WO2002085352A1 - Nmda-antagonisten und nmda-agonisten zur behandlung von suchterkrankungen - Google Patents
Nmda-antagonisten und nmda-agonisten zur behandlung von suchterkrankungen Download PDFInfo
- Publication number
- WO2002085352A1 WO2002085352A1 PCT/EP2002/004525 EP0204525W WO02085352A1 WO 2002085352 A1 WO2002085352 A1 WO 2002085352A1 EP 0204525 W EP0204525 W EP 0204525W WO 02085352 A1 WO02085352 A1 WO 02085352A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- treatment
- nmda
- alcohol
- addiction
- use according
- Prior art date
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Classifications
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/423—Oxazoles condensed with carbocyclic rings
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
Definitions
- the invention relates to the use of at least one NMDA antagonist for the manufacture of a medicament for the treatment of addictions.
- Addictions such as alcohol or opiate addiction, represent a major problem for both those affected and their social environment and for society.
- the costs of withdrawal therapy and illness-related absence from work result in a high level of economics.
- the complications that arise can be medicated, e.g. by administering benzodiazepines.
- the physical withdrawal is followed by a long-term therapy with which the patient before a relapse
- the alcohol addict needs ever larger doses of the drug to feel "normal" (see George F. Koob et al., Science 278, 1997, 52-58). These adaptations are retained even after physical detoxification.
- the patient shows behavioral patterns that are caused by the disruption of the brain's reward system. If the patient experiences a negative mood after the physical withdrawal, he feels a desire for alcohol as a reaction in order to compensate for the low mood through alcohol intake. In such situations, he is therefore at high risk of relapse.
- naltrexone which is used primarily in the United States
- acamprosate which contains calcium acetyl-homourinate as an active ingredient
- Naltrexone is an opioid receptor antagonist. Clinical studies have shown a lower relapse rate in patients who received naltrexone (O'Brian et al., Alcohol, 13, 1996, 35-39). Naltrexone is approved in the United States for the treatment of alcohol addiction.
- Acamprosate which contains calcium acetyl homotaurinate as an active ingredient.
- Acamprosate 0 is thought to work via the glutamatergic system, although the exact mechanism of action is unknown.
- Acamprosat reduces the post-synaptic effectiveness of excitatory amino acid neurotransmitters and neuronal excitation in the rat neocortex in vitro.
- Acamprosat 5 does not affect fluid or food intake. Furthermore, it does not increase the acute or chronic toxic effects of ethanol and shows no hypnotic, antidepressant, anxiolytic or muscle relaxant effects in animal experiments.
- acamprosate In clinical trials, the abstinence rate from Q administration of acamprosate was 35 and 33% after 6 and 12 months, respectively, compared to 25 and 21% in a control group that only received placebos. It is believed that acamprosate has an antagonistic effect on the activity of excitatory amino acids, in particular on the activity of glutamate towards NMDA receptors, and influences the flow of calcium ions 5 through voltage-controlled channels.
- An overview of the pharmacological and clinical potential of acamprosate in the treatment Treatment of alcohol addiction is given, for example, in Ml Wilde, AJ Wagstaff, Drugs, 53, 1997, 1038-1053.
- Active substance class fluoxetine, citalopram, fluvoxamine, however, only show a slight therapeutic effect, with sometimes low tolerance.
- Bromocriptine a dopamine agonist
- craving syndrome appears to be reduced in certain patient groups.
- ondansetron and ritanserin have little effect on the amount of alcohol consumed by addicts, so they only appear to be suitable for the therapy of patients with weak addiction symptoms.
- An overview of therapeutic uses of ondansetron is given by M. I. Wilde, A. Markham: Drugs, 52, 1996, 773-794.
- psychotropic substances such as desipramine were able to counteract a measurable extent of depression as a side effect of the withdrawal, whereby an improvement in the relapse rate compared to a placebo group was also observed over a period of 6 months.
- Buspirone a serotonin agonist
- Buspirone has been used to treat anxiety attacks that are associated with alcohol abuse. A significant reduction in anxiety and lower alcohol intake were observed compared to a group treated with placebos. Do the subjects not suffer After anxiety, buspirone had no effect on alcohol intake.
- Tiapride is a selective dopamine D 2 receptor antagonist that is used in clinical
- the object of the invention is therefore to provide novel medicinal products for the therapy of addictions, in particular alcohol addiction, which enable novel forms of therapy.
- the NMDA receptor is part of the glutamatergic neurotransmitter receptor system, the so-called NMDA receptor / ion channel complex. This consists of various binding sites (NMDA, kainate, AMPA, metabotropic receptor), which are located outside and inside the ion channel modulated by this complex.
- the NMDA receptor in turn has different binding sites (subreceptors). Some of these are named after the preferred ligands: iffenprodil, glutamate, glycine, polyamine and dizocilpin (channel) binding site, which have various functional properties (EHFWong et al., Annu. Rev. Pharmacol. Toxicol. , 31, 1991, 401; M. Masu et al., Ann. NY Acad. Sci. 707, 1993, 153-164; S. Nakanishi et al., Annu. Rev. Biophys. Biomel. Struct., 23 , 1994, 319).
- An NMDA antagonist is understood to mean a substance that binds to one of the NMDA subreceptors described above and shows inhibitory properties on the respective function of the downstream effector.
- NMDA antagonists are suitable for the treatment of addiction.
- Chronic exposure to various substances such as alcohol, nicotine, opioids, cannabinoids or sedatives such as benzodiazepines and barbiturates leads to physical dependence.
- Glutamate receptors are distributed throughout the body and play an essential role in neuronal plasticity, ie they are found on most, if not all, of the essentials
- NMDA-receptor complex Positions that are involved in the development and manifestation of the neuroanatomically justifiable characteristics of physical dependence.
- opioids see, for example, C. Jang et al., Brain Res., 845, 1999, 236-241; for ethanol, see e.g. PA Hardy et al., Brain Res. 819, 1999, 33 - 39; for benzodiazepines see e.g. M. Tsda et al., Neurosci. Lett, 240, 1998, 113 - 115;, for barbiturates see e.g. CG. Jang et al., Brain Res. Bull. 48, 1999, 99-102).
- NMDA antagonists that bind selectively to the iffenprodil binding site are particularly effective.
- the pharmaceuticals according to the invention in particular show an effectiveness in combating alcohol dependence. They are particularly suitable for use in a section of therapy that follows physical detoxification. In animal experiments on rats, it could be shown that the "craving syndrome" could be significantly weakened by NMDA antagonists.
- R 1 is H, halogen or a nitro group
- radicals X, Y and Z can be -O-, -S- or -NH, but XY or YZ is not -OO-, -SS-, -NH-O-, -O-NH-, - Is NH-NH-, -OS-, -SO-,
- A is an alkyl group of 1 to 6 carbon atoms
- these compounds are particularly suitable for the treatment of neurodegenerative diseases or
- the compound of Formula II has been found to have an effect on alcohol consumption in alcohol-dependent rats. The effect is better than that of the standard therapeutic Acamprosat.
- the use of the compound of formula II for the therapy of diseases is known from WO 98/18793. It is described as an excitatory amino acid antagonist for combating neurodegenerative diseases including cerebrovascular diseases, epilepsy, schizophrenia, Alzheimer's, Parkinson's or Huntington's disease, cerebral ischemia, infarcts or psychoses.
- the alcohol-dependent rats were intraperitoneally administered twice daily (bid) for the next 2 weeks (days 15-28, hereinafter referred to as "during treatment").
- Another group served as a control and received only the solvent ( physiological saline) of the active substances
- the active substance EMD 95885 corresponds to the compound of the formula II shown above.
- the treatment phase was followed by an observation phase of one week (days 29-35, hereinafter referred to as “after treatment”), in which the rats received no treatment with active substance or solvent.
- the position of the bottles was also changed during and after the treatment, the absolute amount consumed was determined and the ethanol consumption per day in grams of pure ethanol per kilogram of body weight was calculated.
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Addiction (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10120159.1 | 2001-04-25 | ||
DE10120159A DE10120159A1 (de) | 2001-04-25 | 2001-04-25 | NMDA-Antagonisten und NMDA-Agonisten zur Behandlung von Suchterkrankungen |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2002085352A1 true WO2002085352A1 (de) | 2002-10-31 |
Family
ID=7682608
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2002/004525 WO2002085352A1 (de) | 2001-04-25 | 2002-04-24 | Nmda-antagonisten und nmda-agonisten zur behandlung von suchterkrankungen |
Country Status (3)
Country | Link |
---|---|
AR (1) | AR033261A1 (es) |
DE (1) | DE10120159A1 (es) |
WO (1) | WO2002085352A1 (es) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7005432B2 (en) | 2002-05-16 | 2006-02-28 | Hoffman-La Roche Inc. | Substituted imidazol-pyridazine derivatives |
WO2006137465A1 (ja) * | 2005-06-24 | 2006-12-28 | Shionogi & Co., Ltd. | 含窒素複素環誘導体 |
WO2009046841A2 (de) | 2007-10-05 | 2009-04-16 | Merck Patent Gmbh | Piperidin- und piperazinderivate zur behandlung von tumoren |
WO2011044978A1 (de) | 2009-10-13 | 2011-04-21 | Merck Patent Gmbh | Sulfoxidederivate zur behandlung von tumoren |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0488959A2 (en) * | 1990-11-28 | 1992-06-03 | Sandoz Ltd. | New uses of competitive NMDA receptor antagonists |
US5698553A (en) * | 1994-10-31 | 1997-12-16 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Benzylpiperidine derivatives |
DE19643790A1 (de) * | 1996-10-30 | 1998-05-07 | Merck Patent Gmbh | Benzoxazol-Derivat |
JPH10287568A (ja) * | 1997-04-14 | 1998-10-27 | Grelan Pharmaceut Co Ltd | アルコール依存症治療剤 |
-
2001
- 2001-04-25 DE DE10120159A patent/DE10120159A1/de not_active Withdrawn
-
2002
- 2002-04-24 AR ARP020101479A patent/AR033261A1/es not_active Application Discontinuation
- 2002-04-24 WO PCT/EP2002/004525 patent/WO2002085352A1/de not_active Application Discontinuation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0488959A2 (en) * | 1990-11-28 | 1992-06-03 | Sandoz Ltd. | New uses of competitive NMDA receptor antagonists |
US5698553A (en) * | 1994-10-31 | 1997-12-16 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Benzylpiperidine derivatives |
DE19643790A1 (de) * | 1996-10-30 | 1998-05-07 | Merck Patent Gmbh | Benzoxazol-Derivat |
JPH10287568A (ja) * | 1997-04-14 | 1998-10-27 | Grelan Pharmaceut Co Ltd | アルコール依存症治療剤 |
Non-Patent Citations (9)
Title |
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ALCOHOL, vol. 18, no. 2-3, June 1999 (1999-06-01), pages 131 - 137, ISSN: 0741-8329 * |
DATABASE BIOSIS [online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; 2000, SPIELMANNS P ET AL: "Subtype selectivity of several amino-alkyl-cyclohexanes on NMDA receptors expressed in Xenopus oocytes.", XP002211366, Database accession no. PREV200100065987 * |
DATABASE BIOSIS [online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; June 1999 (1999-06-01), BIENKOWSKI PRZEMYSLAW ET AL: "Effects of N-methyl-D-aspartate receptor antagonists on reinforced and nonreinforced responding for ethanol in rats.", XP002211364, Database accession no. PREV199900403382 * |
DATABASE BIOSIS [online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; March 2000 (2000-03-01), CHRISTIE JASON M ET AL: "Native N-methyl-D-aspartate receptors containing NR2A and NR2B subunits have pharmacologically distinct competitive antagonist binding sites.", XP002211367, Database accession no. PREV200000320067 * |
HÖLTER S M ET AL: "Novel uncompetitive N-methyl-D-aspartate (NMDA)-receptor antagonist MRZ 2/579 suppresses ethanol intake in long-term ethanol-experienced rats and generalizes to ethanol cue in drug discrimination procedure.", THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS. UNITED STATES FEB 2000, vol. 292, no. 2, February 2000 (2000-02-01), pages 545 - 552, XP002211377, ISSN: 0022-3565 * |
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 292, no. 3, March 2000 (2000-03-01), pages 1169 - 1174, ISSN: 0022-3565 * |
MALINOWSKA BARBARA ET AL: "Ifenprodil influences changes in mouse behaviour related to acute and chronic ethanol administration.", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 377, no. 1, 14 July 1999 (1999-07-14), pages 13 - 19, XP002211362, ISSN: 0014-2999 * |
SOCIETY FOR NEUROSCIENCE ABSTRACTS, vol. 26, no. 1-2, 2000, 30th Annual Meeting of the Society of Neuroscience;New Orleans, LA, USA; November 04-09, 2000, pages Abstract No. - 42.6, ISSN: 0190-5295 * |
TRUJILLO K A ET AL: "INHIBITION OF MORPHINE TOLERANCE AND DEPENDENCE BY THE NMDA RECEPTOR ANTAGONIST MK-801", SCIENCE (WASHINGTON D C), vol. 251, no. 4989, 1991, pages 85 - 87, XP002211363, ISSN: 0036-8075 * |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7005432B2 (en) | 2002-05-16 | 2006-02-28 | Hoffman-La Roche Inc. | Substituted imidazol-pyridazine derivatives |
WO2006137465A1 (ja) * | 2005-06-24 | 2006-12-28 | Shionogi & Co., Ltd. | 含窒素複素環誘導体 |
EA017787B1 (ru) * | 2007-10-05 | 2013-03-29 | Мерк Патент Гмбх | Производные пиперазина |
DE102007047737A1 (de) | 2007-10-05 | 2009-04-30 | Merck Patent Gmbh | Piperidin- und Piperazinderivate |
WO2009046841A3 (de) * | 2007-10-05 | 2009-06-18 | Merck Patent Gmbh | Piperidin- und piperazinderivate zur behandlung von tumoren |
JP2010540579A (ja) * | 2007-10-05 | 2010-12-24 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | 腫瘍の治療のためのピペリジンおよびピペラジン誘導体 |
EP2426106A1 (de) | 2007-10-05 | 2012-03-07 | Merck Patent GmbH | Piperidin- und Piperazinderivate zur Behandlung von Tumoren |
WO2009046841A2 (de) | 2007-10-05 | 2009-04-16 | Merck Patent Gmbh | Piperidin- und piperazinderivate zur behandlung von tumoren |
US8754097B2 (en) | 2007-10-05 | 2014-06-17 | Merck Patent Gmbh | Piperidine and piperazine derivatives |
JP2014129427A (ja) * | 2007-10-05 | 2014-07-10 | Merck Patent Gmbh | 腫瘍の治療のためのピペリジンおよびピペラジン誘導体 |
US8791111B2 (en) | 2007-10-05 | 2014-07-29 | Merck Patent Gmbh | Piperidine and piperazine derivatives |
WO2011044978A1 (de) | 2009-10-13 | 2011-04-21 | Merck Patent Gmbh | Sulfoxidederivate zur behandlung von tumoren |
DE102009049211A1 (de) | 2009-10-13 | 2011-04-28 | Merck Patent Gmbh | Sulfoxide |
Also Published As
Publication number | Publication date |
---|---|
AR033261A1 (es) | 2003-12-10 |
DE10120159A1 (de) | 2002-10-31 |
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