarcoma.
  • another particular object of the present invention is the use of a compound of the invention in the preparation of drugs or pharmaceutical compositions for the prevention and / or treatment of human tumor diseases belonging, by way of illustration and without limiting the scope of the invention, at Next group: melanoma, breast cancer, lung cancer, prostate cancer, central nervous system cancer and sarcoma.
  • Another object of the present invention is a pharmaceutical composition, hereinafter pharmaceutical composition of the present invention, which comprises a therapeutically effective amount of a compound or agonist agent of the delta opioid receptor, together with, optionally, one or more adjuvants and / or pharmaceutically acceptable vehicles.
  • Said therapeutic composition is particularly useful against human and animal tumor cells.
  • Another particular object of the present invention is the pharmaceutical composition of the invention in which the agonist compound belongs to the following group, whether peptide structure or not: diarylmethylpiperazine compounds, TAN-67, tetracyclic derivatives of pyridine and pyrazine, pyrrolooctahydroisoquinolones , compound BW373U86, compound SNC 80, DPDPE, deltorfina I and II, biphalin, the DADLE peptide and methadone.
  • the agonist compound belongs to the following group, whether peptide structure or not: diarylmethylpiperazine compounds, TAN-67, tetracyclic derivatives of pyridine and pyrazine, pyrrolooctahydroisoquinolones , compound BW373U86, compound SNC 80, DPDPE, deltorfina I and II, biphalin, the DADLE peptide and methadone.
  • composition of the invention in which the compound is the D-Pen-D-Pen-encephalin agonist (DPDPE).
  • DPDPE D-Pen-D-Pen-encephalin agonist
  • pharmaceutically acceptable carrier refers to those substances, or combination of substances, known in the pharmaceutical sector, used in the preparation of pharmaceutical forms of administration and includes adjuvants, solids or liquids, solvents , surfactants, etc.
  • said pharmaceutical composition may also contain one or more therapeutic agents that, if necessary, enhance the therapeutic action of said agonist compound or that increase its spectrum of action.
  • Said pharmaceutical composition can be used to prevent and / or treat human or animal tumor diseases.
  • the agonist compound will be present in the pharmaceutical composition in a therapeutically effective amount, that is, in an amount appropriate to exert its therapeutic effect.
  • the pharmaceutical composition provided by this invention contains between 0.01% and 99.99% by weight of an agonist compound and mixtures thereof, and can be presented in any pharmaceutical form of appropriate administration depending on the route of chosen administration, for example, oral, parenteral or topical.
  • Another object of the present invention is the use of the pharmaceutical composition of the invention in the treatment of a mammal, preferably a human being, affected by a tumor disease, hereinafter use of the pharmaceutical composition of the present invention, consisting of the administration of said therapeutic composition that reduces tumor progression, for example, migration, extravasation and settlement of tumor cells in locations other than the original (metastasis).
  • the use of the pharmaceutical composition of the invention can therefore be useful for the treatment of patients with different types of cancer, by way of illustration and without limiting the scope of the invention, melanoma, cancer. breast, lung cancer, prostate cancer, central nervous system cancer and sarcoma.
  • the invention provides a method for preventing and / or treating tumor diseases in humans comprising the step of administering to a human being, in need of treatment, a therapeutically effective amount of a pharmaceutical composition provided by this invention.
  • the present invention considers the use of certain opioid drugs not only as analgesics but also as anti-tumor agents, due to cross-modulation by the opioid receptor delta agonists on the CXCL12-CXCR4 transduction cascade that is involved in the tumor progression and generation of metastases.
  • FIG. 1 Representative immunochemical staining of CXCR4 and delta opioid receptor in Bl6 cells of murine melanoma. The cells were permeabilized, fixed and stained as described in materials and methods with anti-CXCR4 antibodies or delta opioid receptor. As a staining control, the cells were incubated with a secondary anti-rabbit antibody labeled with FITC or with a secondary anti-mouse antibody labeled with FITC. The expression of the receptors can be visualized in images B (expression of CXCR4) and D (expression of DOR), while A and C represent the control cells.
  • Figure 2. Desensitization of CXCR4 by DPDPE. Cells were activated with forscolin and ligands as described in materials and methods.
  • Figure 5 Effect of DPDPE on the adhesion and migration of B16 cells.
  • the graph shows the number of metastatic points present on the surface of the lungs in C57 / BL6 mice treated or not with DPDPE 7 days after inoculation of tumor cells. Compared to controls, a reduction of more than 50% is observed in animals treated with DPDPE. The experiment was repeated 3 times with 7 to 10 mice per group.
  • Example 1 Effect of the opioid DPDPE agonist on the CXCR4-CXCL12 receptor-ligand pair.
  • mice melanoma B16 cells expressed the DPDPE and CXCR4 agonist receptors (inumnochemical marking).
  • Mouse B16 melanoma cells (American collection of ATTC type cultures No. CRL-6475; Manassas, VA) were grown in modified Dulbecco-Eagle medium (Sigma, St. Louis, MO), supplemented with 10% inactivated fetal bovine serum by heat (FBS), penicillin and streptomycin.
  • Anti-CXCR4 monoclonal antibodies have been obtained previously by the same inventors (ViIa-Coro, A. J. et al.
  • B16 cells were seeded in wells with adhered fibronectin, fixed with 4% paraformalde hybrid (15 minutes at room temperature), permeabilized with 0.01% Triton XlOO (5 minutes), washed three times with PBS- 0.01% Tween, and blocked with PBS-BSA (1 hour at room temperature). Then, they were incubated with anti-CXCR4 antibody (1:50) or with anti-delta opioid receptor antibody (1: 100), together with the second FITC-anti-mouse antibody (1: 200) or with FITC-anti-conej or (1: 100), respectively. The cells were washed and receptor expression was evaluated by confocal fluorescence microscopy. The results obtained confirmed, in effect, that both receptors are expressed in B16 melanoma cells ( Figure 1).
  • B16 cells were incubated with 10 mM forscolin (3 minutes at 37 ° C) to increase cAMP production; subsequently they were stimulated with the CXCL12 agonists
  • CAMP levels were determined with the AMPc Direct Immunoassay Kit commercial package (Calbiochem, Darmstadt, Germany). In the presence of DPDPE cAMP levels were similar to those that existed in unstimulated cells, from which it is concluded that DPDPE desensitizes CXCR4 ( Figure 2).
  • a surface binding assay was carried out on B16 cells, and more specifically on intact cells to mark only the receptors present on the cell surface.
  • the cells 500,000 cells / well
  • DPDPE 10 ⁇ 5 M
  • the temperature was maintained at 4 ° C.
  • the cells were then treated with 125 I CXCL12 0.15 nM (2000 Ci / mmol; Amersham Pharmacia) for 2 hours at 4 ° C with gentle shaking.
  • Non-specific binding was evaluated by incubating the cells together with unlabeled CXCL12 (500 nM) in the binding medium.
  • Example 2. Effect of DPDPE on different parameters indicative of tumor progression.
  • Non-adhered cells were removed by gentle washing with PBS; Cell adhesion was determined with a luminometer as described by other authors (Chen, C. et al. 2004). The luminescence is directly proportional to the number of cells per well.
  • the cells were seeded on plates coated with CXCL12 / fibronectin in the presence or absence of DPDPE, it being observed that the level of cell adhesion was reduced in the presence of DPDPE and at a dose dependent level ( Figure 5a ).
  • Migration tests were performed in matrigel invasion chambers (BD, Biocat, San Jose, CA) in triplicate.
  • B16 cells (10 5 cells / 100 ⁇ l) were added to the upper chamber compartment and ligands were added to the lower chamber to promote cell migration through the matrigel. The plates were incubated at 37 ° C for 22 hours. Cells that did not migrate were removed from the top of the matrigel with a cotton swab. After the migration test, the matrigel was digested 15 minutes at 37 ° C and the emigrating cells were counted after the complete digestion of the matrigel by flow cytometry (Bartolomé, RA et al, 2004). As expected, CXCL12 induced the migration of B16 cells. However, in the presence of concentrations of 10 ⁇ 5 to 10 ⁇ 3 of DPDPE, migration induced by CXCL12 was inhibited in a dose-dependent manner by DPDPE ( Figure 5b).
  • the inventors also analyzed the effect of DPDPE on the in vivo bearing of B16 melanoma cells, first Critical step of adhesion of blood cells to the walls of the vascular endothelium.
  • the high expression of CXCL12 in organs such as liver and lung could explain the high frequency of metastases in those organs (seed-soil hypothesis).
  • the interaction of melanoma B16 cells with the microvasculature of the ear in the presence or absence of the DPDPE agonist was studied by intravital microscopy (Ludwig, RJ 2004).
  • the mouse was anesthetized by intraperitoneal injection of ketamine (Schwabe-Curamed, Düsseldorf, Germany) and xylazine (Rompun, Bayer, Leverkusen, Germany), and placed in a homothermal blanket.
  • the right common carotid artery was prepared for microsurgery; a catheter was inserted for retrograde injection of the cells.
  • the left ear of the mouse which received 50 ⁇ l of 1.25 ⁇ M of CXCL12, was gently placed between a microscope and a support.
  • Vascular architecture and fluorescently labeled cells (10 ⁇ M CFDA-SE, Molecular Probes, Eugene, OR) were visualized during their passage through the vessels under fluorescent epi-illumination using a multiband filter system (XF 53, Omega Optical, Brattleboro, VT).
  • B16 melanoma cells were injected into the mouse tail vein (10 5 cells / mouse C57BL / 6 and 10 4 cells / mouse CB17 SCID in a volume of 250 ⁇ l). From day 1 to day 3, the mice received a daily intraperitoneal injection of DPDPE (10 ⁇ 4 M; 500 ⁇ l); Control animals were treated with PBS. The first DPDPE injection was applied just before the injection of the cells. The doses of DPDPE used were those established to promote mouse analgesia (Heyman, J. S et al, 1987).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention est basée sur l'effet bloquant de l'agoniste DPDPE sur la cascade de signalisation intramoléculaire, initiée par la paire CXCL12-CXCR4, qui induit la progression tumorale et la formation de métastases. Selon l'invention, le traitement à l'aide de DPDPE in vivo réduit les métastases sur des modèles animaux, au moyen d'un mécanisme qui n'implique pas de réponse immunitaire.
PCT/ES2007/070074 2006-04-12 2007-04-12 Utilisation d'agonistes du récepteur opioïde delta dans l'élaboration de compositions pharmaceutiques qui les contiennent et leurs applications dans le traitement des tumeurs WO2007116114A1 (fr)

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ES200600960A ES2283220B1 (es) 2006-04-12 2006-04-12 Uso de agonistas del receptor opioide delta en la elaboracion de composiciones farmaceuticas, composiciones farmaceuticas que las contienen y sus aplicaciones en el tratamiento de tumores.
ESP200600960 2006-04-12

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019197015A1 (fr) * 2018-04-09 2019-10-17 Peter Truog Composition comprenant des dérivés d'acide 4-phénylbutyrique et des opioïdes

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WO2004004715A2 (fr) * 2002-07-09 2004-01-15 Glaxosmithkline Spa Nouveau procede et composes associes
WO2004041800A1 (fr) * 2002-11-07 2004-05-21 Astrazeneca Ab Derives de 4(phenyl-piperazinyl-methyl) benzamide et leur utilisation pour le traitement de douleur ou de troubles gastro-intestinaux

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WO1999004795A1 (fr) * 1997-07-23 1999-02-04 Toray Industries, Inc. Agoniste du recepteur morphinique delta permettant de lutter contre les lesions ischemiques
WO2003094853A2 (fr) * 2002-05-09 2003-11-20 Ardent Pharmaceuticals, Inc. Compositions et methodes de traitement de dysfonctionnements des voies urinaires basses au moyen d'agonistes du recepteur opioide delta
WO2004004715A2 (fr) * 2002-07-09 2004-01-15 Glaxosmithkline Spa Nouveau procede et composes associes
WO2004041800A1 (fr) * 2002-11-07 2004-05-21 Astrazeneca Ab Derives de 4(phenyl-piperazinyl-methyl) benzamide et leur utilisation pour le traitement de douleur ou de troubles gastro-intestinaux

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HATZOGLOU A. ET AL.: "The antiproliferative effect of opioid receptor agonists on the T47D human breast cancer cell line, is partially mediated through opioid receptors", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 296, 1996, pages 199 - 207 *
KNAPP R.J. ET AL.: "Properties of TAN-67, a nonpeptidic d-opioid receptor agonist, at cloned human d- and u-opioid receptors", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 291, 1995, pages 129 - 134, XP004553483 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019197015A1 (fr) * 2018-04-09 2019-10-17 Peter Truog Composition comprenant des dérivés d'acide 4-phénylbutyrique et des opioïdes

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