EP1814533A2 - Traitement des consequences de l'abus d'alcool, de l'hepatite, de la pancreatite - Google Patents

Traitement des consequences de l'abus d'alcool, de l'hepatite, de la pancreatite

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Publication number
EP1814533A2
EP1814533A2 EP05814328A EP05814328A EP1814533A2 EP 1814533 A2 EP1814533 A2 EP 1814533A2 EP 05814328 A EP05814328 A EP 05814328A EP 05814328 A EP05814328 A EP 05814328A EP 1814533 A2 EP1814533 A2 EP 1814533A2
Authority
EP
European Patent Office
Prior art keywords
disease
sub
hepatitis
general formula
alkylamine
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Withdrawn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
EP05814328A
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German (de)
English (en)
Inventor
Thomas Haehner
Dieter Mueller-Enoch
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Individual
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Individual
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Publication of EP1814533A2 publication Critical patent/EP1814533A2/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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • 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
    • 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
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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

  • Alcohol abuse hepatitis, pancreatitis, Alzheimer's disease, Parkinson's disease, diabetes, toxic kidney disease,
  • the invention relates to the use of lipophilic alkyl groups on and substances having hydrophilic radicals for the preparation of pharmaceutical preparations.
  • Alcohol-induced inflammation of the liver is an optionally life-threatening disease, which may be accompanied by fever, jaundice and an increase in white blood cells.
  • Alcohol-induced inflammations of the liver can be cured by complete alcohol abstinence, excluding scarring in liver cirrhosis.
  • complete alcohol abstinence is not readily achievable in practice.
  • hepatides In addition to these alcohol-induced so-called fatty hepatitis or alcoholic steato-hepatitis (ASH), hepatides also develop in persons who do not engage in alcohol abuse or who do not drink any alcohol at all. Such hepatides are produced, for example, by environmental poisons, for example se when working in paint shops and / or induced by drugs.
  • environmental poisons for example se when working in paint shops and / or induced by drugs.
  • Alzheimer's disease is a progressive dementia disease, which ultimately leads to the complete loss of memory and personality. It is caused by protein deposits in nerve cells, the plaques, which are formed from ß-amyloid or so-called ⁇ -proteins. The actual cause is unknown so far, with both metabolic disorders, gene mutations, as well as so-called slow virus infections or prions are discussed.
  • ROS reactive oxygen species
  • Parkinson's disease is a degeneration of dopaminergic neurons in the substantia nigra of the brain. It is the most common neurological disease in old age. Beginning signs are here in particular trembling movements (tremor), a depressive mood, apathy as well as slowed thinking.
  • cytochromes are a multiplicity of different enzymes whose active center has a heme structure. They catalyze at a Dahl ⁇ number of oxidation reactions the transfer of electrons to an acceptor, which is, for example, when cytochrome c, molecular oxygen ( "O 2 *) thereby forming a free radical superoxide anion.
  • O 2 * molecular oxygen
  • cytochrome P450 which is Again, in a variety of completely different forms, such as IAl, 2Bl, 2C9, 2J2, 2El, 3Al etc.
  • the rat cytochrome P 450 2B1 and human cytochrome P 450 2EI differ in their amino acid sequence by about 60%, i. that both the structures of the active and catalytic centers as well as the size and shape of the access channels for the substrate differ considerably.
  • the isoform 2El reacts with much smaller molecules, such as ethanol, acetone or p-nitrophenol.
  • cytochrome P450-2E1 It is known that the synthesis of cytochrome P450-2E1 is induced both in alcohol consumption and in non-alcoholic fatty liver hepatitis.
  • the function and mode of action of this isoform, which is greatly different from other cytochromes, is described, for example, by MH Wang et al in Archives of Biochemistry and Biophysics, (1995) Vol. 317, pages 299 to 304. Thereafter, the enzyme has an approximately 15- ⁇ long binding pocket, at the end of which the reactive center is seated with a hemming ring having a central internal atom.
  • Müller-Enoch et al. describe in Z. Naturforsch. (2001) 56c, pages 1082-1090, the inhibition of rat cytochrome P450 2Bl by Lysophosphatidylcholinen, lysophosphatidylinositol and arachidonic and oleic acids or by means of monoacylglycerols, monooleylglycerols, and monopalmitoylglycerols.
  • the object of the invention is the development and the consequences of alcoholic and non-alcoholic liver diseases, viral hepatitis of diabetes mellitus type 1 and type 2, pancreatitis, acute renal failure, toxic kidney diseases, side effects when using chemotherapeutic agents, Alzheimer's and Parkinson's disease, Wilson's disease, siderosis and arteriosclerosis to avoid and / or mitigate their course and / or stop altogether.
  • the invention also aims at organ damage in ischemic Zu ⁇ states, z. B. during reperfusion to mitigate and / or avoid ver ⁇ .
  • the invention also aims to treat the organotoxicity of environmental toxins and drugs.
  • the cytochrome P 450 especially the isoforms of group 2, especially 2El, and 2C9, the formation of reactive oxygen species (ROS), in particular oxygen radicals such as the Superoxidanion and the Prevent hydroxyl radical ( » OH) that is not consumed in a direct redox reaction by administering a substance that has a hydrophobic alkyl chain and a polar hydrophilic end.
  • ROS reactive oxygen species
  • Such substances have a hydrophilic and hydrophilic region of at least six carbon atoms in length.
  • These can be both synthetic single-chain lipids such as, for example, alkylphosphocholines, alkylcoumarins or else alkylsulphonic acids, and of course single-chain lipids such as corresponding fatty acids, fatty acid esters or sphingosine or lysophosphatidylinositol. This is all the more surprising than it is known that this isoform in its natural function is responsible for the oxidation of small molecules, such as ethanol and acetone.
  • R represents an alkyl radical which preferably has 7 to 27 C atoms.
  • alkyl radicals having a length of at least 8 carbon atoms with a length of at least 10, in particular at least 11 or 12, carbon atoms being very particularly preferred.
  • alkyl radicals having a maximum number of 20 carbon atoms are preferred, with a maximum size of 18, in particular a maximum of 17 or 16 carbon atoms being very particularly preferred.
  • the alkyl radical may also be straight-chain or branched and may contain one or more carbon double and / or triple bonds.
  • the alkyl radical has not more than 7, in particular not more than 5 double bonds, and preferably contains not more than 3, in particular 2 triple bonds.
  • the alkyl radical may optionally be substituted by further groups as long as these do not affect the hydrophobic behavior of the radical R.
  • Preferred substituents are Ci- Ce alkyl, preferably C vor ⁇ x - to C 4 -, which may also be branched, even though, but are vorzugeweise straight chain.
  • A represents a carbonyl, carboxylic acid, phosphoric acid, amino, ether or mercapto ether group, each having the general formula -CO-, -COO-, PO x 2 ' -, NH Y - and / or -S-.
  • X is a hydrogen atom, a polycyclic, aromatic or aliphatic water-soluble hydrocarbon which contains at least one heteroatom and which is optionally connected to the alkyl radical R with ring closure and to improve the water solubility oxygen, nitrogen and / or sulfur heteroato ⁇ contains me in the ring and / or as or in the substituent.
  • x is a polyol, an amino acid, a sugar, an alkylamine, a Ci to C 3 - alkyl amine, a Ci to C 3 - hydroxyalkyl and / or a Ci to C 3 carboxylic acid.
  • Suitable polyols are all polyhydroxy radicals having multiple hydroxyl groups, such as, for example, glycol, glycerol and cyclic alcohols, for example inositol, sugars and oligosaccharides and sugar residues, which can be either one or more C 5 or C 6 sugars.
  • the substances which have detergent properties and which contain an alkyl or alkyl radical.
  • the substances can be either non-ionic, ionic and zwitterionic detergents, and in particular have a critical micelle concentration (CMC) * 10 "2 M and O, 5 * 1CT S M to between 0.5.
  • CMC critical micelle concentration
  • Preferred substances according to the invention also include fatty acids, phosphoric esters, in particular phosphodiester, fatty acid esters, in particular with alkylamines and amino acids, sphingosine and sphingosine derivatives, and also cyclic alkyls and alkylene derivatives of the general formula CH 3 -RX.
  • Phosphodiesters which can be used according to the invention have the general formula H 3 CR-PO 4 --X, where R has an alkyl radical having 4 to 26 carbon atoms, which is preferably straight-chain. Particularly preferred radicals R are - (CH 2 ) 4 to 24 - #
  • X is a water-solubility-mediating hydrophilic radical or group which in particular has heteroatoms such as N, S, O and in particular contains amino, ammonium and hydroxyl groups.
  • X can also represent hydrogen, so that a phosphorus monoester is formed.
  • Preferred radicals X are amino acids, in particular ⁇ , ⁇ , Y and / or U) amino acids, as well as
  • Preferred fatty acid amino acid esters are in particular carnitine esters of the general formula
  • Substances comprise sphingosines and sphingosine derivatives of the general formula R-Pi-Y, where R is a sphingosyl radical of the general formula
  • Pi is a phosphate radical.
  • Sphingosyl derivatives are understood as meaning any structurally analogous changes in the basic structure, for example a shortening or lengthening of the hydrocarbon chain, the addition of additional double bonds, hydroxyl and / or amino groups or the replacement of these groups by H radicals.
  • Preferred radicals Y groups include hydrogen, choline, sugar radicals such as glucose, galactose and oligosaccharides and cyclic polyalkhol such as inositol, especially myo-inositol.
  • substances whose hydrophilic group comprises a water-soluble, cyclic or polycyclic aromatic and / or aliphatic hydrocarbon radical which increases the solubility of the heteroatoms, in particular o, N and or S in the ring and / or in a substituent thereof or as a substituent itself.
  • the substances which can be used according to the invention also include cyclic alkyl and alkylene derivatives of the general formula
  • X is a water-soluble cyclic hydrocarbon radical which may be aliphatic or aromatic and which has heteroatoms, in particular O, N and / or S.
  • the cyclic hydrocarbons may be connected to the radical R with ring closure, as long as their hydrophobic properties do not change. It is particularly preferred to suppress the formation of micellar structures by means of such cyclic hydrocarbons.
  • Preferred compounds are phosphocholines which, in addition to their phosphocholine group, have no esters, hydroxyl or amino or amido groups or derivatives thereof.
  • X is a Phosphocholinrest and especially a -PO 4 "-R'-N + R 3", wherein R 1 is a C 1 - C 6 alkyl, particularly Ci - C 3 radical and R "are each independently a hydrogen , Methyl, ethyl and / or propyl may be.
  • Such a very particularly preferred substance is hexadecylphosphocholine.
  • L-O-octadecyl-2-O-methyl-Sn-glycerol-3-phosphocholine is also very particularly preferred.
  • Such substances are beispiels ⁇ example in Matzke et al. in European Journal of Cell Biology 80, (2001) 1-10.
  • liver damage or other alcohol-related, inflammatory processes are in particular liver damage or other alcohol-related, inflammatory processes.
  • these are in particular liver damage or other alcohol-related, inflammatory processes.
  • liver damage In addition to the purely alcoholic liver damage and dietary and endocrine factors such.
  • Such alcoholic and non-alcoholic fatty liver diseases are often associated with a viral infection of the liver. This can lead to a very rapid progression of the disease. It has been shown that this z. B. is also due to a synergistic production of reactive oxygen species (ROS) and the associated cell damage. All the aforementioned diseases or their causes or consequences can be treated with the inventive means.
  • ROS reactive oxygen species
  • alcohol abuse also leads to damage of other organs, such as the pancreas, the heart or the nervous system.
  • inflammations of the pancreas are also particularly suitable for the treatment of inflammations of the pancreas.
  • Such inflammations or pancreatitis in addition to alcohol abuse, can also be caused by toxic substances. These include, in particular, environmental toxins, such as occupational chemicals or even medicines. Also viral infections or metabolic-endocrine factors can cause such pancreatic inflammation, in all cases reactive oxygen species being involved in the disease development and progression of the disease.
  • the inventive Pharmaceutical proved to be suitable. It has in fact been shown that ⁇ -islet cells are particularly sensitive to oxidative processes and that they rapidly decrease with increased oxidative stress. This oxidative stress can be avoided with the pharmaceutical according to the invention, but at least greatly reduced.
  • the pharmaceutical of the invention has been found to be effective. It has been found, for example, that with the substances according to the invention the concentration of dopamine can be increased by reduced degradation.
  • toxic kidney diseases as well as other diseases, such as. B. by side effects in the administration of Che ⁇ motherapeutika, in particular cell toxins such as metal complexes such as cisplatin, carboplatin, Titanocendichlorid or gold complexes are caused to be treated with the medicament according to the invention tel.
  • cell toxins such as metal complexes such as cisplatin, carboplatin, Titanocendichlorid or gold complexes are caused to be treated with the medicament according to the invention tel.
  • the organotoxicity of metal complexes or other toxic agents such as halogenated hydrocarbons, both mono- and also polihalogenated hydrocarbons including halothane-type vapor anesthetics, and corresponding aromatic hydrocarbons, nitrosamines, Acrylamide or drugs, such as paracetamol, methotrexate, isoniazid or aminoglycide antibiotics or x-ray contrast agents.
  • the medicament according to the invention is thus also suitable for the treatment of the organotoxicity of environmental poisons, in particular as an antidote for this to organs such as liver, kidney, central nervous system, pancreas, etc.
  • the pharmaceutical preparation according to the invention for the treatment of acute renal failure, in particular renal failure caused by drug-induced intoxication, haemolytic diseases, hemolytic uremic syndrome (Gasser syndrome), rhabdomyolysis (destruction of striated skeletal muscle), circulatory ischemic processes and / or viral infection.
  • acute renal failure in particular renal failure caused by drug-induced intoxication, haemolytic diseases, hemolytic uremic syndrome (Gasser syndrome), rhabdomyolysis (destruction of striated skeletal muscle), circulatory ischemic processes and / or viral infection.
  • it has been shown to treat damage caused by crushing of the striated muscle (crush syndrome) and / or its demise upon administration of drugs (such as CSE inhibitors, eg Lipobay).
  • the agent according to the invention is thus also particularly suitable for the prevention of reperfusion damage in transplanted organs.
  • Such organs are kept in a cooled nutrient solution until their transplantation into the body of a new recipient. After transplantation, they are then again perfused with body fluids after connection to the circulatory system of the recipient, which leads to reperfusion damage.
  • the substances according to the invention have proved to be especially inhibitors of the human isoforms of the gene family 2 of the cytochrome P450 and in particular of the isoforms 2E1 and 2C9 and diseases caused by them.
  • Example 1 The substances according to the invention have proved to be especially inhibitors of the human isoforms of the gene family 2 of the cytochrome P450 and in particular of the isoforms 2E1 and 2C9 and diseases caused by them.
  • Example 1 Example 1 :
  • Enzyme activity determinations p-nitrophenol is considered a specific substrate for cytochrome P450 2El. The determination of the p-nitrophenol hydroxylase activity was based on the work of J.W. Allison and B.L. Robinson, Anal. Biochem. 219, 49-52, 1994.
  • a microsomal fraction was obtained from a human liver as described by MH Wang et al. described in the aforementioned work.
  • the cytochrome P450-mediated oxygen production was determined by fluorimetry using the dichlorofluorescein method (BASF BA et al., Journal of Immunology 130 (4) p. 1910, 1983). The detection is carried out as a function of ver ⁇ different specific substrates of the isoform of gene family 2, z. ChIP 2C9: diclofenac, ChIP 2Cl: p-nitrophenol) and depending on various inhibitory substances (eg alkylphosphocholines, sphingolipids, lysophospholipids). In all cases, a concentration-dependent decrease in the ROS-mediated dichlorofluorescein fluorescence occurred (complete suppression in the range of about 5-15 microns).

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
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  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Addiction (AREA)
  • Psychiatry (AREA)
  • Urology & Nephrology (AREA)
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  • Emergency Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Virology (AREA)
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Abstract

L'invention concerne une préparation pharmaceutique pour prévenir, traiter et soulager les conséquences de l'abus d'alcool, de l'hépatite virale, de la stéato-hépatite, de la pancréatite aiguë et chronique, de la maladie d'Alzheimer, de la maladie de Parkinson, des maladies rénales toxiques, de la défaillance rénale aiguë, des effets secondaires toxiques lors de l'administration d'une chimiothérapie, du diabète sucré, de la maladie de Wilson, de la sidérose et/ou des dommages des reperfusions ischémiques, de l'artériosclérose, ladite préparation servant d'antidote contre les poisons et les intoxications médicamenteuses. La préparation contient un composé de formule (I) utilisé comme principe actif, dans laquelle R représente un reste alkyle C<SUB>5</SUB>-C<SUB>27</SUB>, lequel comprend une seule branche ou peut être ramifié, qui présente des liaisons doubles ou triples et qui peut être substitué ; et A représente CO-, -COO-, -PO<SUB>x</SUB> <SUP>2-</SUP>
EP05814328A 2004-10-29 2005-10-28 Traitement des consequences de l'abus d'alcool, de l'hepatite, de la pancreatite Withdrawn EP1814533A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004052697A DE102004052697A1 (de) 2004-10-29 2004-10-29 Pharmazeutische Zubereitungen zur Behandlung von Folgen des Alkoholmissbrauchs, Hepatitis, Pankreatitis, Alzheimererkrankung, Morbus Parkinson, Diabetes, toxischen Nierenerkrankungen, Reperfusionsschäden, der Arteriosklerose sowie als Antidote gegen Umweltgifte und Medikamentenintoxikation
PCT/DE2005/001938 WO2006045298A2 (fr) 2004-10-29 2005-10-28 Preparations pharmaceutiques pour traiter les consequences de l'abus d'alcool, de l'hepatite, de la pancreatite, de la maladie d'alzheimer, de la maladie de parkinson, du diabete, des maladies renales toxiques, des dommages de reperfusions, de l'arteriosclerose et leurs utilisations en tant qu'antidote contre les poisons et

Publications (1)

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EP1814533A2 true EP1814533A2 (fr) 2007-08-08

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EP05814328A Withdrawn EP1814533A2 (fr) 2004-10-29 2005-10-28 Traitement des consequences de l'abus d'alcool, de l'hepatite, de la pancreatite

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US (1) US20090036400A1 (fr)
EP (1) EP1814533A2 (fr)
KR (1) KR20070085496A (fr)
AU (1) AU2005299148A1 (fr)
DE (2) DE102004052697A1 (fr)
NO (1) NO20072712L (fr)
RU (1) RU2007119712A (fr)
WO (1) WO2006045298A2 (fr)

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DE102006019907A1 (de) * 2006-04-28 2007-10-31 Müller-Enoch, Dieter, Prof. Dr. Verwendung von substituierten Glycerinderivaten zur Herstellung einer pharmazeutischen Zubereitung
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US20090036400A1 (en) 2009-02-05
RU2007119712A (ru) 2008-12-10
AU2005299148A1 (en) 2006-05-04
DE102004052697A1 (de) 2006-05-04
WO2006045298A3 (fr) 2007-05-10
KR20070085496A (ko) 2007-08-27
WO2006045298A2 (fr) 2006-05-04
DE112005003310A5 (de) 2007-10-04
NO20072712L (no) 2007-07-18

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