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WO2007048846A1 - Utilisation de composes chelateurs du fer, composes augmentant l'adenosine monophosphate cyclique ou combinaisons de ces substances pour traiter des lesions axonales dans le systeme nerveux central - Google Patents

Utilisation de composes chelateurs du fer, composes augmentant l'adenosine monophosphate cyclique ou combinaisons de ces substances pour traiter des lesions axonales dans le systeme nerveux central Download PDF

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Publication number
WO2007048846A1
WO2007048846A1 PCT/EP2006/067878 EP2006067878W WO2007048846A1 WO 2007048846 A1 WO2007048846 A1 WO 2007048846A1 EP 2006067878 W EP2006067878 W EP 2006067878W WO 2007048846 A1 WO2007048846 A1 WO 2007048846A1
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Prior art keywords
use according
compounds
iron
casev
lesion
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PCT/EP2006/067878
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German (de)
English (en)
Inventor
Hans Werner Müller
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Neuraxo Biopharmaceuticals Gmbh
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Publication of WO2007048846A1 publication Critical patent/WO2007048846A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to the use of cell implants and / or at least one pharmaceutically acceptable compound for
  • the technical problem underlying the invention was the increase in the likelihood of near complete axon regeneration following injury trauma.
  • the problem underlying the invention is solved by the
  • Iron chelators are typically compounds that can interact with iron in coordinative interactions. In particular, lone pairs of electrons in the compounds are used for this purpose.
  • the use according to the invention protects the otherwise declining by apoptotic processes neurons and thus increases the probability Near-complete axon regeneration because only living neurons can regenerate their axon.
  • axonal lesions can be treated which are caused by traumatic effects, in particular by pinching and / or severing of axons, and / or inflammatory processes, in particular those occurring in the course of neuro-degenerative processes.
  • iron chelating compound N-oxaloglycine; Zn salts; Pyridine derivatives, such as 5-Arylcarbonylamino- or 5-Arylcarbamoylderivate, 2-carboxylate, 2,5 dicarboxylates, their ethyl esters or
  • compounds which promote axon growth can be used those which are neuronal growth and / or the expression of growth-promoting proteins such as neurotrophic factors, fibroblast growth factors, chemokines such as SDF-I, neural cells
  • Adhesion molecules such as Ll (NILE) stimulate growth-associated proteins such as GAP43 and anti-apoptotic proteins such as bcl-2.
  • According to the invention can be used as inhibitors of the intracellular Rho signal pathway z.
  • Activated macrophages Activated macrophages, OEC (olfactory ensheathing cells), adult or embryonic stem cells.
  • the application of the substance (s) to be used according to the invention is typically carried out locally in the injury or damage region in the nervous system, in the case of the soluble substances, in particular also by delayed release.
  • the iron chelating compound and / or CASEV and / or axon growth promoting compounds and / or inhibitors of the intracellular Rho signaling pathway are administered in therapeutically effective amounts, such as 1 ng / kg to 1 mg / kg body weight.
  • therapeutically effective amounts such as 1 ng / kg to 1 mg / kg body weight.
  • FIG. 1 shows a retrograde fluoro-gold marker of pyramidal neurons in the sensorimotor cortex of the rat brain.
  • FIG. 2 shows the neuroprotective long-term effect on primary motor neurons in the rat brain by local application of the iron chelator BPY-DCA and / or cAMP (8Br-cAMP) in the injured spinal cord.
  • Cerebral sections Hydroxystilbamidine (FluoroGold) is a suitable axonal tracer for the retrograde labeling of primary motor neurons in the sensorimotor cortex of the rat.
  • Th7 Th7 injected into the spinal cord.
  • FIG. 1 shows the retrograde fluoro gold labeling of pyramidal neurons in a section preparation (20 ⁇ m) from the sensorimotor cortex (layer V) of the rat brain (sham control).
  • PFA Paraformaldehyde
  • Retrograde axonal tracing of cerebral projection neurons under different treatment conditions after spinal cord injury Retrograde axonal tracing of cerebral projection neurons under different treatment conditions after spinal cord injury.
  • Testparameter Presentation of surviving cortical neurons by retrograde
  • Lesion type wire-knife lesion of the spinal cord at the height of the thoracic segment Th8 Animal groups: sham, lesion without treatment (control with injection of a buffer solution), lesion with RPT treatment Time points: 1 week, 4 weeks Tracer: FluoroGold (retrograde) Standard ("Scouten" wire knife) lesion
  • Animal groups (a) sham, (b) buffer lesion control, (c) lesion with iron chelator (BPY-DCA), (d) lesion with cAMP (8Br-cAMP) and (e) lesion with iron chelator plus cAMP (RPT).
  • BPY-DCA lesion with iron chelator
  • cAMP lesion with cAMP
  • RPT lesion with iron chelator plus cAMP
  • Coronal sections were obtained over the coordinate range of Bregma +0.9 to -2.1. Each 10th scan was photographed by fluorescence microscopic observation and retrograde labeled cortical neurons were counted in both hemispheres. 16 Sections (32 hemispheres) of 3 animals per test condition were counted and statistically evaluated (see evaluation in the annex).
  • FIG. 2 shows, by way of example, the different densities of retrogradely marked pyramidal neurons in the sensorimotor cortex in the intact animal
  • FIG. 2A sham control
  • FIG. 2B lesion control
  • FIG. 2C Local application of BPY-DCA and / or 8Br-cAMP to the spinal cord has a neuroprotective effect on cortical pyramidal neurons of layer V in the sensorimotor cortex
  • the lesion control with Tris buffer shows a clearly recognizable decrease of labeled pyramidal neurons in layer V four weeks after spinal cord injury
  • the retrograde labeling of the cortical pyramidal neurones in cell layer V with fluoro gold gives a very reliable, defined, homogeneous and highly reproducible marking of the sensorimotor brain region in all the animals examined.
  • the brain area of the retrograde labeled neurons extends over approximately 4.4 mm in rostrocaudaler Alignment and is distributed symmetrically over both Hemispheren.
  • the marked cell layer appears as a strip with a height of approx. 0.5 mm and a medio-lateral width of 0.8 to 2 mm, depending on the rostrocaudal distance from the bregma.
  • the lesion-related cell losses are after 4 weeks in one

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  • Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne l'utilisation de greffes cellulaires et/ou d'au moins un composé pharmaceutiquement acceptable sélectionné dans le groupe comprenant des chélateurs du fer, des composés augmentant le niveau d'adénosine monophosphate cyclique (CASEV), des composés promoteurs de la croissance axonale, des inhibiteurs de la voie de signalisation intracellulaire Rho ou des combinaisons de ces substances, pour produire un médicament destiné à protéger de la disparition des neurones atteints de lésions axonales dans le système nerveux central.
PCT/EP2006/067878 2005-10-27 2006-10-27 Utilisation de composes chelateurs du fer, composes augmentant l'adenosine monophosphate cyclique ou combinaisons de ces substances pour traiter des lesions axonales dans le systeme nerveux central WO2007048846A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
EP05110090.7 2005-10-27
EP05110090 2005-10-27
EP06110266 2006-02-22
EP06110266.1 2006-02-22
US78304206P 2006-03-17 2006-03-17
US60/783,042 2006-03-17

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5563048A (en) * 1993-10-14 1996-10-08 Ono Pharmaceutical Co., Ltd. Human stromal derived factor 1α and 1β, and DNAs encoding the same
EP0878480A1 (fr) * 1997-05-14 1998-11-18 H.W. Prof. Dr. Müller Procédé pour ameliorer la régénération nerveuse
WO1999029279A2 (fr) * 1997-12-05 1999-06-17 The Board Of Trustees Of The Leland Stanford Junior University Survie a long terme et regeneration de neurones du systeme nerveux central
WO2000074664A2 (fr) * 1999-06-07 2000-12-14 Yeda Research And Development Co. Ltd. Compositions pharmaceutiques comprenant des agents chelateurs de fer destinees au traitement de troubles neurodegeneratifs et nouveaux agents chelateurs de fer
WO2001072326A1 (fr) * 2000-03-31 2001-10-04 Smithkline Beecham Plc Utilisation d'agonistes des recepteurs de crf pour le traitement ou la prevention de maladies, notamment de maladies neurodegeneratives
WO2002045749A2 (fr) * 2000-11-02 2002-06-13 Research Foundation Of City University Of New York Procedes de stimulation de la regeneration et de la reparation du systeme nerveux par inhibition de la phosphodiesterase de type 4
US20040047843A1 (en) * 2002-02-12 2004-03-11 Uab Research Foundation Method for spinal cord reconnection
WO2004033498A2 (fr) * 2002-10-10 2004-04-22 Centre National De La Recherche Scientifique-Cnrs- Composition pharmaceutique comprenant un recepteur 5-ht4d100a, et ses applications therapeutiques.
WO2005061458A2 (fr) * 2003-12-11 2005-07-07 Memory Pharmaceuticals Corporation Inhibiteurs de la phosphodiesterase 4, notamment analogues de diarylamines n-substituees

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5563048A (en) * 1993-10-14 1996-10-08 Ono Pharmaceutical Co., Ltd. Human stromal derived factor 1α and 1β, and DNAs encoding the same
EP0878480A1 (fr) * 1997-05-14 1998-11-18 H.W. Prof. Dr. Müller Procédé pour ameliorer la régénération nerveuse
WO1999029279A2 (fr) * 1997-12-05 1999-06-17 The Board Of Trustees Of The Leland Stanford Junior University Survie a long terme et regeneration de neurones du systeme nerveux central
WO2000074664A2 (fr) * 1999-06-07 2000-12-14 Yeda Research And Development Co. Ltd. Compositions pharmaceutiques comprenant des agents chelateurs de fer destinees au traitement de troubles neurodegeneratifs et nouveaux agents chelateurs de fer
WO2001072326A1 (fr) * 2000-03-31 2001-10-04 Smithkline Beecham Plc Utilisation d'agonistes des recepteurs de crf pour le traitement ou la prevention de maladies, notamment de maladies neurodegeneratives
WO2002045749A2 (fr) * 2000-11-02 2002-06-13 Research Foundation Of City University Of New York Procedes de stimulation de la regeneration et de la reparation du systeme nerveux par inhibition de la phosphodiesterase de type 4
US20040047843A1 (en) * 2002-02-12 2004-03-11 Uab Research Foundation Method for spinal cord reconnection
WO2004033498A2 (fr) * 2002-10-10 2004-04-22 Centre National De La Recherche Scientifique-Cnrs- Composition pharmaceutique comprenant un recepteur 5-ht4d100a, et ses applications therapeutiques.
WO2005061458A2 (fr) * 2003-12-11 2005-07-07 Memory Pharmaceuticals Corporation Inhibiteurs de la phosphodiesterase 4, notamment analogues de diarylamines n-substituees

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SAGOT Y ET AL: "BCL-2 OVEREXPRESSION PREVENTS MOTONEURON CELL BODY LOSS BUT NOT AXONAL DEGENERATION IN A MOUSE MODEL OF A NEURODEGENERATIVE DESEASE", JOURNAL OF NEUROSCIENCE, NEW YORK, NY, US, vol. 15, no. 11, November 1995 (1995-11-01), pages 7727 - 7733, XP002044575, ISSN: 0270-6474 *
SHIBATA M ET AL: "Single injections of a DNA plasmid that contains the human Bcl-2 gene prevent loss and atrophy of distinct neuronal populations after spinal cord injury in adult rats.", NEUROREHABILITATION AND NEURAL REPAIR 2000, vol. 14, no. 4, 2000, pages 319 - 330, XP009079165, ISSN: 1545-9683 *
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