EP1599479A1 - Imidazotriazines substituees - Google Patents

Imidazotriazines substituees

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Publication number
EP1599479A1
EP1599479A1 EP03735677A EP03735677A EP1599479A1 EP 1599479 A1 EP1599479 A1 EP 1599479A1 EP 03735677 A EP03735677 A EP 03735677A EP 03735677 A EP03735677 A EP 03735677A EP 1599479 A1 EP1599479 A1 EP 1599479A1
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EP
European Patent Office
Prior art keywords
compounds
mmol
alkyl
formula
salts
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP03735677A
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German (de)
English (en)
Inventor
Martin Hendrix
David BRÜCKNER
Arno Friedl
Irene Gerlach
Volker Hinz
Jörg Keldenich
Frank Mauler
Ulrich Niewöhner
Dagmar Karthaus
Karl-Heinz Schlemmer
Adrian Tersteegen
Özkan Yalkinoglu
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Bayer AG
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Bayer Healthcare AG
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Publication of EP1599479A1 publication Critical patent/EP1599479A1/fr
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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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

  • the invention relates to new substituted imidazotriazines, processes for their preparation and their use for the manufacture of medicaments for the treatment and / or prophylaxis of cancer and neurodegenerative diseases, in particular Parkinson's disease and schizophrenia.
  • cyclic nucleotides cGMP and cAMP are among the most important intracellular messengers.
  • Phosphodiesterases (PDEs) play an important role in regulating the concentrations of cGMP and cAMP. So far there are 11
  • Phosphodiesterase isoenzyme groups known (PDE 1-7: Beavo et al. Mol.
  • the PDE 10A hydrolyzes both cAMP and cGMP (Fujishige J. Biol. Chem. 1999, 274, 18438-18445). Transcribed PDE 10A was identified primarily in the putamen and caudate nucleus regions of the brain, as well as in thyroid and testicular tissue. Compared to normal tissue, the PDE IOA mRNA is also increasingly expressed in certain tumor tissues, such as tissues of breast, liver, colon and lung tumors.
  • Parkinson's disease is a chronically progressive, neurodegenerative disease characterized by the loss of dopaminergic neurons of the substantia nigra. The massive disturbances of the dopaminergic neurotransmission caused thereby lead to a serious malfunction of the movement-controlling extrapyramidal system.
  • the main characteristics of early signs and symptoms of Parkinson's disease are rest tremor, slowness of movement, muscle stiffness, and unstable posture.
  • the current medications for Parkinson's disease are of a symptomatic nature, with substitution therapy with L-dopa being the most frequently used form of therapy. Neither preventive nor restorative therapies are currently available (Mendis et al., Can. J. Neurol 1999, 26, 89-103).
  • Parkinson's idiopathic disease is a chronic, progressive neurological disorder that belongs to a broader classification of neurological diseases called parkinsonism. It is clinically defined by the appearance of at least two of the four cardinal symptoms: bradykinesia, resting tremor, muscle stiffness, and postural and movement disorders.
  • the idiopathic form of Parkinson's disease is characterized by the loss of pigmented nerve cells, particularly in the area of the substantia nigra of the brain.
  • the idiopathic Parkinson's disease makes up about 75% of all Parkinsonism diseases. The remaining 25% of cases are referred to as atypical Parkinsonism and include clinical pictures such as multiple
  • Schizophrenia is a chronic psychiatric illness that is characterized by psychoses, so-called "negative symptoms" such as apathy and social seclusion, subtle cognitive deficits and a lack of illness.
  • No. 3,941,785 describes 2-amino-imidazo [5, l-f] - [l, 2,4] triazines as PDE inhibitors with spasmolytic activity for the treatment of asthma, bronchitis, chronic heart failure and skin diseases.
  • EP-A 1 250 923 describes the use of selective PDE10 inhibitors, such as e.g. Papaverine, used to treat central nervous system disorders such as Parkinson's disease.
  • the present invention relates to compounds of the formula (I)
  • R 5 is hydrogen, formyl, d-Ce-alkyl, C 1 -C 6 -alkyl-sulfonyl, C 3 -C 8 -cycloalkylcarbonyl or (3 to 8-membered heterocyclyl) carbonyl, alkylcarbonyl having up to 3 substituents - independently selected from the series halogen, hydroxyl, amino, carboxy, Cj . - C 6 alkoxy, C 6 -C 10 aryl, C 1 -C 6 alkylamino and a 3 to 8-membered heterocyclyl substituted with up to 3 dC 3 alkyl substituents - may be substituted,
  • R 1 and R 5 together with the nitrogen atom to which they are attached form a 5 to 8-membered heterocycle which, with up to 3 substituents - independently of one another selected from the series halogen, hydroxy,
  • C ⁇ -C 6 -A ⁇ kyl, Ci-C ö alkoxy, C 6 -C 10 aryl, amino and alkyl amino dC ⁇ - may be substituted
  • A is an oxygen atom or NH
  • R 4 C 6 -C 10 aryl which has up to 3 substituents - independently selected from the series halogen, formyl, carboxyl, carbamoyl, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, -Ce-alkyl, Ci-C ⁇ - Alkoxy, l, 3-dioxa-propane-l, 3-diyl, Ci-Ce-alkylthio and -NR 6 R 7 - can be substituted, embedded image in which
  • R 6 and R 7 are independently hydrogen, Ci-C ⁇ -alkyl or (Cj-C6 -. Alkyl) carbonyl stand mean
  • the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers).
  • 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.
  • salts which are physiologically acceptable are the salts
  • Physiologically acceptable salts of the compounds (T) include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid,
  • Physiologically acceptable salts of the compounds (I) also include salts more commonly
  • Bases such as, for example and preferably, 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 having 1 to 16 carbon atoms, for example and preferably emylamine, diethylamine, Triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclo-hexylamine, Dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, del ydroabietyl-arnine, arginine, lysine, ethylenediamine and methylpiperidine.
  • 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 having 1 to 16 carbon atoms, for example and preferably
  • solvates are those forms of the compounds which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvate, in which coordination takes place with water.
  • Ci-Ce-alkoxy stands for a straight-chain or branched alkoxy radical having 1 to 6, preferably 1 to 4, particularly preferably having 1 to 3 carbon atoms.
  • Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • Q-Ce-alkylamino stands for a straight-chain or branched alkylamino radical having 1 to 6, preferably 1 to 4, particularly preferably having 1 to 3 carbon atoms.
  • Nonlimiting examples include methylamine, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino and n-hexylamino, dimemylamino, diethylamino, di-n-propylarnino, diisopropylamino, di-t-butylamino, Di-n-pentylarnino, di-n-hexylamino, E & ylmemylamino, isopropylmemylamino, n-butylethylamino, n-hexyl-i-penlylamino.
  • Ct-Ce-alkyl represents a straight-chain or branched alkyl radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
  • (C 1: C 6 alkyl) carbonyl represents a straight-chain or branched alkylcarbonyl radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms.
  • Non-limiting examples include acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, pentylcarbonyl and hexylcarbonyl.
  • (3 to 8-membered cycloalkyl) carbonyl stands for monocyclic cycloalkyl bonded via a carbonyl group.
  • Non-limiting examples include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl and cycloheptylcarbonyl.
  • (3 to 8-membered heterocyclyl) carbonyl stands for a heterocyclyl bonded via a carbonyl group.
  • Non-limiting examples include tetrahydrofuran-2-ylcarbonyl, pyrrolidin-2-ylcarbonyl, pyrrohdin-3-ylcarbonyl, pyrrolinylcarbonyl, piperidinylcarbonyl, morpholinylcarbonyl and perhydroazepinylcarbonyl.
  • Ci-Ce-alkylsulfonyl represents a straight-chain or branched alkylsulfonyl radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms.
  • Nonlimiting examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl and n-hexylsulfonyl.
  • C -C 6 -Akylthio represents a straight-chain or branched alkylthio radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms.
  • Non-limiting examples include methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio.
  • C ⁇ -Cio-Ary! stands for an aromatic radical with 6 to 10 carbon atoms. Non-limiting examples include phenyl and naphthyl.
  • Halogen stands for fluorine, chlorine, bromine and iodine. Fluorine, chlorine, bromine are preferred, fluorine and chlorine are particularly preferred.
  • 3 to 8-membered heterocyclyl stands for a mono- or polycyclic, preferably mono- or bicyclic, non-aromatic radical with generally 4 to 8, preferably 5 to 8 ring atoms and up to 3, preferably atoms up to 2 Heter ⁇ - "or hetero groups selected from N, O, S, SO, SO 2.
  • the heterocyclyl residues can be saturated or partially unsaturated. Not -limiting examples include 5- to 8-membered, monocyclic saturated heterocyclyl radicals having up to two hetero ring atoms from the series O, N and S, such as tetrahydrofuran-2-yl,
  • 5 to 8-membered heterocycle stands for a mono- or polycyclic, heterocyclic radical with 5 to 8 ring atoms and up to 3, preferably 2 hetero atoms or hetero groups from the series N, O, S, SO, SO 2 , where at least one of the heteroatoms or hetero groups is a nitrogen atom.
  • 5- to 7-membered heterocycle stands for a mono- or polycyclic, heterocyclic radical with 5 to 8 ring atoms and up to 3, preferably 2 hetero atoms or hetero groups from the series N, O, S, SO, SO 2 , where at least one of the heteroatoms or hetero groups is a nitrogen atom.
  • Heterocyclyl is preferred. Mono- or bicyclic heterocyclyl is preferred.
  • Monocyclic heterocyclyl is particularly preferred. O, N and S are preferred as heteroatoms.
  • the heterocyclyl residues can be saturated or partially unsaturated. Saturated heterocyclyl residues are preferred. 5- to 7-membered, monocyclic saturated heterocyclyl with up to two heteroatoms from the series O, N and S is particularly preferred.
  • Non-limiting examples include pyrrolinyl,
  • C 3 -C 4 cycloalkyl stands for monocyclic cycloalkyl, such as. B. cyclopropyl and cyclobutyl.
  • 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)
  • R 1 is hydrogen
  • R 5 is hydrogen, (C 3 -C 6 -cycloalkyl) carbonyl, (4 to 6-membered heterocyclyl) carbonyl or (Ci-d-Alkyrjcarbonyl, wherein alkylcarbonyl with hydroxy or
  • Amino can be monosubstituted
  • A is an oxygen atom or NH
  • R 4 is phenyl, which can be substituted with up to 3 substituents, independently of one another selected from the group consisting of halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy and their salts, solvates or solvates of the salts. • - "
  • Another embodiment of the invention relates to compounds of the formula (I)
  • R 5 is hydrogen, (C 3 -C6-cycloalkyl) carbonyl, (4 to 6-membered heterocyclyl) carbonyl or (C] .- C 3 -alkyl) carbonyl, where alkylcarbonyl can be monosubstituted with hydroxy or amino, and
  • R 1 , R 2 , R 3 , R 4 and A have the meanings given above
  • Another embodiment of the invention relates to compounds of the formula (I)
  • R 2 is dC 6 alkyl
  • R 1 , R 5 , R 3 , R 4 and A have the meanings given above
  • Another embodiment of the invention relates to compounds of the formula (T)
  • R 4 is phenyl, which can be substituted by 1 to 3 (dC 6 ) alkoxy radicals, and R 1 , R 5 , R 2 , R 3 and A have the meanings given above
  • Another embodiment of the invention relates to compounds of the formula (I)
  • R 4 represents 3,4,5-trimethoxyphenyl
  • R 1 , R 5 , R 2 , R 3 and A have the meanings given above.
  • the invention further relates to processes for the preparation of the compounds according to the invention by reacting
  • R 1 , R 5 , R 2 and R 3 have the meaning given above,
  • R 5 has the meaning given above and X 1 represents halogen, preferably bromine or chlorine, or hydroxyl,
  • R 1 and R 5 have the meaning given above
  • reaction according to process [A] can generally be carried out in inert solvents, if appropriate in the presence of base and auxiliary reagents, preferably in a temperature range from 20 to 120 ° C. at atmospheric pressure or without solvent in the melt.
  • Auxiliary reagents are, for example, potassium fluoride or dimethylaminopyridine, and / or crown ether, preferably 15-crown-5, 18-crown-8 or 12-crown-4.
  • reaction according to process [B] can generally be carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from 0 ° C. to 50 ° C. at atmospheric pressure.
  • reaction can generally be carried out in inert solvents, if appropriate in the presence of a base, in the presence of customary solvents
  • Condensing agents preferably in a temperature range from 20 ° C to 50 ° C at normal pressure.
  • Condensing agents are, for example, carbodiimides such as, for example, N-N'-dethyl, N, N, '-' dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylamino-isopropyl) -N '-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium- 3-sulfate or 2-tert-butyl-5-methyl-isoxazolium per
  • Inert solvents for processes [A] and [B] are, for example, 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, 1,2-dimethoxyethane, or
  • Diethylene glycol dimethyl ether such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or nitroalkanes such as nitromethane, or carboxylic acid esters such as ethyl acetate, N-alkylated carboxamides such as dimethylformamide, dimethylacetamide, or ketones such as acetone, 2-butoxide, or alkyl such as dimethyl sulfoxide, or acyl nitriles such as acetonitrile or heteroaromatics such as pyridine.
  • hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or nitroalkanes such as nitromethane
  • carboxylic acid esters such as ethyl acetate
  • N-alkylated carboxamides such as dimethylformamide, dimethylacetamide
  • Preferred for process [A] are pyridine, glycol di methyl ether, tetrahydrofuran, dioxane or dimethyl sulfoxide and preferably for the " process [B] if X 1 is halogen, are tetrahydrofuran or methylene chloride and, if X 1 is hydroxy, tetrahydrofuran, dimethylformamide or methylene chloride.
  • Bases for processes [A] and [B] are, for example, alkali metal hydroxides such as sodium or potassium hydroxide, alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, alkali metal alcoholates such as sodium or potassium methoxide, sodium or potassium ethanolate or potassium tert-butoxide, amides such as sodium amide , Lithium bis (trimethylsilyl) amide, lithium diisopropylamide, organometallic compounds such as
  • Preferred for process [A] are sodium hydride, triethylamine, potassium tert-butoxide or DBU, and preferred for process [B], if X 1 is halogen, is triethylamine.
  • reaction according to process [C] is generally carried out in inert solvents, optionally in the presence of a base, in the presence of catalysts, preferably in a temperature range from 50 to 150 ° C. at atmospheric pressure.
  • Inert solvents are, for example, hydrocarbons such as benzene, xylene, toluene, toluene is preferred.
  • Bases are, for example, alkali alcoholates such as potassium tert-butoxide or alkali carbonates such as cesium carbonate, sodium or potassium carbonate.
  • Catalysts are palladium complexes which can be used preformed or can be generated in situ from a suitable palladium source, such as, for example, bis (dibenzylidene acetone) palladium (O) or tetrakis-iriphenylphosphine palladium (O) and a suitable phosphine ligand.
  • a suitable palladium source such as, for example, bis (dibenzylidene acetone) palladium (O) or tetrakis-iriphenylphosphine palladium (O) and a suitable phosphine ligand.
  • a suitable palladium source such as, for example, bis (dibenzylidene acetone) palladium (O) or tetrakis-iriphenylphosphine palladium (O) and a suitable phosphine ligand.
  • the use of is particularly preferred
  • the compounds (V) can be prepared using the appropriate starting materials analogously to process [A].
  • the reaction is generally carried out in inert solvents, preferably in a temperature range from 20 to 150 ° C. at atmospheric pressure to 3 bar.
  • Reducing agents are, for example, hydrogen, tin dichloride or titanium trichloride; hydrogen or tin dichloride is preferred.
  • Inert solvents are, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, T ⁇ lüoL hexane, "cyclohexane or petroleum fractions, amides such as dimethylformamide, dimethylacetamide, alkyl nitriles such as acetonitrile, heteroaromatics such as pyridine, methanol, ethanol, isopropanol or (when using tin dichloride are preferred ) Dimethylformamide.
  • ethers such as diethyl ether, methyl tert-butyl ether, 1,2-
  • a chlorinating agent preferably phosphorus oxychloride, phosphorus pentachloride, sulfuryl chloride and / or thionyl chloride.
  • reaction is generally carried out in inert solvents, if appropriate in
  • Presence of a base preferably in a temperature range from -20 ° C to 20 ° C at normal pressure (see e.g. Knutsen et al., J. Chem. Soc, Perkin Trans 1, 1985, 621-630; A. Kraszewski, J. Stawinski, Tetrahedron Lett. 1980, 21, 2935).
  • the inert solvents of the type mentioned for processes [A] and [B] can be used for the reaction; pyridine, trichloromethane, diethylphenylamine, dioxane or acetonitrile are preferred.
  • dehydration reagents e.g. Lewis acids
  • suitable dehydration reagents e.g. Lewis acids
  • phosphorus oxychloride, phosphorus pentoxide, polyphosphoric acid or methyl sulfonic acid chloride e.g. phosphorus oxychloride, phosphorus pentoxide, polyphosphoric acid or methyl sulfonic acid chloride.
  • the reaction is generally carried out in inert solvents, preferably in a temperature range from 40 to 80 ° C at normal pressure (see e.g. Charles et al.
  • Suitable inert solvents are those mentioned for processes [A] and [B]; 1,2-dichloroethane is preferred.
  • R 1 , R 5 and R 3 have the meanings given above,
  • Y 1 represents halogen, preferably bromine or chlorine, or hydroxy.
  • the reaction can generally be carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from 0 ° C. to 50 ° C. under normal pressure.
  • inert solvents are those mentioned for processes [A] and [B]; tetrahydrofuran or methylene chloride are preferred.
  • Suitable bases are those recommended for methods [A] and [B]
  • the reaction can generally be carried out in inert solvents, if appropriate in the presence of a base, in the presence of customary condensing agents, preferably in a temperature range from 20 ° C. to 50 ° C.
  • Suitable inert solvents are those mentioned for processes [A] and [B]; tetrahydrofuran, dimethylformamide or methylene chloride are preferred.
  • Suitable condensing agents are those recommended for process [B] or mixtures thereof.
  • Suitable bases are those mentioned for processes [A] and [B].
  • the compounds (XI) are known or can be synthesized from the corresponding starting materials by known processes.
  • the reaction can generally be carried out in inert solvents, preferably in a temperature range from 20 ° C. to 100 ° C. at normal pressure.
  • Suitable inert solvents are those which are suitable for the reduction of (VLT); methanol or ethanol are preferred.
  • Acids are, for example, trifluoroacetic acid, sulfuric acid, hydrogen chloride, hydrogen bromide and acetic acid or mixtures thereof, optionally with the addition of water; hydrogen chloride or hydrogen chloride / water are particularly preferred.
  • R 2 and R 3 have the meanings given above, and
  • R 8 represents -C 4 alkyl, preferably methyl or ethyl.
  • the reaction of the first stage can generally be carried out in inert solvents, preferably in a temperature range from -10 ° C to 50 ° C at normal pressure (cf. e.g. K. M. Doyle, F. Kurzer, Synthesis 1974, 583).
  • the reaction of the second stage can generally be carried out in inert solvents, preferably in a temperature range from 20 to 80 ° C. at normal pressure.
  • Inert solvents for the reactions of the first and second stages are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, amides such as dimethylformamide, alkyl sulfoxides such as dimethyl sulfoxide, methanol or are preferred ethanol.
  • the compounds (IXa) can be obtained using compounds (XIT) and compounds (Xül),
  • R 1 and R 5 have the meanings given above and
  • Y 2 represents cyano or methoxycarbonyl
  • Y 2 is cyano - with ammonium bromide or chloride and gaseous ammonia at 140 ° C to 150 ° C in an autoclave, or with lithium bis (trimethylsilyl) amine and hydrogen chloride in diethyl ether (see RT Boere, et al ., J.
  • the reaction can in general be carried out in inert solvents, preferably in a temperature range from first at -20 ° C. and then at 20 ° C. to 80 ° C. under normal pressure (cf., for example, RS Garigipati, Tetrahedron Lett. 1990 , 31, 1969-1972).
  • Suitable inert solvents are those which are suitable for processes [A] and [B], preferably toluene.
  • the compounds (XTV) are known or can be synthesized from the corresponding starting materials in analogy to known processes.
  • R 1 and R 5 have the meanings given above,
  • the compounds (XV) are known or can be synthesized from the corresponding starting materials analogously to known processes.
  • R 2 and R 3 have the meanings given above,
  • R 8 has the meaning given above and
  • X 2 represents halogen, preferably chlorine or bromine.
  • the reaction is generally carried out in inert solvents, if appropriate in the presence of a base and a catalyst such as dimethylaminopyridine, preferably in a temperature range from 20 to 80 ° C. at atmospheric pressure (see, for example, Charles, J.
  • Suitable inert solvents are those mentioned for processes [A] and [B], preferably tetrahydrofuran or diethyl ether.
  • Suitable bases are those for those recommended analogously to those in processes [A] and [B] - r ; " preferred pyridine, sodium hydride, potassium tert-butoxide, lithium diisopropylamide, piperidine or triethylamine.
  • the compounds (XVII) are known or can be synthesized from the corresponding starting materials analogously to known processes.
  • R 3 has the meaning given above
  • X represents halogen, preferably chlorine or bromine.
  • reaction is generally carried out in inert solvents, if appropriate in
  • a base optionally in the presence of trimethylsilyl chloride, preferably in a temperature range from -10 to 50 ° C at normal pressure.
  • Suitable inert solvents are those mentioned for processes [A] and [B], preferably methylene chloride.
  • Suitable bases include those recommended for processes [A] and [B], preferably triethylamine, sodium or potassium hydroxide in aqueous solution.
  • the compounds according to the invention are suitable for use as medicaments in the treatment of humans and animals.
  • the compounds according to the invention show an unforeseeable, valuable spectrum of pharmacological activity. They stand out as PDE LOA inhibitors.
  • the compounds according to the invention are used. Due to their pharmacological properties, the compounds according to the invention, alone or in combination with other medicaments for the treatment and or prevention of Parkinson's disease, in particular idiopathic Parkinson's disease, and cancer diseases, in particular tumors, and for the treatment of schizophrenia be used.
  • Parkinson's disease in particular idiopathic Parkinson's disease
  • cancer diseases in particular tumors, and for the treatment of schizophrenia be used.
  • Parkinson's idiopathic disease is a chronic, progressive neurological disorder that belongs to a broader classification of neurological diseases called parkinsonism. It is clinically defined by the occurrence of at least two of the four cardinal symptoms: bradykinesia, resting tumor, muscle stiffness and postural and movement disorders.
  • the idiopathic form of Parkinson's disease is pathologically caused by the loss of pigmented
  • Idiopathic Parkinson's disease accounts for approximately 75% of all Parkinson's diseases. The remaining 25% of cases are referred to as atypical Parkinsonism and include clinical pictures such as multiple system atrophy, striatonigral degeneration or vascular Parkinsonism.
  • tumors includes both benign and malignant tumors and thus, for example, also benign neoplasias, dysplasias, hyperplasias, and also neoplasias with metastasis formation.
  • Other examples of tumors are carcinomas, sarcomas, carcinosarcomas, tumors of the hematopoietic organs, tumors of the nerve tissue, for example the brain or Tumors from skin cells. Tumor formation leads to uncontrolled or insufficiently controlled cell division.
  • the tumor can be localized, but it can also infiltrate the surrounding tissue and then settle in a new location through the lymphatic system or through the bloodstream.
  • Primary tumors originated in the organ in which they are found. Secondary tumors have established themselves in another organ through metastasis and then spread to their new location.
  • Abnormal basal ganglia function is not only relevant for psychoses, schizophrenia and related schizoaffective disorders, but also plays a role in other neuropsychiatric changes such as depression (Kapur, Biol. Psychiatr. 1992, 32, 1-17; Lafer, et al, Psychiatr Clin. North. 1997, 20, 855-896) and ailments (Jetty, et al., Psychiatric Clin. North. 2001, 24, 75-97).
  • the compounds according to the invention are suitable for the treatment of further diseases which can be treated by influencing the cGMP level and / or the cAMP level, such as dementia, stroke, traumatic brain injury, Alzheimer's disease, dementia with frontal lobe degeneration, Lewy - Body dementia, vascular dementia, attention deficit syndromes, attention and concentration disorders, mood disorders, psychoses, neuroses, mania or manic-depressive disorders, Pick's disease, pain and epilepsy.
  • PDE 10A (WO 01/29 199, Fig. IA) is in Sf9 insect cells (Invitrogen, Carlsbad,
  • the cells are harvested and 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 HI [CalBiochem, La Jolla, CA USA]) suspended.
  • the cells are sonicated at 4 ° C for 1 minute and then centrifuged at 10,000 ° C for 30 minutes at 4 ° C.
  • the supernatant (PDE 10A preparation) was collected and stored at -20 ° C.
  • test substances are used to determine their in vitro activity on PDE 10A
  • the dilution of the PDE 10A preparation is chosen so that less than 70% of the substrate is converted during the later incubation (typical dilution: 1: 10000; dilution buffer: 50 mM Tris / HCl pH 7.5, 8.3 mM MgCl 2 , 1.7 mM EDTA, 0.2% BSA).
  • the substrate [5 ', 8- 3 H] adenosine 3', 5'-cyclic phosphate (1 uCi / ul; Amersham Pharmacia Biotech.
  • Piscataway, NX 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 incubated for 60 min at 20 ° C. and the reaction by adding 25 ⁇ L of a suspension with 18 mg / mL yttrium
  • PDE 8A GenBank / EMBL Accession Number: AF_056490, Fisher et al. Biochem. Biophys. Res. Commun. 1998 246, 570-577
  • PDE 9A GenBank / EMBL Accession Number: NM_002606, Fisher et al. J. Biol. Chem. 1998 273, 15559-15564
  • PDE HA GenBank / EMBL Accession Number: NM_016953, Fawcett et al. Proc. Natl. Acad. Be 2000 97, from 3702 to 3707
  • Sf9 cells "dit aid of pFASTBAC baculovirus expression system (GibcoBRL).
  • Test protocol determined. To determine a corresponding effect on recombinant PDE IC, PDE 2A, PDE5A and PDE 9A, the protocol is adapted as follows: With PDE IC, additional calmodulin (10 "7 M) and CaCl 2 (3 mM) are added to the reaction mixture. PDE 2A is stimulated in the test by adding cGMP (1 ⁇ M) and tested with a BSA concentration of 0.01% for PDE 5A and
  • PDE 9A is used as a substrate [8- 3 H] cGMP (Amersham Pharmacia Biotech., Piscataway, NJ).
  • the neuroleptic haloperidol is a high affinity antagonist on the dopamine D2 receptor. In humans and animals, the administration of a higher dose causes
  • Haloperidol is a transient blockade of doparninergic neurotransmission. This blockage leads to a disruption of extrapyramidal motor skills, so-called catalepsy, in which a given posture is maintained longer than normal. Animal neuroleptic catalepsy is generally considered a model for sedentary lifestyle and rigidity in Parkinson's patients (Elliott et al.,
  • male rats are randomly divided into groups that receive either vehicles or different dosages of those to be tested Connections are applied. Each rat receives one 1.5mg / kg haloperidol. The cataleptic behavior of the animals is recorded 120 min after the haloperidol administration. The compounds to be tested are applied to the rats at such a time interval before the catalepsy test that the maximum plasma concentration is reached at the time of the behavioral test.
  • the animal is placed with both front paws on a wooden block of 9 x 5.5 x 5.5 cm height x depth x width. The time it takes an animal to take both paws off the block is recorded as the length of catalepsy. After 180 seconds, the animals are removed from the block.
  • 6-hydroxydopamine (6-OH-DA lesion in the rat
  • Parkinson's disease The degeneration of dopaminergic nigrostriatal and striatopallidal neurotransmission is the main characteristic of Parkinson's disease
  • the clinical picture of Parkinson's disease can largely be simulated in an animal model in which the neurotoxin 6-OH-DA is injected intracerebrally in rats.
  • the animals were given Pargyline (Sigma, St. Louis, MO, USA; 50 mg / kg ip) and desmethylimipramine hydrochloride (Sigma; 25 mg / kg ip) 30 minutes before the lesion on the day of surgery to improve the metabolism of 6-hydroxydopamine to prevent or to prevent the absorption of 6-hydroxydopamine in noradrenergic structures.
  • Pargyline Sigma, St. Louis, MO, USA; 50 mg / kg ip
  • desmethylimipramine hydrochloride Sigma; 25 mg / kg ip
  • the test animals are fixed in a stereotactic frame.
  • the lesion of the nigrostriatal neurotransmission occurs through a unilateral, " single injection of 8 ⁇ g 6-OH-DA hydrobromide (Sigma, St. Louis, MO, USA), dissolved in 4 ⁇ l of a 0.01% ascorbic acid saline solution. The solution is slowly injected (1 ⁇ l / min.) The coordinates of the injection are according to König and Klippel: 2.4 mm anterior, 1.49 mm lateral, 2.7 mm ventral. After the injection, the injection needle was left in situ for 5 minutes to ensure the diffusion of the neuro- to facilitate toxins.
  • the animals are placed on a hot plate and returned to their cages under control after awakening, where they receive food and water ad libidum.
  • the animals are treated with substance one day after the operation until the end of the experiment 28 days after the operation.
  • 6-OHDA-injured animals are divided into different treatment groups, which receive either vehicles or different dosages of the compound to be examined.
  • a group of pseudo-injured animals is also carried (0.9% sodium chloride solution in water is injected instead of 6-OHDA).
  • the antipsychotic haloperidol also dissolves in sufficiently high levels
  • EP-A 1 250 923 describes that the selective PDE10 inhibitor papaverin triggers potentiation of haloperidol catalepsy.
  • the new active compounds can be converted into the customary formulations in a known manner, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions,
  • the therapeutically active compound should be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts that are sufficient to achieve the stated dosage range.
  • 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 the usual way, preferably orally, transdermally or parenterally, in particular perlingually or intravenously. However, it can also be inhaled through the mouth or nose, for example with the aid of a spray, or topically via
  • N-Acetyl-alanine (4.92 g, 37.5 mmol), 9.10 ml pyridine and 150 mg DMAP are dissolved in 200 ml THF and the solution is brought to a boil. At the boiling point, 8.6 ml (10.5 g, 75 mmol) of ethyl oxalyl chloride are added dropwise; after the addition has ended, the mixture is stirred at the boil for a further 3 h. After cooling, the reaction mixture is poured onto 600 ml of ice water, extracted with ethyl acetate (4 x 150 ml), the combined organic phases are saturated with 200 ml. Washed sodium chloride solution, dried over sodium sulfate and concentrated. The material obtained is immediately dissolved in ethanol and further reacted.
  • the reaction mixture is concentrated, the residue is mixed with aqueous sodium hydrogen carbonate solution, and the mixture is extracted with dichloromethane.
  • the organic phase is dried (sodium sulfate) and the solvent is removed in vacuo.
  • the residue is purified by flash chromatography (mobile phase: dichloromethane / methanol 100: 1).
  • the reaction mixture is concentrated, the residue is mixed with aqueous sodium hydrogen carbonate solution and the mixture is extracted with dichloromethane.
  • the organic phase is dried (sodium sulfate) and the solvent is removed in vacuo.
  • the residue is purified by flash chromatography (mobile phase: dichloromethane / methanol 100: 1).
  • the reaction mixture is concentrated, the residue is mixed with aqueous sodium hydrogen carbonate solution and the mixture is extracted with dichloromethane.
  • the organic phase is dried (sodium sulfate) and the solvent is removed in vacuo.
  • the residue is purified by flash chromatography (mobile phase: dichloromethane / methanol 100: 1).
  • Example 17A Analogously to Example 1, 620 mg (1.38 mmol) of 5,7-dimethyl-2- (4-nitrophenyl) -N- (3,4,5-trimethoxyphenyl) in ⁇ dazo [5, lf] [l, 2,4] azm- 4-an in Example 17A in the presence of 200 mg of palladium on carbon (10%) hydrogenated.
  • Example 3 Analogously to Example 2, 14.28 mg (0.24 mmol) acetic acid, 32.14 mg (0.24 mmol) HOBt, 72.17 mg (0.71 mmol) 4-methylmorpholine, 45.6 mg (0.24 mmol) EDC and 100 mg (0.24 mmol) N- [2- ( 4-aminophenyl) -5,7-dimethylimidazo [5, lf] [1,2,4] triazin-4-yl] -N- (3,4,5-trimethoxyphenyl) amine from Example 3. The processing takes place via HPLC separation.
  • Example 15A hydrogenated in the presence of 120 mg palladium on carbon (10%).
  • Example 18A Analogously to Example 1, 340 mg (0.76 mmol) of 5,7-dimethyl-2- (3-nitrophenyl) -N- (3,4,5-trimemoxyphenyl) imidazo [5, lf] [1,2,4] triazine 4-amine from Example 18A in the presence of 110 mg of palladium on carbon (10%) hydrogenated.
  • Example 7 Analogously to Example 2, 14 mg (0.21 mmol) of acetic acid, 31 mg (0.23 mmol) of HOBt, 63 mg (0.62 mmol) of 4-methylmo ⁇ holin, 44 mg (0.23 mmol) of EDC and 87 mg (0.21 mmol) of 3- [5.7 -Dimethyl-4- (3,4,5-1ximethoxvphenoxy) in ⁇ dazo- [5, l-fJ [l, 2,4] triazin-2-yljanilin from Example 7 implemented.

Abstract

L'invention concerne de nouvelles imidazotriazines substituées, des procédés pour leur production et leur utilisation pour la production de médicaments servant au traitement ou à la prophylaxie du cancer et de maladies neurodégénératives, notamment de la maladie de Parkinson et de la schizophrénie.
EP03735677A 2002-07-08 2003-06-25 Imidazotriazines substituees Withdrawn EP1599479A1 (fr)

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DE10230605A DE10230605A1 (de) 2002-07-08 2002-07-08 Substituierte Imidazotriazine
DE10230605 2002-07-08
PCT/EP2003/006661 WO2004005290A1 (fr) 2002-07-08 2003-06-25 Imidazotriazines substituees

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WO2005097800A1 (fr) * 2004-04-02 2005-10-20 Osi Pharmaceuticals, Inc. Inhibiteurs de la proteine kinase heterobicycliques a substitution de noyau bicyclique 6,6
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JP5572388B2 (ja) 2006-11-22 2014-08-13 インサイト・コーポレイション キナーゼ阻害剤としてのイミダゾトリアジンおよびイミダゾピリミジン
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WO2009091939A1 (fr) * 2008-01-18 2009-07-23 Osi Pharmaceuticals, Inc. Dérivés d'imidazopyrazinol pour le traitement des cancers
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