WO2004113306A1 - 6-arylamino-5-cyano-4-pyrimidinone als pde9a-inhibitoren - Google Patents
6-arylamino-5-cyano-4-pyrimidinone als pde9a-inhibitoren Download PDFInfo
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- WO2004113306A1 WO2004113306A1 PCT/EP2004/006477 EP2004006477W WO2004113306A1 WO 2004113306 A1 WO2004113306 A1 WO 2004113306A1 EP 2004006477 W EP2004006477 W EP 2004006477W WO 2004113306 A1 WO2004113306 A1 WO 2004113306A1
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- 0 BNC(N=C(C*)NC1=O)=C1C#N Chemical compound BNC(N=C(C*)NC1=O)=C1C#N 0.000 description 1
- ZNFPFVJNALAYKY-KHPPLWFESA-N COC(/C(/C#N)=C(/Nc1cc(F)ccc1)\SC)=O Chemical compound COC(/C(/C#N)=C(/Nc1cc(F)ccc1)\SC)=O ZNFPFVJNALAYKY-KHPPLWFESA-N 0.000 description 1
- KRUXNJRWSRMFKN-XFXZXTDPSA-N COC(/C(/C#N)=C(/Nc1ccccc1OC)\SC)=O Chemical compound COC(/C(/C#N)=C(/Nc1ccccc1OC)\SC)=O KRUXNJRWSRMFKN-XFXZXTDPSA-N 0.000 description 1
- MQSVWFUCWPJFFI-UHFFFAOYSA-N Cc1ccc(C)c(NC(N=C(CC2CCCC2)NC2=O)=C2C#N)c1 Chemical compound Cc1ccc(C)c(NC(N=C(CC2CCCC2)NC2=O)=C2C#N)c1 MQSVWFUCWPJFFI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- 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
- A61P25/28—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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the invention relates to new 6-arylamino-5-cyano-4-pyrimidinones, processes for their production, and their use for the production of medicaments for improving perception, concentration, learning and / or memory.
- Inhibition of phosphorus diester modulates the levels of the cyclic nucleotides 5 '-3' cyclic adenosine monophosphate (cAMP) or 5 '-3' cyclic guanosine monophosphate (cGMP).
- cAMP and cGMP are important second messengers and therefore play a central role in the cellular signal transduction cascades. Both activate, among other things, but not exclusively, protein noses again.
- the protein kinase activated by cAMP is called Protein Kinase A (PKA)
- PKA Protein Kinase A
- cGMP protein kinase activated by cGMP
- Prötemkmase ' G (called xXGJ. Activated PKA or PKG can in turn phosphorylate a number of cellular effector proteins (eg ion channels, G protein-coupled receptors, structural proteins).
- the second messengers cAMP and cGMP can perform a wide variety of physiological processes in a wide variety of organs
- the cyclic nucleotides can also act directly on effector molecules, for example it is known that cGMP can act directly on ion channels and can thus influence the cellular ion concentration (overview in: Wei et al., Prog..Neurobiol., 1998 , 56: 37-64) .
- a control mechanism to control the alctivity of cAMP and cGMP and thus these physiological processes are the phosphodiesterases (PDE), PDEs hydrolyze the cyclic monophosphates to the inactive monophosphates AMP and GMP meanwhile at least 21 PDE genes have been described (Exp.
- PDE genes can be divided into 11 PDE families (nomenclature suggestion see http://depts.washington.edu/pde/Nomenclature.html.). Individual PDE genes within a family are distinguished by letters (eg PDE1A and PDE1B). If there are still different splice variants within a gene, this is indicated by an additional numbering after the letter (eg PDE1A1).
- the Humane PDE9A was idoned and sequenced in 1998.
- the amino acid identity to other PDEs is a maximum of 34% (PDE8A) and a minimum of 28% (PDE5A).
- Km value Michaelis-Menten constant
- PDE9A is highly affine for cGMP.
- PDE9A has no cGMP binding domain, which would suggest an allosteric enzyme regulation by cGMP.
- the mouse PDE9A was developed in 1998 by Soderling et al. (J. Biol. Chem., 1998, 273 (19): 15553-15558) cloned and sequenced. Like the human form, this is highly affinity for cGMP with a Km of 70 nM. A particularly high expression was found in the kidneys, brain, lungs and heart in the mouse.
- the mouse PDE9A is also not inhibited by IBMX in concentrations below 200 ⁇ M; the IC 50 - ⁇ , ext.fi ' jr. Zaprinast is 29 uM (Soderling et al., J. Biol. Chem., 1998, 273 (19): 15553-15558).
- PDE9A is strongly expressed in some brain regions. These include the olfactory bulb, hippocampus, cortex, basal ganglia and basal forebrain (Andreeva et al., J. Neurosci., 2001, 21 (22): 9068 - 9076).
- the hippocampus, cortex and basal forebrain in particular play an important role in learning and memory processes.
- PDE9A inhibitors can therefore lead to an increase in the basal cGMP concentration.
- No. 5,256,668 discloses aminopyrimidine derivatives which are distinguished as antiviral agents and can be used for the treatment of the respiratory syncytial virus.
- WO 99/41253 describes pyrimidine derivatives with antiviral activity which can be used in particular for the treatment of human cytomegalovirus infections.
- EP 130735 discloses aminopyrimidine derivatives which stand out as heart-strengthening agents.
- the present invention relates to compounds of the formula
- Ci-Cg-alkyl, C 3 -C 8 -cycloalkyl, tetrahydrofuryl or tetrahydropyranyl which optionally with up to 3 radicals independently selected from the group -
- C ⁇ -C 6 -alkyl, C 6 -alkoxy, C 6 alkylamino, C ⁇ -C6 alkylaminocarbonyl, C ⁇ -C 6 - alkoxycarbonyl, C ⁇ -C 6 alkylcarbonyl, C ⁇ -C 6 alkylsulfonyl, and CC 6 alkylthio optionally with one or more radicals selected from the group consisting of hydroxy, cyano, halogen, hydroxycarbonyl and a group of the formula - NR 3 R ⁇
- R 3 and R 4 independently of one another are hydrogen or Ci-C ⁇ -alkyl
- R 3 and R 4 together with the nitrogen atom to which they are attached represent 5- to 8-membered heterocyclyl
- B phenyl or heteroaryl the ' optionally with up to 3 radicals each independently selected from the group -C-C 6 alkyl, CC 6 -alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, trifluoromethoxy, amino, nitro, hydroxy, -C-C 6 Alkylamino, halogen, -CC 6 -alkylaminocarbonyl, -C-C 6 -alkoxycarbonyl, CC 6 -alkylcarbonyl, -C-C 6 - alkylsulfonyl and -CC 6 -alkylthio are substituted, where CC 6 -alkyl, -C-C 5 -alkoxy, C ⁇ -C 6 -alkylamino, CC 6 -alkylaminocarbonyl, C ⁇ -C 6 - alkoxycarbonyl, dC 6 -Al ylcarbonyl, C ⁇ -C 6 -alky
- R 3 and R 4 have the meanings given above,
- the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers) and tautomeric forms.
- the invention therefore relates to the enantiomers or diastereomers and their respective mixtures.
- the stereoisomerically uniform constituents can be isolated in a known manner from such mixtures of enantiomers and / or diastereomers.
- preferred salts are physiologically acceptable salts of the compounds according to the invention.
- Physiologically acceptable salts of the compounds (I) include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example: salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, acetic acid, acetic acid - acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
- Physiologically acceptable salts of the compounds (I) also include salts of conventional bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 1 to 1 ' 6 Carbon atoms, such as, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine,
- alkali metal salts for example sodium and potassium salts
- alkaline earth metal salts for example calcium and magnesium salts
- ammonium salts derived from ammonia or organic amines with 1 to 1 ' 6 Carbon atoms such as, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanol
- solvates are those forms of the compounds which, in the solid or liquid state, are coordinated with solvent molecules Form complex. Hydrates are a special form of solvate, in which coordination takes place with water.
- ⁇ Cr-C-alkyl, G-Cfi-alkyl, O-C alkyl and G- -alkyl represent a straight-chain or branched alkyl radical having 1 to 8, preferably 1 to 6, particularly preferably 1 to 5 and 1 to 4 carbon atoms.
- Preferred examples include methyl, ethyl, n-propyl, isopropyl, 2-butyl, 2-pentyl and 3-pentyl.
- CrCfi-Alkoxy stands for a straight-chain or branched alkoxy radical. 1 to 6, preferably 1 to 4, particularly preferably with Abis "3" carbon atoms. Preferred examples include
- C 1 -C 6 alkoxycarbonyl represents a straight-chain or branched alkoxycarbonyl radical having 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms.
- Preferred examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
- branched mono- or dialkylamino radical having 1 to 6, preferably 1 to 4 and particularly preferably having 1 to 3 carbon atoms.
- Preferred examples include methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino and n-hexylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-tert-butylamino, di-n-pentylamino , Di-n-hexylamino, ethylmethylamino, isopropylmethylamino, n-butylethylamino and n-hexyl-i-pentylamino.
- C 1 -C ⁇ alkylaminocarbonyl represents a group linked via a carbonyl mono- or dialkylamino, where the alkyl radicals may be identical or different, straight-chain or branched and in each case 1 to 6, preferably 1 to 4, and particularly preferably 1 to 3 carbon atoms included.
- Preferred examples include methylaminocarbonyl, ethylaminocarbonyl, n-
- Propylaminocarbonyl isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, dimethylaminocarbonyl, diethylamiriocarbonyl, di-n-propylaminocarbonyl, diisopropylaminocarbonyl, di-t-butylaminocarbonyl, di-n-pentylaminocarbonyl, di-nyl-pentylaminocarbonyl Isopropylmethyl inocarbonyl, n-butylethylaminocarbonyl and n-hexyl-i-pentylaminocarbonyl.
- the two alkyl radicals together with the nitrogen atom to which they are attached can form a 5- to 8-membered heterocyclyl.
- C 1 -C 6 alkylsulfonyl represents a straight-chain or branched alkylsulfonyl radical having 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms.
- Preferred examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl and n-hexylsulfonyl.
- C r Cfi-alkylthio represents a straight-chain or branched alkylthio radical having 1 to 6, preferably 1 to 4 and particularly preferably having 1 to 3 carbon atoms.
- Preferred examples include
- Halogen stands for fluorine, chlorine, bromine and iodine. Fluorine, chlorine, bromine are preferred, fluorine and chlorine are particularly preferred.
- Heteroaryl stands for an aromatic, monocyclic radical with 5 to 6 ring atoms and up to 3 heteroatoms from the series S, 0 and / or N. 5- to 6-membered heteroaryls with up to 2 heteroatoms are preferred.
- the heteroaryl radical can be bound via a carbon or nitrogen atom
- Preferred examples include thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, pyridyl, pyrimidinyl and pyridazinyl.
- 3- to 8-membered cycloalkyl stands for saturated and partially unsaturated non-aromatic.
- Cycloalkyl radicals having 3 to 8, preferably 3 to 6 and particularly preferably 5 to 6 carbon atoms in the
- Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl.
- 5- to 8-membered heterocyclic stands for a mono- or polycyclic, heterocyclic radical with 5 to 8 ring atoms and up to 3, preferably 2 heteroatoms or hetero groups from the series N, O, S, SO, S0 2 .
- Mono- or bicyclic heterocyclyl is preferred.
- Monocyclic heterocyclyl is particularly preferred.
- N and O are preferred as heteroatoms.
- the heterocyclyl residues can be saturated or partially unsaturated. Saturated heterocyclyl residues are preferred.
- 5- to 7-membered heterocyclyl radicals are particularly preferred.
- Preferred examples include oxetan-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, tetrahydrofuranyl, tetra-hydrothienyl, pyranyl, piperidinyl, thiopyranyl, morpholinyl, perhydroazepinyl. If radicals in the compounds according to the invention are optionally substituted, a substitution with up to three identical or different substituents is preferred, unless otherwise specified.
- Another embodiment of the invention relates to compounds of the formula (I)
- a -C-C 5 alkyl or C 3 -C 6 cycloalkyl which optionally with up to 3 radicals independently selected from the group C ⁇ -C 4 alkyl, -C-C 4 alkoxy, hydroxycarbonyl, cyano, amino, hydroxy , C 1 -C 4 alkylamino, fluorine, chlorine, bromine, -CC 4 -alkoxycarbonyl, Cr -alkylcarbonyl, -CC 4 -alkylsulfonyl and -CC 4 -alkylthio are substituted,
- R 3 and R 4 independently of one another are hydrogen or C 1 -C 4 -alkyl
- R 3 and R 4 together with the nitrogen atom to which they are attached represent 5- to 6-membered heterocyclyl
- B phenyl, thienyl or pyridyl, optionally with up to 3 radicals each independently selected from the group CC 4 -alkyl, C 1 -C 4 -alkoxy, hydroxycarbonyl,
- R 3 and R 4 have the meanings given above, are substituted,
- Another embodiment of the invention relates to compounds of the formula (I)
- B phenyl or pyridyl, optionally with up to 3 radicals each independently selected from the group methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, ethoxy, fluorine and chlorine,
- one of the residues on the phenyl or pyridyl is located in the ortho position relative to the point of attachment of the amino function
- the invention relates to compounds of the formula (I),
- AC 3 -C 6 cycloalkyl means and
- Another embodiment of the invention relates to compounds of the formula (I)
- A is 2-methylpropyl, 2-butyl, 2-pentyl or 3-pentyl and
- Another embodiment of the invention relates to compounds of the formula (I) in which
- B phenyl, thienyl or pyridyl, optionally with up to 3 radicals each independently selected from the group C 3 -C 3 -alkyl, trifluoromethyl, hydroxy, methoxy, ethoxy, cyano, dimethylamino, diethylamino, methoxycarbonyl, ethoxycarbonyl, methylcarbonyl, ethylcarbonyl, Fluorine and chlorine are substituted,
- High-boiling, inert organic solvents which do not change under the reaction conditions are suitable for process step (ET) + (IH) -> ⁇ (IV).
- These preferably include dimethylformamide, dimethyl sulfoxide or sulfolane. It is also possible to carry out the reaction in the melt without solvent. Reaction control without solvents or in dimethylformamide is particularly preferred.
- the reaction generally takes place in a temperature range from + 10 ° C. to + 200 ° C., preferably in a temperature range from + 125 ° C. to + 150 ° C.
- the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
- the compound of the formula (ET) is used here in an amount of 1 to 2 mol, preferably in an equivalent amount of 1 mol, based on 1 mol of the compound of the formula (11).
- Conventional organic solvents which do not change under the reaction conditions are suitable for process step (IV) + (V) - »(T). These preferably include dimemylformamide, dimethyl sulfoxide, acetonitrile, dioxane or alcohols - such as methanol, ethanol, propanol, isopropanol, n-butanol or tert-butanol. It is also possible to use mixtures of the solvents mentioned. Dimethylformamide or acetonitrile is particularly preferred.
- the reaction generally takes place in a temperature range from + 50 ° C. to + 150 ° C., preferably in a temperature range from + 70 ° C. to + 100 ° C.
- the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
- Suitable bases for process step (fV) + (V) -> (I) are preferably alkali metal carbonates such as
- Lithium, sodium, potassium or cesium carbonate or organic amine bases such as pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine. Potassium carbonate is particularly preferred.
- the base is used in an amount of 1.5 to 4 mol, preferably in an amount of 1.5 to 2 mol, based on 1 mol of the compound of the formula (IV).
- (V) is used in an amount of 1 to 1.5 mol, preferably in an amount of 1.2 mol, based on 1 mol of the compound of the formula (IV).
- the compounds according to the invention show an unforeseeable, valuable pharmacological spectrum of action. They are particularly characterized by an inhibition of PDE9A.
- the compounds according to the invention are suitable for the production of medicaments for improving perception, concentration, learning or memory.
- the compounds according to the invention can be used alone or in combination with other medicaments to improve perception, concentration, learning and / or memory.
- Particularly compounds of the invention to improve cognition are, * 'Könzentratioiis ⁇ ' ei 'stung learning or memory after cognitive disorders, such as seven in particular in situations / diseases / syndromes such as "Mild cognitive impairment"
- Age-related learning and memory disorders age-related memory loss, vascular dysfunction, and vascular dysfunction, and vascular dysfunction, and vascular dysfunction.
- post stroke dementia dementia that occurs after strokes
- post-traumatic dementia general concentration disorders, concentration disorders in children with learning and memory problems, Alzheimer's disease
- ALS amyotropic lateral sclerosis
- Huntington's disease multiple sclerosis
- PDE8A (GenBank / EMBL Accession Number: AF_056490, Fisher et al. Biochem. Biophys. Res. Commun. 1998 246, 570-577), PDE9A (Fisher et al, J. Biol. Chem, 1998, 273 (25): 15559 - 15564), E10A (GenBank / EMBL Accession Number: NM_06661, Fujishige et al. J Biol Chem. 1999, 274, 18438-45.), PDE11A (GenBank / EMBL Accession Number: NM_016953, Fawcett et al. Proc. Natl. ⁇ cad 2000, 97, 3702-3707) were expressed in Sf9 cells using the pFASTBAC baculovirus expression system (GibcoBRL).
- test substances are dissolved in 100% DMSO and serially diluted. Typically, dilution series from 200 ⁇ M to 1.6 ⁇ M he are made (resulting final concentrations in the test: 4 ⁇ M to 0.032 ⁇ M). 2 ⁇ L of the diluted substance solutions are placed in the wells of microtiter plates (Isoplate; Wallac Ine, Atlanta, GA). Then 50 ⁇ L of a dilution of the PDE9A preparation described above are added. The dilution of the PDE9A preparation is chosen so that less than 70% of the substrate is converted during the later incubation (typical
- Dilution 1: 10,000; Dilution buffer: 50 mM Tris / HCl pH 7.5, 8.3 mM MgCl 2 , 1.7 mM
- Pharmacia Biotech, Piscataway, NJ is diluted 1: 2000 with assay buffer (50 mM Tris / HCl pH 7.5, 8.3 mM MgCl 2 , 1.7 mM EDTA) to a concentration of 0.0005 ⁇ Ci / ⁇ L.
- the enzyme reaction is finally started by adding 50 ⁇ L (0.025 ⁇ Ci) of the diluted substrate.
- the test batches are inhibited for 60 min at room temperature and the reaction is stopped by adding 25 ⁇ l of a PDE9A inhibitor dissolved in assay buffer (for example the inhibitor from preparation example 1, 10 ⁇ M final concentration).
- the protocol is additionally adapted as follows: With PDEIC, additional Calmodulin 10 "7 M and CaCl 2 3mM are added to the reaction mixture.
- PDE2A is stimulated by adding cGMP 1 ⁇ M and tested at a concentration of 0.01% BSA for PDEIC and PDE2A as a substrate [5 ', 8- 3 H] adenosine 3', 5'-cyclic phosphate. (1 uCi / ul; Amersham Pharmacia Biotech, Piscataway, NJ) , For
- PDE5A [8- 3 H] guanosine 3 ', 5'-cyclic phosphate (1 uCi / ul; Amersham Pharmacia Biotech, Piscataway, NJ) are used. long-term potentiation
- Rat hippocampi are placed at an angle of approximately 70 degrees in relation to the cutting blade (chopper).
- the hippocampus is cut at intervals of 400 ⁇ m.
- the sections are removed from the blade with the aid of a very soft, heavily wetted brush (raccoon hair) and placed in a glass vessel with carbogenized cooled nutrient solution (124 mM NaCl, 4.9 mM KC1, 1.3 mM MgSO 4 * 7H 2 0, 2.5 mM CaCl 2+ water-free, 1.2 mM KH 2 P0 4j 25.6 M NaHC0 3; 10 mM glucose, pH 7.4) transferred.
- carbogenized cooled nutrient solution 124 mM NaCl, 4.9 mM KC1, 1.3 mM MgSO 4 * 7H 2 0, 2.5 mM CaCl 2+ water-free, 1.2 mM KH 2 P0 4j 25.6 M NaHC0 3; 10 mM glucose, pH 7.4
- the flow rate is 2.5 ml / min.
- Pre-gassing takes place under slight overpressure (about 1 atm) and via a micro-cannula in the antechamber.
- the cutting chamber is connected to the antechamber in such a way that a mini circulation can be maintained.
- the carbogen flowing out through the microcannula is used to drive the mini-circulation.
- the freshly prepared hippocampal slices are adapted in the cutting chamber at 33 ° C for at least 1 hour.
- the stimulus strength is chosen so that the focal excitative post-synaptic potential (fEPSP) is 30% of the maximum excitatory post-synaptic potential (EPSP).
- fEPSP focal excitative post-synaptic potential
- AM-Systems 2100 the creators are locally
- Edge of the cutting chamber is located, with the help of a DC amplifier.
- the field potentials are filtered using a low-pass filter (5 kHz).
- a low-pass filter 5 kHz.
- fEPSP rise the slope of the fEPSPs (fEPSP rise) is determined.
- PWIN software program developed in the Neurophysiology department. The averaging of the fEPSP
- the social recognition test is a learning and memory test. It measures the ability of rats to distinguish between known and unknown species. This test is therefore suitable for testing the learning or memory-improving effect of the compounds according to the invention.
- the adult animals are either at a fixed interval (e.g. 1 hour) before Trial 1 or immediately after Trial 1 either with vehicle (10% ethanol, 20% Solutol, 70% physiological saline) or 0.1 mg / kg, 0 , 3 mg / kg, 1.0 mg / kg or 3.0 mg / kg of the compound according to the invention, dissolved in 10% ethanol, 20% Solutol, 70% physiological saline injected intraperitoneally.
- Vehicle-treated rats show no reduction in social interaction time in Trial 2 compared to Trial 1 '. As a result, they have forgotten that they have had contact with the young animal before.
- the social interaction time in the second round after treatment with the compounds according to the invention is significantly reduced compared to the vehicle treated. This means that the substance-treated rats have remembered the juvenile animal and thus the compounds according to the invention have an improving effect on learning and memory.
- the new active ingredients can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and Solutions using inert, non-toxic, pharmaceutically acceptable carriers or solvents.
- the therapeutically active compound should in each case be present in a concentration of approximately 0.5 to 90% by weight of the total mixture, ie in amounts which are sufficient to achieve the dosage range indicated.
- the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and or dispersants, e.g. if water is used as the diluent, organic solvents can optionally be used as auxiliary solvents.
- the application is carried out in a conventional manner, preferably orally, transdermally or parenterally, in particular perlingually or intravenously. However, it can also be done by inhalation through the mouth or nose, for example with the aid of a spray, or topically via the skin.
- Device type MS Micromass ZQ
- Device type HPLC Waters Alliance 2795; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20mm x 4mm; Eluent A: 1 1 water + 0.5 ml 50% formic acid, eluent B: 1 1 acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A flow 1 ml / min ⁇ 2.5 min 30% A flow 2 ml / min ⁇ 3.0 min 5% A flow 2 ml / min ⁇ 4.5 min 5% A flow 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.
- Device type MS Micromass ZQ
- Device type HPLC HP 1100 Series
- UV DAD Column: Grom-Sil 120 ODS-4 HE 50 mm x 2 mm, 3.0 ⁇ m
- Eluent A water + 500 ⁇ l 50% formic acid / 1
- eluent B acetonitrile + 500 ul 50% formic acid / 1
- Oven 50 ° C
- Flow 0.8 ml / min
- UV detection 210 nm.
- Device type MS Micromass ZQ
- Device type HPLC Waters Alliance 2795
- Column Merck Chromolith SpeedROD RP-18e 50 mm x 4.6 mm
- Eluent A water + 500 ⁇ l 50% formic acid / 1
- Eluent B acetonitrile + 500 ⁇ l 50% formic acid / 1; Gradient: 0.0 min 10% B ⁇ 3.0 min 95% B ⁇ 4.0 min 95% B; Oven: 35 ° C; Flow: 0.0 min 1.0 ml / min ⁇ 3.0 min 3.0 ml / min ⁇ 4.0 min 3.0 ml / min; UV detection: 210 nm.
- Device type MS Micromass ZQ
- Device type HPLC HP 1100 Series
- UV DAD Pillar: Phenomenex
- Device type MS Micromass ZQ
- Device type HPLC Waters Alliance 2790
- Eluent A water + 500 ul 50% formic acid / 1
- eluent B acetonitrile + 500 ul 50% formic acid / 1
- Flow 0.0 min 0.75 ml / min ⁇ 4.5 min 0.75 ml / min
- Device type MS Micromass ZQ
- Device type HPLC Waters Alliance 2790
- Column Grom-Sil 120 ODS-4 HE 50 mm x 2 mm, 3.0 ⁇ m
- Eluent A water + 500 ul 50% formic acid / 1
- eluent B acetonitrile + 500 ul 50% formic acid / 1
- Gradient 0.0 min 0% B ⁇ 0.2 min 0% B ⁇ - 2.9 min 70% B ⁇ 3.1 min 90% B ⁇ 4.5 min 90% B
- Oven 45 ° C
- Flow 0.8 ml / min
- UV detection UV detection:
- Example 2A Analogously to the preparation of Example 2A, 0.53 g (48% of theory) of the title compound is obtained from 0.5 g (3.9 mmol) of 3-chloroaniline and 0.79 g (3.9 mmol) of methyl 3,3-bis (methylthio) -2-cyanoacrylate Get solid.
- Example 2A Analogously to the preparation of Example 2A, 0.57 (4.0 mmol) of 3-methoxyaniline and 0.8 g (4.0 mmol) of methyl 3,3-bis (methylthio) -2-cyanoacrylate 0.47 g (41% of theory) of the title compound as Get solid.
- Example 2A Analogously to the preparation of Example 2A, 0.25 g (1.59 mmol) of 3-fluoro-2-methylaniline and 0.32 g (1.59 mmol) of methyl 3,3-bis (methylthio) -2-cyanoacrylate are 0.15 g (34% of theory ) of the title compound as a solid.
- Example 2A Analogously to the preparation of Example 2A, 0.54 g (4.4 mmol) of 2,5-dimethylaniline and 0.9 g (4.4 mmol) of methyl .3,3-bis (methylthio) -2-cyanoacrylate became 0.9 g (75% of theory). obtained the title compound as a solid.
- Example 2A Analogously to the preparation of Example 2A, 0.9 g (67% of theory) of the title compound is obtained from 0.6 g (5.0 mmol) of 2-methoxyaniline and 1.0 g (5.0 mmol) of methyl 3,3-bis (methylthio) -2-cyanoacrylate Get solid.
- Example 2A Analogously to the preparation of Example 2A are prepared from 0.62 g (5.0 mmol) of 2-methyl-4-fluoroaniline and 1.01g (5.0 mmol) 'is methyl 3,3-bis (methylthio) -2-cyanoacrylate 0.7 g (50% of d. Th .) Obtaining the title compound as a solid.
- Example 2A Analogously to the preparation of Example 2A, 1.6 g (15.0 mmol) of 2-methylaniline and 3.01 g (15.0 mmol) of methyl 3,3-bis (methylthio) -2-cyanoacrylate 2.5 g (63% of theory) of the title compound as Get solid.
- Example 2A 10. Analogously to the preparation of Example 2A, 0.5 g (3.7 mmol) of 2-propylaniline and 0.7 g (3.7 mmol) of methyl 3,3-bis (methylthio) -2-cyanoacrylate become 0.7 g (61% of theory) of Obtain title compound as a solid.
- the product is purified by preparative HPLC (YMC Gel ODS-AQ S 5/15 ⁇ m; eluent A: water, eluent B: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95% B) cleaned. 60 mg (25% of theory) of the product are obtained.
- the product is purified by preparative HPLC (YMC Gel ODS-AQ S ' 5/15 ⁇ m; eluent A: water, eluent B: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95% B) cleaned. 433 mg (88% of theory) of the product are obtained.
- Example 4 Analogously to the preparation of Example 4, 0.1 g (0.35 mmol) of methyl 2-cyano-3 - [(3-chlorophenyl) amino] -3- (methylsulfanyl) -2-propenoate, 0.06 g (0.38 mmol) of 2-cyclopentylethanami- din-hydrochloride and 0.1 g (0.79 mmol) of potassium carbonate 45 mg (39% of theory) of the title compound as a colorless solid.
- Example 4 Analogously to the preparation of Example 4, 0.08 g (0.28 mmol) of methyl 2-cyano-3 - [(3-methoxyphenyl) amino] -3- (methylsulfanyl) -2-propenoate, 0.05 g (0.31 mmol) of 2-cyclopentylethane amidine hydrochloride and 0.09 g (0.63 mmol) potassium carbonate 40 mg (42% of theory) of the title compound as a colorless solid.
- Example 4 Analogously to the preparation of Example 4, 0.1 g (0.37 mmol) of methyl 2-cyano-3 - [(2,5-dimethylphenyl) amino] -3- (methylsulfanyl) -2-propenoate, 0.06 g (0.39 mmol) of 2- Cyclopentylethane amidine hydrochloride and 0.1 g (0.79 mmol) potassium carbonate 53 mg (45% of theory) of the title compound are obtained as a colorless solid.
- Example 4 Analogously to the preparation of Example 4, 0.2 g (0.71 mmol) of methyl 2-cyano-3 - [(2-methoxyphenyl) amino] -3- (methylsulfanyl) -2-propenoate, 0.13 g (0.79 mmol) of 2-cyclopentylethane amidine hydrochloride and 0.22 g (1.58 mmol) potassium carbonate 62 mg (26% of theory) of the title compound as a colorless solid.
- Example 4 Analogously to the preparation of Example 4, 0.1 g (0.36 mmol) of methyl 2-cyano-3 - [(4-fluoro-2-methylphenyl) amino] -3- (methylsulfanyl) -2-propenoate, 0.06 g (0.39 mmol) 2-Cyclopentylethane amidine hydrochloride and 0.1 g (0.78 mmol) potassium carbonate 54 mg (46% of theory) of the title compound as a colorless solid.
- Example 4 Analogously to the preparation of Example 4, 0.1 g (0.34 mmol) of methyl 2-cyano-3- (methylsulfanyl) -3 - [(2-propylphenyl) amino] -2-propenoate, 0.06 g (0.37 mmol) of 2- Cyclopentylethanamidin- Hydrochloride and 0.1 g (0.76 mmol) of potassium carbonate 57 mg (49% of theory) of the title compound as a colorless solid.
- Example 4 Analogously to the preparation of Example 4, 0.2 g (0.76 mmol) of methyl 2-cyano-3- (methylsulfanyl) -3 - [(2-methylphenyl) amino] -2- ⁇ ropenoate, 0.17 g (1.14 mmol) (35 ) -3-methylpentane amidine hydrochloride and 0.23 g (1.66 mmol) of potassium carbonate 183 mg (80% of theory) of the title compound as a colorless solid.
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Abstract
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Priority Applications (9)
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AU2004249392A AU2004249392A1 (en) | 2003-06-25 | 2004-06-16 | 6-arylamino-5-cyano-4-pyrimidinones as PDE9A inhibitors |
EP04739944A EP1644339B1 (de) | 2003-06-25 | 2004-06-16 | 6-arylamino-5-cyano-4-pyrimidinone als pde9a-inhibitoren |
DE502004006055T DE502004006055D1 (de) | 2003-06-25 | 2004-06-16 | 6-arylamino-5-cyano-4-pyrimidinone als pde9a-inhibitoren |
JP2006515952A JP4728954B2 (ja) | 2003-06-25 | 2004-06-16 | Pde9a阻害剤としての6−アリールアミノ−5−シアノ−4−ピリミジノン化合物 |
MXPA05013874A MXPA05013874A (es) | 2003-06-25 | 2004-06-16 | 6-arilamino-5-ciano-4-pirimidinonas como inhibidores de pde9a. |
CA002530461A CA2530461A1 (en) | 2003-06-25 | 2004-06-16 | 6-arylamino-5-cyano-4-pyrimidinones as pde9a inhibitors |
US10/559,954 US7488733B2 (en) | 2003-06-25 | 2004-06-16 | 6-arylamino-5-cyano-4-pyrimidinones as pde9a inhibitors |
IL172694A IL172694A0 (en) | 2003-06-25 | 2005-12-19 | 6-arylamino-5-cyano-4-pyrimidinones as pde9a inhibitors |
US12/339,393 US20090111838A1 (en) | 2003-06-25 | 2008-12-19 | 6-arylamino-5-cyano-4-pyrimidinones as pde9a inhibitors |
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DE10328479A DE10328479A1 (de) | 2003-06-25 | 2003-06-25 | 6-Arylamino-5-cyano-4-pyrimidinone |
DE10328479.6 | 2003-06-25 |
Related Child Applications (1)
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US12/339,393 Continuation US20090111838A1 (en) | 2003-06-25 | 2008-12-19 | 6-arylamino-5-cyano-4-pyrimidinones as pde9a inhibitors |
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PCT/EP2004/006477 WO2004113306A1 (de) | 2003-06-25 | 2004-06-16 | 6-arylamino-5-cyano-4-pyrimidinone als pde9a-inhibitoren |
Country Status (13)
Country | Link |
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US (2) | US7488733B2 (de) |
EP (2) | EP1644339B1 (de) |
JP (1) | JP4728954B2 (de) |
CN (1) | CN1835929A (de) |
AU (1) | AU2004249392A1 (de) |
CA (1) | CA2530461A1 (de) |
DE (2) | DE10328479A1 (de) |
ES (1) | ES2298769T3 (de) |
IL (1) | IL172694A0 (de) |
MX (1) | MXPA05013874A (de) |
RU (1) | RU2006101824A (de) |
WO (1) | WO2004113306A1 (de) |
ZA (1) | ZA200510319B (de) |
Cited By (9)
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WO2006125554A1 (de) * | 2005-05-27 | 2006-11-30 | Bayer Healthcare Ag | Verwendung von cyanopyrimidinen für die behandlung von herz-kreislauf-erkrankungen |
US8623879B2 (en) | 2008-04-02 | 2014-01-07 | Boehringer Ingelheim International Gmbh | 1-heterocyclyl-1,5-dihydro-pyrazolo[3,4-D] pyrimidin-4-one derivates and their use as PDE9A modulators |
US8623901B2 (en) | 2009-03-31 | 2014-01-07 | Boehringer Ingelheim International Gmbh | Compounds for the treatment of CNS disorders |
US8648085B2 (en) | 2007-11-30 | 2014-02-11 | Boehringer Ingelheim International Gmbh | 1, 5-dihydro-pyrazolo (3, 4-D) pyrimidin-4-one derivatives and their use as PDE9A mudulators for the treatment of CNS disorders |
US8809345B2 (en) | 2011-02-15 | 2014-08-19 | Boehringer Ingelheim International Gmbh | 6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders |
US8912201B2 (en) | 2010-08-12 | 2014-12-16 | Boehringer Ingelheim International Gmbh | 6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders |
US9067945B2 (en) | 2002-08-23 | 2015-06-30 | Boehringer Ingehleim International GmbH | Selective phosphodiesterase 9A inhibitors as medicaments for improving cognitive processes |
US9079905B2 (en) | 2008-09-08 | 2015-07-14 | Boehringer Ingelheim International Gmbh | Compounds for the treatment of CNS disorders |
US9617269B2 (en) | 2012-08-08 | 2017-04-11 | Sun Yat-Sen University | N-substituted pyrazolo [3,4-D] pyrimidine ketone compound, and preparation process and use thereof |
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DE10238724A1 (de) | 2002-08-23 | 2004-03-04 | Bayer Ag | Alkyl-substituierte Pyrazolpyrimidine |
DE10238723A1 (de) * | 2002-08-23 | 2004-03-11 | Bayer Ag | Phenyl-substituierte Pyrazolyprimidine |
DE10320785A1 (de) * | 2003-05-09 | 2004-11-25 | Bayer Healthcare Ag | 6-Arylmethyl-substituierte Pyrazolopyrimidine |
US8044060B2 (en) * | 2003-05-09 | 2011-10-25 | Boehringer Ingelheim International Gmbh | 6-cyclylmethyl- and 6-alkylmethyl pyrazolo[3,4-D]pyrimidines, methods for their preparation and methods for their use to treat impairments of perception, concentration learning and/or memory |
DE10328479A1 (de) * | 2003-06-25 | 2005-01-13 | Bayer Ag | 6-Arylamino-5-cyano-4-pyrimidinone |
DE102004001873A1 (de) * | 2004-01-14 | 2005-09-29 | Bayer Healthcare Ag | Cyanopyrimidinone |
TW201118099A (en) * | 2009-08-12 | 2011-06-01 | Boehringer Ingelheim Int | New compounds for the treatment of CNS disorders |
CA2832343A1 (en) * | 2011-04-18 | 2012-10-26 | Basf Se | Multicomponent crystalline system of rosuvastatin calcium salt and vanillin |
WO2016145614A1 (en) * | 2015-03-17 | 2016-09-22 | Merck Sharp & Dohme Corp. | Triazolyl pyrimidinone compounds as pde2 inhibitors |
MA53841A (fr) | 2017-06-08 | 2021-09-22 | Merck Sharp & Dohme | Inhibiteurs pde9 de pyrazolopyrimidine |
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- 2003-06-25 DE DE10328479A patent/DE10328479A1/de not_active Withdrawn
-
2004
- 2004-06-16 ES ES04739944T patent/ES2298769T3/es not_active Expired - Lifetime
- 2004-06-16 US US10/559,954 patent/US7488733B2/en not_active Expired - Lifetime
- 2004-06-16 EP EP04739944A patent/EP1644339B1/de not_active Expired - Lifetime
- 2004-06-16 WO PCT/EP2004/006477 patent/WO2004113306A1/de active IP Right Grant
- 2004-06-16 CN CNA2004800233928A patent/CN1835929A/zh active Pending
- 2004-06-16 RU RU2006101824/04A patent/RU2006101824A/ru not_active Application Discontinuation
- 2004-06-16 JP JP2006515952A patent/JP4728954B2/ja not_active Expired - Lifetime
- 2004-06-16 AU AU2004249392A patent/AU2004249392A1/en not_active Abandoned
- 2004-06-16 DE DE502004006055T patent/DE502004006055D1/de not_active Expired - Lifetime
- 2004-06-16 MX MXPA05013874A patent/MXPA05013874A/es unknown
- 2004-06-16 CA CA002530461A patent/CA2530461A1/en not_active Abandoned
- 2004-06-16 EP EP07121390A patent/EP1905765A1/de not_active Withdrawn
-
2005
- 2005-12-19 IL IL172694A patent/IL172694A0/en unknown
- 2005-12-20 ZA ZA200510319A patent/ZA200510319B/xx unknown
-
2008
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Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
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US9067945B2 (en) | 2002-08-23 | 2015-06-30 | Boehringer Ingehleim International GmbH | Selective phosphodiesterase 9A inhibitors as medicaments for improving cognitive processes |
WO2006125554A1 (de) * | 2005-05-27 | 2006-11-30 | Bayer Healthcare Ag | Verwendung von cyanopyrimidinen für die behandlung von herz-kreislauf-erkrankungen |
US8648085B2 (en) | 2007-11-30 | 2014-02-11 | Boehringer Ingelheim International Gmbh | 1, 5-dihydro-pyrazolo (3, 4-D) pyrimidin-4-one derivatives and their use as PDE9A mudulators for the treatment of CNS disorders |
US8623879B2 (en) | 2008-04-02 | 2014-01-07 | Boehringer Ingelheim International Gmbh | 1-heterocyclyl-1,5-dihydro-pyrazolo[3,4-D] pyrimidin-4-one derivates and their use as PDE9A modulators |
US9096603B2 (en) | 2008-04-02 | 2015-08-04 | Boehringer Ingelheim International Gmbh | 1-heterocyclyl-1,5-dihydro-pyrazolo[3,4-D] pyrimidin-4-one derivatives and their use as PDE9A modulators |
US9079905B2 (en) | 2008-09-08 | 2015-07-14 | Boehringer Ingelheim International Gmbh | Compounds for the treatment of CNS disorders |
US8623901B2 (en) | 2009-03-31 | 2014-01-07 | Boehringer Ingelheim International Gmbh | Compounds for the treatment of CNS disorders |
US9102679B2 (en) | 2009-03-31 | 2015-08-11 | Boehringer Ingelheim International Gmbh | Compounds for the treatment of CNS disorders |
US8912201B2 (en) | 2010-08-12 | 2014-12-16 | Boehringer Ingelheim International Gmbh | 6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders |
US9328120B2 (en) | 2010-08-12 | 2016-05-03 | Boehringer Ingelheim International Gmbh | 6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders |
US8809345B2 (en) | 2011-02-15 | 2014-08-19 | Boehringer Ingelheim International Gmbh | 6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders |
US9617269B2 (en) | 2012-08-08 | 2017-04-11 | Sun Yat-Sen University | N-substituted pyrazolo [3,4-D] pyrimidine ketone compound, and preparation process and use thereof |
Also Published As
Publication number | Publication date |
---|---|
US20070105881A1 (en) | 2007-05-10 |
US7488733B2 (en) | 2009-02-10 |
ZA200510319B (en) | 2007-03-28 |
JP4728954B2 (ja) | 2011-07-20 |
IL172694A0 (en) | 2006-04-10 |
EP1905765A1 (de) | 2008-04-02 |
CA2530461A1 (en) | 2004-12-29 |
JP2007506662A (ja) | 2007-03-22 |
EP1644339B1 (de) | 2008-01-23 |
DE10328479A1 (de) | 2005-01-13 |
DE502004006055D1 (de) | 2008-03-13 |
RU2006101824A (ru) | 2006-07-27 |
CN1835929A (zh) | 2006-09-20 |
AU2004249392A1 (en) | 2004-12-29 |
MXPA05013874A (es) | 2006-07-06 |
EP1644339A1 (de) | 2006-04-12 |
ES2298769T3 (es) | 2008-05-16 |
US20090111838A1 (en) | 2009-04-30 |
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