EP1420772A2 - Verwendung von beta-adrenozeptor-agonisten zur behandlung von neurodegenerativen erkrankungen - Google Patents

Verwendung von beta-adrenozeptor-agonisten zur behandlung von neurodegenerativen erkrankungen

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Publication number
EP1420772A2
EP1420772A2 EP02797607A EP02797607A EP1420772A2 EP 1420772 A2 EP1420772 A2 EP 1420772A2 EP 02797607 A EP02797607 A EP 02797607A EP 02797607 A EP02797607 A EP 02797607A EP 1420772 A2 EP1420772 A2 EP 1420772A2
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EP
European Patent Office
Prior art keywords
encephalopathy
use according
cells
disease
day
Prior art date
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Application number
EP02797607A
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German (de)
English (en)
French (fr)
Inventor
Josef Krieglstein
Carsten Culmsee
Vera Junker
Helmut Blum
Wolfgang Greb
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.)
EUCRO European Contract Research GmbH and Co KG
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EUCRO European Contract Research GmbH and Co KG
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
Priority claimed from DE10142175A external-priority patent/DE10142175A1/de
Priority claimed from DE10142176A external-priority patent/DE10142176A1/de
Priority claimed from DE10142178A external-priority patent/DE10142178A1/de
Priority claimed from DE10149611A external-priority patent/DE10149611A1/de
Application filed by EUCRO European Contract Research GmbH and Co KG filed Critical EUCRO European Contract Research GmbH and Co KG
Publication of EP1420772A2 publication Critical patent/EP1420772A2/de
Withdrawn legal-status Critical Current

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    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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Definitions

  • ß-adrenoceptor agonists for the treatment of neurodegenerative diseases
  • the present invention relates to the use of ⁇ -adrenoceptor agonists for the treatment of neurodegenerative diseases.
  • the brain is the central organ of the conscious and unconscious processing of the stimuli acting on the human body, of thinking and feeling, of purposeful action, learning and memory.
  • One of the most important services of the human brain is information processing in speech; also the control center for a large number of organ functions as well as breathing, heart rate and temperature control.
  • Examples of such clinical pictures are Alzheimer's disease, cerebrovascular dementias,
  • Parkinson's disease Pick's disease, Huntington's chorus, amyotrophic lateral sclerosis, Lewy
  • Body dementia stroke and brain trauma, such as contusio and commotio cerebri as well as brain and spinal cord injuries or cross-sectional injuries, spina bifida, as well as diseases of the inner ear, for example diseases associated with the occurrence of tinnitus, such as subacute or chronic tinitus, hearing loss, Crohn's
  • the goal of causal therapy is to prevent the destruction of nerve cells.
  • the object of the present invention was to find drugs which protect nerve cells from damage and which can at least partially restore the function of partially or completely degenerated cells.
  • the present invention accordingly relates to the use of ⁇ -adrenergic agonists for restoring and / or maintaining the function of partially or completely damaged cells of the central nervous system and / or other nerve cells.
  • damaged cell means that the cell has been damaged by external influences or is partially or completely destroyed in the sense of degeneration by processes taking place in the cell, which can be associated with an impairment of bodily functions.
  • the expression “damage to the cell” includes both the damage to individual cells or cell types and the damage to the strands or pathways of nerve cells.
  • the nerve cells also include the cells of the spinal cord and all other nerve cells in the body.
  • ⁇ -adrenoceptors respond in particular to adrenergic drugs.
  • ⁇ -adrenergic agonists which are preferably used in the present invention because of their good activity are clenbuterol, formoterol, fenoterol, salbutamol, orciprenaline, isoetharine, cimaterol, ractopamine, reproterol, salmeterol, terbutaline, their isomers, acid addition salts, Analogues and any mixtures of the above.
  • ⁇ -adrenergic agonists mentioned above are in part known medicinal substances.
  • clenbuterol is known from the prior art as a branch agent.
  • the lipophilic ß-adrenoceptor agonists can permeate into the brain and stimulate the ß-adrenoceptors of the astrocytes there.
  • the stimulation of these receptors in turn leads to activation of the astrocytes and, as a result, to an increased release of growth factors, such as NGF, which can protect nerve cells from damage.
  • the beta-adrenoceptor agonists are administered for therapy in the amounts customary for these medicaments, in particular in an amount of 0.01 to 100 mg / day, preferred ranges of amounts also being able to depend on the particular beta-adrenoceptor agonist.
  • substances such as clenbuterol, formoterol, fenoterol and salmeterol, a particularly good neuroprotective effect is obtained if they are administered in an amount of 0.01 to 5 mg / day.
  • Terbutaline is preferably applied in an amount of 1.0 to 30 mg / day, salbutamol in an amount of 1.0 to 50 mg / day, and orciprenaline and reproterol in an amount of 1.0 to 100 mg / day.
  • ⁇ 1-adrenoceptor agonists such as Dobuta in
  • the ⁇ -adrenoceptor agonists used according to the invention are used in combination with the ⁇ 1 and / or ⁇ 2 adrenoceptor agonists.
  • the ⁇ -adrenergic agonists are used in combination with NMDA antagonists, as a result of which a supplementary or further principle of action is used.
  • the NMDA antagonists e.g. the adamantane derivatives are known compounds which are often used for the treatment of various diseases.
  • the dopaminergic influence of amantadine (1-adamantanamine) is known.
  • European patent application EP-392 059 describes the use of adamantane derivatives for the prevention and treatment of cerebral ischemia. According to this publication, the use of the adamantane derivatives prevents the destruction of brain cells after ischemia by using the adamantane derivatives as antagonists for the NMDA receptor channels of the nerve cells in the brain.
  • R 1 and R 2 are the same or different and represent hydrogen or a straight-chain or branched CC 6 alkyl group or together with the N atom can represent a heterocyclic group with 5 or 6 ring atoms
  • R 3 and R 4 are the same or different are and represent hydrogen, a straight-chain or branched CC 6 alkyl group or a C 5 -C 6 cycloalkyl group or a vinyl group
  • R 1 and R 2 are the same or different and represent hydrogen or a straight-chain or branched CC 6 alkyl group or together with the N atom can represent a heterocyclic group with 5 or 6 ring atoms
  • R 3 and R 4 are the same or different are and represent hydrogen, a straight-chain or branched CC 6 alkyl group or a C 5 -C 6 cycloalkyl group or a vinyl group
  • R 5 represents hydrogen or a straight-chain or branched CrCe alkyl group.
  • adamantane derivatives with the formula I can be used in the form of the compounds described by the formula I or in the form of their pharmaceutically acceptable salts.
  • Preferred pharmaceutically acceptable salts include the acid addition salts, such as the hydrochlorides, hydrobromides, sulfates, acetates, succinates, tartrates, the hydrochlorides being preferred.
  • Preferred compounds with the formula I are those in which R 1 , R 2 and R 4 are hydrogen and R 3 and R 5 are a methyl and / or ethyl group.
  • R 1 , R 2 and R 4 are hydrogen and R 3 and R 5 are a methyl radical, or their hydrochloride. This connection is known as the INN Memantine.
  • the ß-adrenoceptor agonists used according to the invention and, if appropriate, other customary medicinal substances which do not negatively influence or support the therapy and usual ingredients, can be present in pharmaceutical dosage forms, in particular as a solution, suspension, emulsion, tablets, suppository, etc. it can be used in special formulations such as liposomes, nanosomes, slow-release pellets, etc.
  • the mode of administration is preferably selected such that the impaired cells can be reached as quickly as possible by the drug according to the invention.
  • the ⁇ -adrenoceptor agonists used according to the invention are particularly suitable for the production of medicaments for the treatment of neurodegenerative diseases.
  • diseases are Alzheimer's disease, cerebrovascular dementias, Parkinson's disease, Pick's disease, Huntington's chorea, amyotrophic lateral sclerosis, Lewy-body dementia, stroke and brain trauma such as contusion and cerebral sprain, as well as brain and spinal cord injuries or cross-sectional injuries, spina bifida , as well as diseases of the inner ear, for example diseases that are associated with the occurrence of tinnitus, such as subacute or chronic tinitus, sudden hearing loss, Meniere's disease, and diseases that are associated with impaired hearing or impaired vision, etc.
  • the ⁇ -adrenergic agonists are used to restore and / or maintain the function of cells of the central nervous system and / or other nerve cells which have been partially or completely damaged by encephalopathy.
  • Encephalopathy is one of the pathological non-inflammatory brain changes with variable neurological and / or psychological symptoms.
  • encephalopathies that can be treated according to the invention with ⁇ -adrenergic agonists are toxic encephalopathy, encephalopathia diabetica, encephalopathia hepatica, encephalopathia hypertensive, metabolic encephalopathy, such as encephalopathy caused by metabolic disorders, eg endogenous, renal encephalopathy, eg in case of enzyme disorders, enzymatic disorders, endogenous enzymes Liver diseases, disturbances in the water-electrolyte or acid-base balance, myclonic infantile encephalopathy (Kinsboorne syndrome), encephalopathia postictereca infantum (bilirubin encephalopathy), post-combinatory encephalopathy, encephalopathy caused by heavy metals, especially organic compounds, such as inorganic and organic compounds, especially from inorganic and organic compounds, especially from inorganic and organic compounds, especially from inorganic and organic compounds , especially from inorganic and organic compounds , Mercury and
  • the compounds used according to the invention are used as additive (s) for culture media to promote the growth and / or differentiation and / or protection of mammalian cells and human cells.
  • astrocytes Primary cultures of astrocytes were obtained from the cerebral cortex tissue of newborn Fischer 344 rats within 24 hours after birth. The brains were dissected out of the skull cap under sterile conditions, the bark tissue (cortex) was isolated and the cells were dissociated by a close-meshed wire network. The cells were placed in cell culture bottles and cultured in serum-containing DMEM solution (containing fetal calf serum and a penicillin-streptomycin mixture) until the cells confluent. Oligodendrocytes and microglia were removed by washing with cold buffer solution.
  • serum-containing DMEM solution containing fetal calf serum and a penicillin-streptomycin mixture
  • the confluent astrocytes were then detached from the bottom of the culture flasks with a trypsin solution and sown at a density of 20,000 cells / cm 2 in petri dishes on coverslips and cultivated in serum-containing medium until the cells re-confluent.
  • the medium was changed with serum-free medium and after 24 hours another medium change, also with serum-free medium.
  • Twenty-four hours after the second medium change salmeterol was added.
  • the astrocytes were photographed in 200x microscopic magnification to document the morphological changes (Fig. 1/7). The figure shows the astrocytes 6 hours after the start of treatment.
  • the changes from the polygonal, flat and light-refractive cells in the controls compared to the activated, star-shaped and light-refracting astrocytes in the groups treated with salmeterol can be clearly seen.
  • the culture medium was collected four hours after the start of the Clenbuterol incubation.
  • the NGF content in the medium was determined using a standardized enzyme-linked immune reaction (ELISA).
  • ELISA enzyme-linked immune reaction
  • the chambers of a multiwell plate were coated with an NGF antibody and then incubated in the individual chambers with the medium of the different groups. The NGF thus bound in the chambers from the medium was then incubated with a beta-galactosidase : conjugated NGF antibody.
  • beta-galactosidase catalyzed conversion of chlorophenol red beta-galactopyranoside to a red dye which was measured photometrically.
  • standard dilutions of NGF were also measured to create a standard curve. The NGF content in the samples was determined using the standard curve (Fig. 2/7).
  • the medium was changed and the cells were incubated for 1 hour with L-glutamate (1mM) in serum-free medium. The medium was then changed again with serum-free medium in order to remove the glutamate from the cultures. Propranolol and clenbuterol were added freshly with each change of medium and were thus present in the medium during the glutamate treatment and up to 18 hours afterwards. Eighteen hours after the damage to glutamate, the cells were incubated with a trypan blue solution, fixed, and the damaged, blue-stained neurons were quantified under 200 ⁇ microscopic magnification (Fig. 3/7).
  • the body temperature of the rats was regulated to 37 + 0.5 ° C during the operation and kept stable for 2 hours after the procedure with the help of a heat lamp at an ambient temperature of 30 ° C.
  • Physiological parameters blood pressure, plasma glucose level, arterial pH, CO 2 and O 2 partial pressures
  • coronal sections (20 ⁇ M) of the brains were made at defined intervals of 0.5 mm. The brain sections were then stained with cresyl violet, whereby the area of the infarct showed only a weak color and could thus be distinguished from the healthy tissue.
  • Salmeterol was added fresh each time the medium was changed and was thus present in the medium during the glutamate treatment and up to 18 hours afterwards. Eighteen hours after the damage to glutamate, the cells were incubated with a trypan blue solution, fixed, and the damaged, blue-stained neurons were quantified under a 200-fold microscopic magnification (Fig. 5/7). The values given are mean values and standard deviation from 5-6 cultures per group. * P ⁇ 0.05; ** p ⁇ 0.01; and * * * * p ⁇ 0.001 compared to the control treated with glutamate (analysis of variance, Scheffe test). 6) Neuroprotective effect of salmeterol in vivo
  • Focal cerebral ischemia of the mouse was produced by ligating the cerebral artery.
  • Male NMRI mice (26-31 g, 10-12 animals per group) were used for the experiments.
  • the animals were anesthetized by an intraperitoneal injection of tribromoethanol (600 mg / kg).
  • the surgical field was then opened through a 2 cm incision between the left eye and ear, the temporalis muscle was removed with a thermocauter and the bone was removed with a fine bur to expose the cerebral artery.
  • This artery and its two distal branches were permanently occluded.
  • the body temperature of the mouse was measured and kept constant at 37 +/- 1 ° C by an infrared heat lamp.
  • mice were anesthetized again with tribromoethanol 48 hours after occlusion of the cerebral artery and perfused with a 1.5% neutral red solution (0.5 ml intraperitoneally). As a result, the perfused brain tissue turned red and the infarcted area remained bright.
  • the isolated brains were fixed with 4% formaldehyde buffer (pH 7.4) for at least 24 hours and then the unstained area on the brain surface (infarct area) became a computer -supported (NIH image software) measured.
  • the salmeterol dissolved in 0.9% NaCI was injected interperitoneally 5 hours before the operation.
  • the animals in the control group received only 0.9% NaCI solution (Fig. 6/7). The values are mean values and standard deviation of 15-16 animals per group. * p ⁇ 0.05 compared to the control (analysis of variance, Duncan's test)
  • the body temperature of the mouse was measured and kept constant at 37 +/- 1 ° C by an infrared heat lamp. After the preparation, the animals were left for an additional two hours at an ambient temperature of 30 ° C. To determine the infarct area, the mice were again treated with tribromoethanol 48 hours after occlusion of the cerebral artery anesthetized and perfused with a 1.5% neutral red solution (0.5 ml intraperitoneally). As a result, the perfused brain tissue turned red and the infarcted area remained bright.
  • the isolated brains were fixed with 4% formaldehyde buffer (pH 7.4) for at least 24 hours and then the unstained area on the brain surface (infarct area) became a computer -supported (NIH image software) measured.
  • the two pharmaceuticals to be investigated Memantine and Clenbuterol, were dissolved in 0.9% NaCl for injection. Memantine (20 mg / kg) was injected interperitoneally 30 minutes before surgery and clenbuterol 2 hours after surgery. The animals in the control group received only 0.9% NaCI solution (Fig. 7/7).

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EP02797607A 2001-08-29 2002-08-22 Verwendung von beta-adrenozeptor-agonisten zur behandlung von neurodegenerativen erkrankungen Withdrawn EP1420772A2 (de)

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
DE10142175A DE10142175A1 (de) 2001-10-09 2001-08-29 Verwendung von ß-Adrenozeptor-Agonisten zur Behandlung von neurodegenerativen Erkrankungen
DE10142176A DE10142176A1 (de) 2001-08-29 2001-08-29 Verwendung einer Kombination aus ß-adrenergen Agonisten und NDMA-Antagonisten
DE10142175 2001-08-29
DE10142178 2001-08-29
DE10142178A DE10142178A1 (de) 2001-08-29 2001-08-29 Verwendung von Clenbuterol zur Behandlung von neurodegenerativen Erkrankungen
DE10142176 2001-08-29
DE10149611A DE10149611A1 (de) 2001-08-29 2001-10-09 Verwendung von ß-Adrenozeptor Agonisten zur Behandlung von neurodegenerativen Erkrankungen
DE10149611 2001-10-09
PCT/EP2002/009369 WO2003020257A2 (de) 2001-08-29 2002-08-22 VERWENDUNG VON β-ADRENOZEPTOR-AGONISTEN ZUR BEHANDLUNG VON NEURODEGENERATIVEN ERKRANKUNGEN

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GB0519274D0 (en) * 2005-09-21 2005-11-02 Arakis Ltd The treatment of neurodegenerative diseases
CA2645678A1 (en) * 2006-03-16 2007-09-20 Yeda Research And Development Co. Ltd. Method and composition for protecting neuronal tissue from damage induced by elevated glutamate levels
CN101915841B (zh) * 2010-07-26 2013-01-02 河南省科学院生物研究所有限责任公司 β-兴奋剂沙丁胺醇、盐酸克伦特罗、莱克多巴胺三元检测测试条制备方法
US9265735B2 (en) 2010-11-30 2016-02-23 New York University Methods for screening to identify therapeutic agents for Alzheimer's disease and use thereof
US20140249180A1 (en) * 2011-10-03 2014-09-04 National Center For Geriatrics And Gerontology Tau aggregation inhibitor
JP6313750B2 (ja) 2013-04-02 2018-04-18 学校法人同志社 タウ凝集阻害剤
CN115531368A (zh) * 2021-06-14 2022-12-30 谭文 R-氨基甲酸酯-β-苯乙醇胺类化合物治疗学习和记忆缺陷以及神经退行性疾病的应用
CN116236467B (zh) * 2023-02-07 2023-10-27 中国人民解放军总医院 西马特罗或其衍生物的新用途

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