EP1404677A1 - Imidazotriazines utilisees comme inhibiteurs de phosphodiesterase - Google Patents

Imidazotriazines utilisees comme inhibiteurs de phosphodiesterase

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Publication number
EP1404677A1
EP1404677A1 EP02747362A EP02747362A EP1404677A1 EP 1404677 A1 EP1404677 A1 EP 1404677A1 EP 02747362 A EP02747362 A EP 02747362A EP 02747362 A EP02747362 A EP 02747362A EP 1404677 A1 EP1404677 A1 EP 1404677A1
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European Patent Office
Prior art keywords
mmol
compounds
nmr
mhz
theory
Prior art date
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EP02747362A
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German (de)
English (en)
Inventor
Jens-Kerim ERGÜDEN
Marcus Bauser
Nils Burkhardt
Dietmar Flubacher
Arno Friedl
Irene Gerlach
Volker Hinz
Reinhard Jork
Paul Naab
Maria Theresia Niewöhner
Thorsten Oliver Repp
Karl-Heinz Schlemmer
Jürgen Stoltefuss
David BRÜCKNER
Martin Hendrix
Dagmar Schauss
Adrian Tersteegen
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Bayer AG
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Bayer Healthcare AG
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Publication of EP1404677A1 publication Critical patent/EP1404677A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • IMIDAZOTRIAZINE AS PHOSPHODIESTERASE INHIBITORS
  • the invention relates to novel imidazotriazines, processes for their preparation, and their use for the preparation of medicaments for the treatment and / or prophylaxis of neurodegenerative diseases, in particular Parkinson's disease.
  • cyclic nucleotides cGMP and cAMP are among the most important intracellular messengers.
  • Phosphodiesterases (PDEs) play an important role in the regulation of cGMP and cAMP levels. So far 11
  • Phosphodiesterase isoenzyme groups known (PDE 1-7: Beavo et al., Mol.
  • PDE 10A hydrolyzes both cAMP and cGMP (Fujishige J Biol. Chem. 1999, 274, 18438-18445). Transcribed PDE 10A was identified mainly in the putamen and caudate nucleus regions of the brain as well as in thyroid and testicular tissue. In addition, as compared to normal tissue, PDE10A mRNA is increasingly expressed in certain tumor tissues such as breast, liver, colon, and lung tumor tissues.
  • No. 3,941,785 describes 2-aminoimidazo [5,1-fj- [1,2,4] triazines as PDE inhibitors with spasmolytic activity for the treatment of asthma, bronchitis, chronic heart failure and skin diseases.
  • the present invention relates to compounds of the general formula (I),
  • R 1 is (C 6 -C 10 ) -aryl which is optionally identical or different and is selected from radicals selected from among halogen, formyl, carbamoyl, cyano, hydroxyl,
  • R and R independently of one another denote hydrogen or (C 1 -C 6 ) -alkyl
  • NR 5 R 6 bonded via a nitrogen atom, optionally identically or differently, by radicals selected from the group consisting of oxo, halogen, (C 1 -C 6 ) -alkyl and (C 1 -C 4 -acyl-substituted, 4 to 8-membered heterocyclyl,
  • R 2 is a saturated or partially unsaturated hydrocarbon radical having 1 to 10 carbon atoms
  • R J is methyl or ethyl, is O, S or NR 7 ,
  • R 7 is hydrogen or optionally (C 1 -C 3 ) -alkoxy-substituted (C 1 -C 6) -alkyl,
  • R 4 is (C 6 -C 10) -aryl or 5- to 10-membered heteroaryl, where aryl and heteroaryl are optionally identical or different by radicals selected from the group consisting of halogen, formyl, carboxyl, carbamoyl, -SO 3 H, amino - Sulfonyl, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, (-CC 6 ) - alkyl, (-CC 6 ) -alkoxy, l, 3-dioxa-propane-l, 3-diyl, (-C-C 6 ) -Alkylthio,
  • R 8 and R 9 are independently hydrogen, (C ⁇ -C6) - alkyl or (C t -C ö) - acyl mean
  • the compounds according to the invention can be prepared in stereoisomeric forms which are either like image and mirror image (enantiomers) or which are not like image and
  • the invention relates to both the enantiomers or diastereomers or their respective mixtures. This Mixtures of the enantiomers and diastereomers can be separated in a known manner in the stereoisomerically uniform components.
  • the compounds according to the invention can also be present in the form of their salts, hydrates and / or solvates.
  • Acid addition salts of the compounds with mineral acids, carboxylic acids or sulfonic acids be. Particularly preferred are e.g. Salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
  • Solvates of the compounds of the invention are stoichiometric compositions of the compounds or their salts with solvent.
  • the substituents generally have the following meaning:
  • (d-QVacyl is a straight-chain or branched acyl radical having 1 to 6 carbon atoms, for example: acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, pentylcarbonyl and hexylcarbonyl to 4 carbon atoms, particularly preferred are acetyl and ethylcarbonyl.
  • (C 1 -C 3 ) -alkanediyl in the context of the invention is a straight-chain or branched alkanediyl radical having 1 to 3 carbon atoms. Examples which may be mentioned are methylene, ethylene, ethane-l, l-diyl, propylene, propane-l, 2-diyl, propane-2,2-diyl. Methylene is preferred.
  • (C 1 -C 6 ) -Alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy. Particularly preferred is a straight-chain or branched alkoxy radical having 1 to 3 carbon atoms.
  • (C 1 -C 6 ) -alkyl is a straight-chain or branched alkyl radical having 1 to 6 carbon atoms.
  • Preferred is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
  • Particularly preferred is a straight-chain or branched alkyl radical having 1 to 3 carbon atoms.
  • (C 1 -C 6 ) -Alkylsulfinyl represents a straight-chain or branched alkylsulfinyl radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched alkylsulfinyl radical having 1 to 4 carbon atoms. For example:
  • Particularly preferred is a straight-chain or branched alkylsulfinyl radical having 1 to 3 carbon atoms.
  • (C i -C 6 ) - Alkylsulfonyl represents a straight-chain or branched Alkylsulfonylrest having 1 to 6 carbon atoms.
  • a straight-chain or branched alkylsulfonyl radical having 1 to 4 carbon atoms is preferred. Examples which may be mentioned are: methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl and n-hexylsulfonyl. Particularly preferred is a straight-chain or branched alkylsulfonyl radical having 1 to 3 carbon atoms.
  • (C t -C 6 ) -Alkylthio in the context of the invention represents a straight-chain or branched alkylthio radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched alkylthio radical having 1 to 4 carbon atoms. Examples which may be mentioned: methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio. Particularly preferred is a straight-chain or branched one
  • Alkylthio radical having 1 to 3 carbon atoms.
  • (C -C 10 ) -Aryl is in the context of the invention an aromatic radical having 6 to 10 carbon atoms.
  • Preferred aryl radicals are phenyl and naphthyl.
  • Halogen is in the context of the invention generally fluorine, chlorine, bromine and iodine. Preference is given to fluorine, chlorine and bromine. Particularly preferred are fluorine and chlorine.
  • 5- to 10-membered heteroaryl in the context of the invention generally represents an aromatic, mono- or bicyclic radical having 5 to 10 ring atoms and up to 5 heteroatoms from the series S, O and / or N. Preferred are 5-6 -membered heteroaryls with up to 4 heteroatoms.
  • the heteroaryl radical may be bonded via a carbon or heteroatom. Examples which may be mentioned are: thienyl, furyl,
  • a 4- to 8-membered heterocyclyl bonded via a nitrogen atom is generally a monocyclic or polycyclic, heterocyclic radical having 4 to 8 ring atoms and up to 3, preferably 2, heteroatoms or hetero groups from the series N, O, S, SO, SO 2 , wherein at least one of the heteroatoms or hetero groups is a nitrogen atom.
  • 5- to 7-membered heterocyclyl is preferred.
  • Mono- or bicyclic heterocyclyl is preferred. Particularly preferred is monocyclic heterocyclyl.
  • the heterocyclyl radicals may be saturated or partially unsaturated. Saturated heterocyclyl radicals are preferred.
  • the heterocyclyl radicals can be bonded via a carbon atom or a heteroatom. Particular preference is given to 5- to 7-membered, monocyclic saturated heterocyclyl radicals having up to two heteroatoms from the series O, N and S. Examples which may be mentioned are: pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, piperidinyl, morpholinyl , Perhydroazepinyl.
  • a saturated or partially unsaturated hydrocarbon radical having 1 to 10 carbon atoms in the context of the invention is a straight-chain or branched, cyclic or partially cyclic, nonaromatic, organic radical which contains 1 to 10 carbon atoms and has one to several double and one carbon atoms may contain triple bonds and, depending on the degree of saturation and cyclization, is saturated with hydrogen atoms.
  • Saturated organic radicals are preferred.
  • the hydrocarbon radical may consist of a straight-chain or branched alkyl radical, where two geminal, vicinal or non-adjacent Hydrogen atoms of the alkyl radical may in turn be replaced by a straight-chain or branched alkanediyl radical.
  • Examples include: straight-chain or branched (C 1 -C ⁇ 0) alkyl, (C 3 -C 10) -cycloalkyl and a total of 3 to 10 carbon atoms containing mono- or di-alkyl-cycloalkyl, cycloalkyl-alkyl, and [ (alkyl) cycloalkyl] alkyl.
  • Examples which may be mentioned are: methyl, ethyl, vinyl, n-propyl, i-propyl, allyl, propargyl, butyl, pentyl, but-2-yl, n-hept-3-yl, cyclopropyl, 2-methylcyclopropyl 1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dimethyl-cyclohexane-1, 1-diyl, 4-tert. Butylcyclohexyl, 2-cyclohexyl-prop-1-yl.
  • a further embodiment of the invention relates to compounds of the general formula (I),
  • R 1 is phenyl which is optionally monosubstituted or disubstituted by radicals selected from the group consisting of fluorine, chlorine, methoxy, ethoxy or a radical of the formula -SO 2 NR 5 R 6 , where appropriate in which
  • NR 5 R 6 is a 5- to 7-membered heterocyclyl bonded via a nitrogen atom
  • R 2 is (C 1 -C 8 ) -alkyl or (C 3 -C 8 ) -cycloalkyl
  • R 3 is methyl or ethyl
  • A is O or NH
  • R 4 is phenyl which is optionally identical or different and is substituted by radicals selected from among fluorine, chlorine, methoxy or ethoxy,
  • A is O or NH
  • R 1 , R 2 , R 3 , E and R 4 have the abovementioned meaning
  • a further embodiment of the invention relates to compounds of the general formula (I),
  • R 1 , R 2 , R 3 , A and R 4 have the abovementioned meaning
  • a further embodiment of the invention relates to compounds of the general formula (I),
  • R 2 is (C i -C 8) - cycloalkyl represents alkyl or (C 3 -C 8), and
  • R 1 , R 3 , A, E and R 4 have the abovementioned meaning
  • a further embodiment of the invention relates to compounds of the general formula (I),
  • R, 3 is methyl
  • R 1 , R 2 , A, E and R 4 have the abovementioned meaning, and their salts, hydrates and / or solvates.
  • a further embodiment of the invention relates to compounds of the general formula (I),
  • R 4 is phenyl which is mono- to trisubstituted by methoxy
  • R 1 , R 2 , R 3 , A and E have the abovementioned meaning
  • a further embodiment of the invention relates to compounds of the general formula (I),
  • R 4 is 3,4,5-trimethoxyphenyl
  • R 1 , R 2 , R 3 , A and E have the abovementioned meaning
  • R 4 is 3,4,5-trimethoxyphenyl, A is O or NH,
  • R 1 , R and R J have the abovementioned meaning
  • a further embodiment of the invention relates to compounds of the general formula (I)
  • R 2 is (C 1 -C 6) -alkyl or (C 3 -CG) -cycloalkyl
  • R 3 is methyl or ethyl
  • R 4 is 3,4,5-trimethoxyphenyl
  • A is O or NH
  • R 1 has the abovementioned meaning
  • the invention further relates to processes for the preparation of the compounds of the formula (I).
  • process for the preparation of the compounds of the formula (I).
  • R 1 , R 2 and R 3 have the abovementioned meaning
  • R 4 , A and E have the abovementioned meaning
  • R 1 , R 2 , R 3 , R 4 , A and E have the abovementioned meaning
  • inert solvents these include halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofiirane, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as Benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, ethyl acetate, dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane, dimethylsulfoxide, acetonitrile or pyridine, are preferably pyridine, glycol dimethyl ether, diethylene glycol dimethyl methyl
  • DBU triethylamine or diisopropylethylamine, preferably sodium hydride, Triethylamine, potassium tert-butoxide or DBU, optionally in the presence of auxiliary reagents, preferably potassium fluoride or dimethylaminopyridine, optionally in the presence of crown ether, preferably 15-crown-5, 18-crown-8 or 12-crown-4, preferably in one Temperature range from room temperature to the reflux of the solvent at atmospheric pressure, to.
  • R, R and R have the abovementioned meaning
  • R 4 and E have the abovementioned meaning
  • X 1 is a leaving group, preferably mesylate, tosylate or halogen, more preferably bromine or iodine,
  • R. 1, R r> 2, r R> 3, r R> 4 and E have the abovementioned meaning
  • halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene
  • ethers such as diethyl ether, methyl tert-butyl ester, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether
  • hydrocarbons such as benzene, xylene , Toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, ethyl acetate, dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane, dimethyl sulfoxide, acetonitrile or pyridine, preferred are dimethyl sulfoxide, dimethylformamide or
  • Tetrahydrofuran if appropriate in the presence of a base, such as, for example, alkali metal carbonates, such as cesium carbonate, sodium or potassium carbonate, or potassium tert-butylate, or amides, such as sodium amide, lithium bis (trimethylsilyl) amide, lithium diisopropylamide, or organometallic compounds, such as butyllithium or phenyllithium, or other bases such as sodium hydride, DBU, triethylamine or
  • Diisopropylethylamine preferably triethylamine, sodium carbonate or sodium hydrogencarbonate, preferably in a temperature range from room temperature to the reflux of the solvent at normal pressure, in order.
  • the compounds of general formula (V) are known or can be synthesized by known methods from the corresponding starting materials.
  • R 1 , R 2 and R 3 have the abovementioned meaning
  • a chlorinating agent preferably phosphorus oxychloride, phosphorus pentachloride, sulfuryl chloride and / or thionyl chloride,
  • halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane,
  • Acetonitrile, diethylphenylamine or pyridine preferred are pyridine, trichloromethane, diethylphenylamine, dioxane or acetonitrile, optionally in the presence of a base such as alkali metal carbonates such as cesium carbonate, sodium or Potassium carbonate, or other bases such as DBU, triethylamine, diethylphenylamine or diisopropylethylamine, are preferably triethylamine, pyridine or diethylphenylamine, preferably in a temperature range from -20 ° C. to room temperature at atmospheric pressure (cf., for example, Knutsen et al., J. Chem. Perkin Trans 1, 1985, 621-630, A. Kraszewski, J. Stawinski, Tetrahedron Lett., 1980, 21,
  • R 2 and R 3 have the abovementioned meaning
  • R 5 and R 6 independently of one another represent hydrogen or (C 1 -C 6 ) -alkyl
  • NR 5 R 6 for a bonded via a nitrogen atom optionally the same or different selected by radicals selected from the group consisting of oxo, halogen, (-CC 6 ) - alkyl and (-CC 6 ) -acyl, 4- to 8-membered Heterocyclyl, and R 7 is hydrogen, halogen, formyl, carbamoyl, cyano, hydroxy,
  • R 2 , R 3 and R 7 have the abovementioned meaning
  • R and R have the abovementioned meaning, to.
  • the first step is optionally in inert solvents, which include halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, Hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitro methane, dimethylacetamide, 1,2-dimethoxyethane, dimethyl sulfoxide, acetonitrile or pyridine, preferably methylene chloride, trichloromethane, tetrahydrofuran or 1,2-dichlor
  • the second stage is carried out in inert solvents, which include halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofiirane, glycol dimethyl ether or diethylene glycol dimethyl ether , Hydrocarbons such as benzene, xylene, toluene,
  • Hexane, cyclohexane or petroleum fractions, or other solvents such as nitro methane, dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane, dimethyl sulfoxide, acetonitrile or pyridine, preferably methylene chloride, trichloromethane, tetrahydrofuran or dimethylformamide, preferably in a temperature range from room temperature to reflux of Solvent carried out at atmospheric pressure.
  • the compounds of general formula VTI are known or can be synthesized by known methods from the corresponding starting materials.
  • compounds of the general formula (IV) are reacted with phosphorus pentasulfide, optionally in inert solvents, these include halohydrocarbons, such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers, such as diethyl ether , Methyl tertiary butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, 1,2-dimethoxyethane, dimethylsulfoxide, acetonitrile or pyridine Pyr
  • this reaction also with Lawesson's reagent in inert solvents, these include halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, Glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, 1,2-dimethoxyethane, dimethyl sulfoxide
  • halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroe
  • R 1 , R 2 and R 3 have the abovementioned meaning
  • dehydrating reagents for example Lewis acids
  • suitable dehydrating reagents for example Lewis acids
  • phosphorus oxychloride, phosphorus pentoxide, polyphosphoric acid or methylsulfonyl chloride if appropriate in inert solvents, these include halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or Trichlorethylene, ethers like
  • R 1 is phenyl, which is optionally substituted by halogen, formyl, carbamoyl, cyano,
  • R 1 and R 3 have the abovementioned meaning, with compounds of the general formula (X),
  • Y is halogen, preferably bromine or chlorine, or hydroxy
  • halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene
  • ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether
  • hydrocarbons such as benzene, xylene , Toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane, 2-butanone, dimethylsulfoxide, acetonitrile, pyridine or hexamethylphosphoric triamide, preferably
  • inert solvents these include halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or Diethylenglykoldi- methyl ether, hydrocarbons such as benzene , Xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane, dimethylsulfoxide, acetonitrile or pyridine, preferably
  • Triethylamine, N-methylmoholin, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine particularly preferred is the combination of N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) and 1-hydroxybenzotriazole (HOBt ) and the combination of benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) and triethylamine, preferably in a temperature range from room temperature to 50 ° C at atmospheric pressure to.
  • EDC N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride
  • HOBt 1-hydroxybenzotriazole
  • BOP benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluoro
  • the compounds of general formula (X) are known or can be synthesized by known methods from the corresponding starting materials.
  • R 1 and R 3 have the abovementioned meaning
  • halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether , Alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, ethyl acetate, acetone, dimethylformamide, Dimethylacet
  • Sulfuric acid, hydrochloric acid, hydrogen bromide and acetic acid or a mixture thereof, optionally with the addition of water, is particularly preferred Hydrogen chloride or hydrogen chloride / water, preferably in a temperature range from room temperature to 100 ° C at atmospheric pressure, in order.
  • R 1 has the meaning indicated above
  • Do not change reaction conditions e.g. Alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or other solvents such as dimethylformamide or dimethyl sulfoxide, preferably methanol or ethanol, in a temperature range from -10 ° C to 50 ° C at Normal pressure (cf., for example, KM Doyle, F. Kurzer, Synthesis 1974, 583),
  • Alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or other solvents such as dimethylformamide or dimethyl sulfoxide, preferably methanol or ethanol, in a temperature range from -10 ° C to 50 ° C at Normal pressure (cf., for example, KM Doyle, F. Kurzer, Synthesis 1974, 583),
  • R "2" u ⁇ nd J ⁇ R> 3 have the meaning indicated above, and R 8 is (C 1 -C 4 ) -alkyl, preferably methyl or ethyl,
  • inert solvents e.g. Alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or other solvents such as dimethylformamide or dimethyl sulfoxide, preferably methanol or ethanol, in a temperature range from room temperature to reflux of the solvent at atmospheric pressure, around.
  • solvents e.g. Alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or other solvents such as dimethylformamide or dimethyl sulfoxide, preferably methanol or ethanol, in a temperature range from room temperature to reflux of the solvent at atmospheric pressure, around.
  • R 2 is methyl
  • R 1 has the abovementioned meaning
  • Y 2 is cyano or methoxycarbonyl
  • halogenated hydrocarbons such as
  • Methylene chloride trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene
  • ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether
  • hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as 1, 2-dimethoxyethane , Acetonitrile or pyridine, preferably toluene with trimethylaluminum in hexane and
  • Ammonium chloride first at -20 ° C and then at room temperature to 80 ° C at atmospheric pressure (see, e.g., R.S. Garigipati, Tetrahedron Lett., 1990, 31, 1969-1972), or
  • R 1 has the meaning indicated above
  • R 2 and R 3 have the abovementioned meaning
  • R 8 has the abovementioned meaning
  • X 1 is halogen, preferably chlorine or bromine
  • these include halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-
  • ethers such as diethyl ether, methyl tert-butyl ether, Dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane, 2-butanone, dimethyl sulfoxide, Acetonitrile or pyridine, preferably tetrahydrofuran or diethyl ether, if appropriate in the presence of a base, for example alkali metal carbonates, such as cesium carbonate, sodium or potassium carbonate, or potassium tert-butoxide, or amides, such as sodium amide, lithium bis (trimethyls), a base, for example alkali metal carbonates
  • Lithium diisopropylamide, piperidine or triethylamine optionally in the presence of a catalyst such as dimethylaminopyridine at room temperature until the solvents reflux at normal pressure (see, e.g., Charles, J. Chem. Soc, Perkin Trans., 7, 1980, 1139).
  • R, 3 has the meaning indicated above, with compounds of the general formula (XVIH),
  • R 2 has the meaning given above, and
  • X 2 is halogen, preferably chlorine or bromine
  • halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene
  • ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether
  • hydrocarbons such as benzene , Xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane, 2-butanone, dimethylsulfoxide, acetonitrile or pyridine, preferably methylene chloride, optionally in the presence
  • the compounds of the general formula (I) according to the invention are suitable for use as medicaments in the treatment of humans and animals.
  • the compounds of the invention show an unpredictable, valuable spectrum of pharmacological activity.
  • the compounds according to the invention can be used alone or in combination with other medicaments for the treatment and / or prevention of Parkinson's disease and cancer.
  • PDE10A (WO 01/29199, Figure IA) is recombinantly expressed in Sf9 insect cells (Invitrogen, Carlsbad, CA) using the Bac-to-Bac TM baculovirus expression system from Life Technologies (Gaithersburg, MD). 48 h after infection, cells are harvested and dissolved in 20 mL (per IL culture) lysis buffer (50 mM Tris-HCl, pH 7.4, 50 mM NaCl, 1 mM MgCl 2 , 1.5 mM EDTA, 10% glycerol plus 20 ⁇ L protease inhibitor Cocktail Set III [CalBiochem, La Jolla, Calif. USA]). The cells are sonicated at 4 ° C for 1 minute and then centrifuged for 30 minutes at 4 ° C at 10,000 rpm. The supernatant (PDE10A preparation) was collected and stored at -20 ° C.
  • test substances are resolved to determine their in vitro effect on PDE 10A in 100% DMSO and serially diluted. Typically, serial dilutions of 200 ⁇ M to 1.6 ⁇ M are prepared (resulting final concentrations in the assay: 4 ⁇ M to 0.032 ⁇ M). 2 ⁇ L each of the diluted substance solutions are introduced into the wells of microtiter plates (Isoplate; Wallac Inc., Atlanta,
  • the substrate [5 ', 8- 3 H] adenosine 3', 5'-cyclic phosphate (1 ⁇ Ci / ⁇ L; Amersham Pharmacia Biotech., Piscataway, NJ) is assayed 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. By adding 50 ⁇ L (0.025 ⁇ Ci) of the diluted substrate, the enzyme reaction is finally started.
  • assay buffer 50 mM Tris / HCl pH 7.5 , 8.3 mM MgCl 2 , 1.7 mM EDTA
  • test mixtures are incubated for 60 min at room temperature and the reaction is stopped by addition of 25 ⁇ L of a suspension of 18 mg / mL Yttrium Scintillation Proximity Beads (Amersham Pharmacia Biotech., Piscataway, NJ).
  • the microtiter plates are sealed with a foil and left for 60 min at room temperature.
  • the plates are then measured for 30 seconds per well in a Microbeta scintillation counter (Wallac Inc., Atlanta, GA).
  • IC 50 values are determined by plotting the concentration of the substance against the percent inhibition.
  • PDE1C GenBank / EMBL Accession Number: NM_005020
  • PDE2A Rosman et al, Gene 1997, 191, 89-95
  • PDE3B Mosman et al, Genomics 1996 36, 476-485
  • PDE4B Bosiger et al., Mol. Cell Biol. 1993 13, 6558-6571
  • PDE5A Recombinant PDE1C (GenBank / EMBL Accession Number: NM_005020), PDE2A (Rosman et al, Gene 1997, 191, 89-95), PDE3B (Miki et al, Genomics 1996 36, 476-485), PDE4B (Böiger et al., Mol. Cell Biol. 1993 13, 6558-6571), PDE5A
  • PDE7B is determined according to the test protocol described above for PDE 10A. The log is adjusted as follows for determining a corresponding effect on recombinant PDE IC, PDE2A and PDE5A: In PDE IC calmodulin are added 10 "7 M and CaCl 2 3 mM to the reaction mixture in addition PDE2A is stimulated 1 uM in the assay by the addition of cGMP. and with a BSA
  • 6-hydroxydopamine (6-OH-DAV lesion in the rat
  • Parkinson's disease The degeneration of dopaminergic nigrostriatal and striatopallidal neurotransmission is the major hallmark of Parkinson's disease
  • Parkinson's disease can be largely simulated in an animal model in which rats are injected intracerebrally with the neurotoxin 6-OH-DA.
  • the trial Animals are kept under controlled conditions (humidity, temperature) and a 12 hour light-dark cycle. The animals have - if they were not in an experiment - free access to water and food.
  • the lesion of nigrostriatal neurotransmission is done by a unilateral, single injection of 8 ⁇ g of 6-OH-DA HBr (Sigma, St. Louis, Mo., USA) dissolved in 4 ⁇ l of 0.01% ascorbic acid saline. The solution was slowly injected with 1 ⁇ l min. The coordinates of the injection are King and Klippel: 2.4 mm anterior, 1.49 mm lateral, -2.7 mm anterior. After injection, the injection needle was left in situ for a further 5 minutes to facilitate diffusion of the neurotoxin.
  • the animals are placed on a hot plate and returned to their cages after awakening under control and fed and
  • the animals are treated with substance one day after surgery until the end of the experiment, 28 days after surgery.
  • MPTP l-methyl-4-phenyl-l, 2,3,6-tetrahydropyridine
  • MPTP is a neurotoxin that causes the degeneration of dopaminergic neurons in the substantia nigra typical of Parkinson's disease in humans and animals.
  • Parkinson's Monkey Scale Humans and in the monkey the motor symptoms typical for Parkinson's disease. These symptoms are rated on a Parkinson's Monkey Scale.
  • rhesus monkeys (Macaca fascicularis) are treated daily with MPTP (0.2 mg / kg iv) until they reach a score of 8 on the parkinson scale.
  • MPTP 0.2 mg / kg iv
  • the first Parkinson's symptoms occur after 5-10 days of MPTP treatment Due to the long-term effects of the neurotoxin, the clinical symptoms of the animals continue to develop until full Parkinsonism (score> 15).
  • the new active compounds can be converted into the customary formulations in a known manner, such as tablets, dragees, pills, granules, aerosols, syrups, emulsions,
  • the therapeutically active compound should be present in each case in a concentration of about 0.5 to 90 wt .-% of the total mixture, i. in amounts sufficient to achieve the stated dosage margin.
  • the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. in the case of using water as the diluent, organic solvents may optionally be used as auxiliary solvents.
  • the application is carried out in a customary manner, preferably orally, transdermally or parenterally, in particular perlingually or intravenously. However, it can also be effected by inhalation via the mouth or nose, for example with the aid of a spray, or topically via the skin.
  • TIPS triisopropylsilyl titr. titrated
  • Trimethylaluminum 200 ml 2 M solution in hexane
  • Trimethylaluminum 200 ml 2 M solution in hexane
  • the reaction is stirred at room temperature until no evolution of gas is observed (about 1.5 h).
  • a solution of 33.6 g (200 mmol) of 3,4-dirnethoxybenzonitrile in 100 ml of dry toluene is added dropwise and the reaction mixture is stirred at 80 ° C for 18 h.
  • Example 1 A The preparation is carried out as described for Example 1 A by reacting 29.4 g (180 mmol) of 3,5-dimethoxybenzonitrile with 19.1 g (360 mmol) of ammonium chloride and 360 mmol of trimethylaluminum (179 ml of 2 M solution in hexane) in toluene ,
  • the mixture is stirred at room temperature for 1 h and at 40 ° C. for 1 h.
  • Example 1 A (5.42 g, 25 mmol) is initially charged in 100 ml of ethanol. 1.34 ml of hydrazine hydrate (1.34 g, 27.5 mmol) are added and the mixture is stirred at 45 ° C. for 3 h. After this time, Example 6A is added in 50 ml of ethanol and the reaction mixture for 6 h at 80 ° C bath temperature, then stirred for 12 h at room temperature. The mixture is concentrated and the residue is flash-chromatographed
  • Example HA 8.00 g (25, lmmol) of Example HA are presented in 400 ml of ethanol, with stirring in portions with 400 ml of conc. Hydrochloric acid and the mixture stirred for 20 h at reflux. After cooling, the clear, yellow soln. Is evaporated to dryness, the residue is treated with about 100 ml of toluene and the solution was concentrated on a rotary evaporator. This process is repeated 4 more times. The amorphous, yellow product is then dried for 20 hours in a high vacuum.
  • Example 12A (9.00 g, 25.9 mmol) and 9.03 ml (64.7 mmol) of triethylamine are placed under argon in 120 ml of THF. A solution of 3.43 g (25.9 mmol) of cyclopentanecarbonyl chloride in 10 ml is added dropwise at 0 ° C. to the suspension at 0.degree
  • Example 2A (0.93 g, 5.00 mmol) and 0.27 ml (5.50 mmol) of hydrazine hydrate are dissolved in 25 ml of ethanol and stirred at 40 ° C for 2.5 h. After this time, Example 9A (total amount) in 15 ml of ethanol is added, stirred for 2 h at 80 ° C bath temperature and then allowed to stand overnight at room temperature. The precipitated solid is filtered off, washed with a little cold ethanol and dried.
  • Example 16A Preparation analogous to Example 12A from 3.00 g (9.30 mmol) Example 16A. The product obtained is reacted without further purification.
  • Example 17A 700 mg, 2.50 mmol and triethylamine (1.04 mL, 7.48 mmol) are presented in 15 mL of dry THF. At 0 ° C., 451 mg (3.74 mmol) of 3-methylbutanoic acid chloride are added dropwise and the cloudy reaction mixture is stirred for 16 h at room temperature. The mixture is concentrated and the residue is purified by flash chromatography on silica gel (eluent gradient dichloromethane, dichloromethane / methanol 20: 1) by flash chromatography.
  • Example 4A (11.8 g) is initially charged in 150 ml of ethanol. 3.50 ml of hydrazine hydrate
  • Example 6A (16.8 g) is added dropwise in 76 ml of ethanol and the reaction mixture for 3 h at 80 ° C bath temperature, then stirred overnight at room temperature. The batch is concentrated and the residue is purified by flash chromatography (eluent dichloromethane / methanol 95: 5).
  • Example HA (2.60 g, 8.13 mmol) is initially charged in 100 ml of 1,2-dichloroethane and the solution is treated with 0.19 ml (2.04 mmol) of phosphoryl chloride. The mixture is stirred for 24 h in the boiling heat. After cooling, the precipitate is filtered off with suction, the residue is washed with water (2 ⁇ 50 ml) and diethyl ether (50 ml) and dried.
  • Example 14A (342 mg, 1.00 mmol) is initially charged in 1, 2-dichloroethane and the solution is treated with phosphoryl chloride (0.02 ml, 0.25 mmol). The batch is stirred for 5 h at boiling heat. After cooling, the reaction mixture is added to 50 ml of ice-water and extracted with ethyl acetate (5 x 50 ml). The united org. Phases are dried (sodium sulfate), concentrated and purified by flash chromatography (eluent dichloromethane / methanol 40: 1).
  • Phosphorus pentasulfide (666 mg, 3.00 mmol) and Example 24A (300 mg, 1.00 mmol) are dissolved under argon in 20 mL of pyridine and stirred at reflux for 24 h.
  • Example 30A (1.02 g, 3.00 mmol) is added under argon in portions in 20 ml of chlorosulfonic acid (ice bath cooling) and stirred for 2 h at RT. The clear, yellowish solution is added slowly, in small portions in about 500 ml of ice water and extracted with a mixture of ethyl acetate / THF 2: 1 (2 x 200 ml each). The united org. Phases are dried (sodium sulfate), filtered and concentrated. 1.2 g (92% of theory) of crystalline product are obtained. Mp .: 204 ° C
  • Example 31A (103 mg, 0.24 mmol) is dissolved in THF under argon and treated dropwise at RT with 0.08 ml (0.94 mmol) of morpholine. The mixture is stirred for 15 h at RT, diluted with 10 ml of ethyl acetate and washed with 2 N hydrochloric acid (ca.
  • the crude material is dissolved in ethyl acetate, passed through a frit with silica gel 60 (70-230 mesh), the filtrate concentrated, the crist. Triturated residue with diethyl ether and filtered with suction. The colorless solid is dried under high vacuum.
  • Example 16A 0.92 g (2.85 mmol) of Example 16A are suspended in 50 ml of dichloromethane and admixed with 0.15 ml (1.57 mmol) of phosphoryl chloride. It is stirred under boiling for 2 hours and concentrated. The evaporation residue is eluted over silica gel with dichloromethane / methanol 95: 5. 283 mg (33% of theory) of slightly beige-colored crystals are obtained.
  • Example 51A Preparation analogous to Example 37A from 98 mg (0.32 mmol) Example 51A. Purification is carried out by column chromatography (eluent dichloromethane / methanol 95: 5).
  • Example 37A 30 mg (0.09 mmol) of Example 37A are initially charged in 2 ml of pyridine and admixed with a solution of 180 mg (0.96 mmol) of 3,4,5-trimethoxyamine in 4 ml of pyridine.
  • Example 37A Prepared analogously to Example 1 from Example 37A (80 mg, 0.23 mmol) and 3,5-dimethoxybenzylamine (396 mg, 2.32 mmol). Purification is by flash chromatography (eluent dichloromethane / methanol 80: 1).
  • Example 27A A solution of Example 27A (50 mg, 0.16 mmol) in 5 mL of DMSO is added to 5 mL of a saturated sodium bicarbonate solution. Subsequently, 80 mg (0.32 mmol) of 3-picolyl bromide hydrobromide are added and the reaction mixture is stirred overnight at 60.degree. After cooling, the batch is poured into 50 ml of dichloromethane and washed with water (3 x 50 ml). The organic phase is dried (sodium sulfate) and the solvent removed in vacuo. The resulting crude material is purified by flash chromatography (eluent dichloromethane / methanol 20: 1).
  • Example 38 A Preparation analogous to Example 1 from 60 mg (0.16 mmol) of Example 38 A and 308 mg (1.63 mmol) of 3,4,5-trimethoxyaniline. Purification is by flash chromatography (eluent dichloromethane / methanol 80: 1) and recrystallization from pentane / dichloromethane.
  • Example 41 A 400 mg 0.99 mmol and 3,4,5-dimethoxyaniline (373 mg, 1.97 mmol) are dissolved in 5 ml of diglyme and the mixture is stirred for 16 h at 170 ° C. After cooling, the dark-brown solution is mixed with 50 ml of water and dichloromethane and the organic phase is separated off. This was washed with water (4 x
  • Example 38A Preparation analogous to Example 1 from 54 mg (0.15 mmol) of Example 38A and 275 mg (1.57 mmol) of 2-bromoaniline. Purification is by flash chromatography (eluent dichloromethane / methanol 80: 1).
  • Example 41 A 80 mg (0.20 mmol) of Example 41 A and 68 mg (0.39 mmol) of 2-bromoaniline are dissolved in 10 ml of THF and the mixture is stirred for 4 h at 70 ° C. After cooling, the solvent is removed and the residue is purified by flash chromatography (eluent dichloromethane / methanol 80: 1). 79 mg (79% of theory) are obtained
  • Example 37A (117 mg, 0.33 mol) and 4-methoxyaniline (62 mg, 0.50 mmol) are stirred in 10 mL of diglyme overnight at 170 ° C. After cooling, the batch is mixed with 50 ml of water, and the precipitate was filtered off with suction. The solid obtained is taken up in 20 ml of dichloromethane, the organic phase washed with 20 ml of water, dried (sodium sulfate) and concentrated. The resulting dark residue is suspended in ether and filtered off with suction. This gives a colorless solid which is dried under high vacuum.
  • Example 41A (82 mg, 0.20 mmol) and 2- (3,4-dimethoxyphenyl) ethylamine (73 mg, 0.40 mmol) are stirred in 10 mL of dioxane for 18 h in the boiling heat. After cooling, the solvent is removed in vacuo and the crude product is purified by flash chromatography (eluent gradient cyclohexane-cyclohexane / ethyl acetate 2: 1). Yield: 76 mg (73% of theory)
  • Example 28A Preparation analogous to Example 4 from 55 mg (0.15 mmol) of Example 28A and 75 mg (0.30 mmol) of 3-picolyl bromide hydrobromide. Purification is by flash chromatography (eluent dichloromethane / methanol 40: 1).
  • Example 37A 65 mg (0.18 mmol) of Example 37A and 162 mg (0.92 mmol) of 3-chloroanisidine are reacted analogously to Example 14.
  • the reaction time is 48 h.
  • the crude material is purified by HPLC (mobile phase acetonitrile-water mixture). In addition to the desired product (30 mg, 37% of theory), 17% of Example 37A are recovered.
  • Example 37A 67 mg (0.19 mmol) of Example 37A and 144 mg (0.95 mmol) of 4-methoxy-3,5-dimethylaniline are refluxed in 10 ml of pyridine overnight. After cooling, the reaction solution is diluted with 50 ml of dichloromethane and washed with 1N hydrochloric acid (3 x 50 ml), sat. Sodium bicarbonate solution (2 x 50 ml), and
  • Example 41A Analogously to Example 14, 80 mg (0.20 mmol) of Example 41A and 149 mg (0.99 mmol) of 4-methoxy-3,5-dimethylaniline are reacted. After flash chromatographic purification (eluent dichloromethane / methanol 80: 1), 15% of Example 41 A are recovered and 57 mg (59% of theory) of product are obtained.
  • Example 41A (78 mg, 0.19 mmol) is initially charged in 15 ml of DMSO, 3-chloro-p-anisidine (168 mg, 0.96 mmol) and potassium fluoride (23 mg, 0.38 mmol) are added and the reaction mixture over Heated to reflux overnight. After cooling, the mixture is poured onto 100 ml of dichloromethane and washed with sat. Sodium chloride soln. washed (3 x 50 ml). The united org. Phases are dried (sodium sulfate) and concentrated. The crude product is purified by HPLC.
  • Example 41 A The preparation is carried out analogously to Example 11 from 81 mg (0.20 mmol) of Example 41 A and 197 mg (0.40 mmol) of 3,4,5-trimethoxybenzylamine.
  • the crude product is purified by flash chromatography (mobile phase gradient dichloromethane-dichloromethane / methanol 30: 1).
  • the resulting solid is suspended in a little diethyl ether / pentane mixture and filtered off with suction.
  • Example 41 A 81 mg (0.20 mmol) of Example 41 A and 37 mg (0.24 mmol) of 2,4-dimethoxyaniline are stirred for 16 h in 5 ml of THF at 100 ° C. After cooling, the mixture is concentrated and purified by flash chromatography (mobile phase gradient cyclohexane-cyclohexane / ethyl acetate 1: 1), then purified by HPLC.
  • Example 41A The synthesis is carried out analogously to Example 22 from 80 mg (0.20 mmol) of Example 41A and 73 mg (0.39 mmol) of 3,4,5-trimethoxyphenol.
  • Example 41 A The synthesis is carried out analogously to Example 10 from 150 mg (0.37 mmol) of Example 41 A and 68 mg (0.55 mmol) of 4-methoxyaniline.
  • Example 41 A The preparation is carried out analogously to Example 10 from 150 mg (0.37 mmol) of Example 41 A and 68 mg (0.55 mmol) of 3-methoxyaniline.
  • Example 14 The synthesis is carried out analogously to Example 14 from 68 mg (0.13 mmol) Example 42A and 119 mg (0.65 mmol) of 3,4,5-trimethoxyaniline.
  • the purification is carried out by flash chromatography (mobile phase dichloromethane / methanol 80: 1).
  • Example 33A A solution of 40 mg (0.11 mmol) of Example 33A and 100 mg (0.65 mmol) of 3,4-dimethoxyaniline in 2 ml of dioxane is stirred at 100 ° C for 20 hours. It is concentrated, dissolved in ethyl acetate, washed twice with water, dried and concentrated. It is purified over a silica gel column with dichloromethane / ethyl acetate to 2: 1. Crystals are obtained which are filtered off with a mixture of diethyl ether / heptane.
  • Example 50A A solution of 50 mg (0.14 mmol) of Example 50A and 50 mg (0.26 mmol) of 4-ethoxy-3-methoxyphenethylamine in 3 ml of dioxane is stirred at room temperature overnight. It is concentrated, dissolved in ethyl acetate, washed with water, dried and concentrated. The crystalline evaporation residue is with

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Abstract

L'invention concerne de nouvelles imidazotriazines de la formule générale (I), leur procédé de production et leur utilisation pour la production de médicaments destinés au traitement et/ou à la prophylaxie de maladies neurodégéneratives, notamment de la maladie de Parkinson.
EP02747362A 2001-06-22 2002-06-10 Imidazotriazines utilisees comme inhibiteurs de phosphodiesterase Withdrawn EP1404677A1 (fr)

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DE10130167A DE10130167A1 (de) 2001-06-22 2001-06-22 Imidazotriazine
DE10130167 2001-06-22
PCT/EP2002/006322 WO2003000693A1 (fr) 2001-06-22 2002-06-10 Imidazotriazines utilisees comme inhibiteurs de phosphodiesterase

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US6936609B2 (en) 2005-08-30
WO2003000693A1 (fr) 2003-01-03
CA2451525A1 (fr) 2003-01-03
DE10130167A1 (de) 2003-01-02
GT200200122A (es) 2003-06-05
AR036103A1 (es) 2004-08-11
SV2003001107A (es) 2003-03-18
PE20030129A1 (es) 2003-03-13
DOP2002000429A (es) 2003-10-15
JP2004534827A (ja) 2004-11-18
US20040249148A1 (en) 2004-12-09

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