WO2004080998A1 - Imidazol-4-yl-ethynyl-pyridine derivatives - Google Patents
Imidazol-4-yl-ethynyl-pyridine derivatives Download PDFInfo
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- WO2004080998A1 WO2004080998A1 PCT/EP2004/002276 EP2004002276W WO2004080998A1 WO 2004080998 A1 WO2004080998 A1 WO 2004080998A1 EP 2004002276 W EP2004002276 W EP 2004002276W WO 2004080998 A1 WO2004080998 A1 WO 2004080998A1
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- methyl
- imidazol
- ylethynyl
- halogen
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- 0 *c1nccc(N)c1 Chemical compound *c1nccc(N)c1 0.000 description 1
- LEWCJJCQJZURAF-UHFFFAOYSA-N CC(C(P(OC)(OC)=O)=[NH+][NH-])=O Chemical compound CC(C(P(OC)(OC)=O)=[NH+][NH-])=O LEWCJJCQJZURAF-UHFFFAOYSA-N 0.000 description 1
- BKCJFJCLIIANJS-UHFFFAOYSA-M Cc1nc(C=O)c[n]1[AlH2] Chemical compound Cc1nc(C=O)c[n]1[AlH2] BKCJFJCLIIANJS-UHFFFAOYSA-M 0.000 description 1
- MQRMTENGXFRETM-UHFFFAOYSA-N Cc1nc(CO)c[nH]1 Chemical compound Cc1nc(CO)c[nH]1 MQRMTENGXFRETM-UHFFFAOYSA-N 0.000 description 1
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- 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
- C07D401/06—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 carbon chain containing only aliphatic carbon atoms
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- A61P25/16—Anti-Parkinson drugs
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- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- 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
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- 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
- C07D401/14—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 three or more hetero rings
Definitions
- the present invention relates to novel imidazole derivatives, to processes for their production, their use as pharmaceuticals and to pharmaceutical compositions comprising them.
- the present invention provides in a first aspect novel 4- [1 -aryl and 1- heteroaryl-imidazol-4-ylethynyl] -2-alkyl-pyridine derivatives as well as pharmaceutically acceptable salts thereof.
- R 1 is Q- alkyl
- R 2 is Ci-C 6 alkyl or C 3 ⁇ C 12 cycloalkyl
- R 3 is aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted by one, two or three substituents selected from halogen, C alkyl, S-CrC ⁇ alkyl, - alkyl-halogen, C ⁇ -C 6 alkoxy, halogen-Ci-C 6 alkoxy, C 3 -C ⁇ 2 cycloalkyl, C 2 - C ⁇ heterocycloalkyl, CrC ⁇ alkylamino, di-Ci-C ⁇ alkylamino, -Cealkoxyamino, ( -
- R 4 is hydrogen, C(O)H or CH 2 R 5 wherein R 5 is hydrogen, OH, CrC 6 alkyl or C 3 -
- the present invention provides a compound of formula I* wherein
- R 1 signifies lower alkyl
- R 2 signifies lower alkyl
- R 3 signifies aryl or heteroaryl, optionally substituted, preferably by one, two or three substituents, selected from the group consisting of halogen, lower alkyl, lower alkyl- halogen or cyano; as well as to pharmaceutically acceptable salts thereof.
- the compounds of general formula I are metabo- tropic glutamate receptor 5 antagonists.
- Compounds of formula I are distinguished by having valuable therapeutic properties. They can be used in the treatment or prevention of mGluR5 receptor mediated disorders.
- the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor.
- Glutamate is the major excitatory neurotransmitter in the brain and plays a unique role in a variety of central nervous system (CNS) functions.
- the glutamate-dependent stimulus receptors are divided into two main groups.
- the first main group namely the ionotropic receptors, forms ligand-controlled ion channels.
- the metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G- protein coupled receptors.
- these eight receptors can be sub-divided into three sub-groups:
- mGluRl and mGluR5 belong to group I
- mGluR2 and mGluR3 belong to group II
- mGluR4 mGluR6, mGluR7 and mGluRS belong to group III.
- Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, epilepsy, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, as well as chronic and acute pain.
- acute and/or chronic neurological disorders such as psychosis, epilepsy, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, as well as chronic and acute pain.
- treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia.
- Further treatable indications are ischemia, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopafhic parkinsonism or parkin- sonism caused by medicaments as well as conditions which lead to glutamate- deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, drug abuse/dependance such as nicotine addiction, opiate addiction, and alcohol abuse, anxiety, vomiting, dyskinesia and depressions.
- ALS amyotrophic lateral sclerosis
- dementia caused by AIDS
- eye injuries retinopathy
- idiopafhic parkinsonism or parkin- sonism caused by medicaments as well as conditions which lead to glutamate-
- Disorders mediated full or in part by mGluR5 are for example acute, traumatic and chronic degenerative processes of the nervous system, such as Alzheimer's disease, senile dementia, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric diseases such as schizophrenia and anxiety, depression, pain and drug dependency [Expert Opin. Ther. Patents 12:12 (2002)].
- Selective mGluR5 antagonists are especially useful for the treatment of anxiety and pain.
- Objects of the present invention are compounds of formula I and their pharmaceutically acceptable salts, the above-mentioned compounds as pharmaceutically active substances and their production. Further objects of the invention are medicaments based on a compound in accordance with the invention and their manufacture as well as the use of the compounds in the control or prevention of mGluR5 receptor mediated disorders, and, respectively, for the production of corresponding medicaments.
- lower alkyl used in the present description denotes straight-chain or branched saturated hydrocarbon residues with 1 to 6 carbon atoms, preferably with 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl and the like.
- the term “diagoalkyl” used in the present description denotes cyclic saturated hydrocarbon residues with 3 to 12 carbon atoms. Examples for cycloallcyl include cyclopropyl, cyclobutyl and cyclopentyl.
- Examples for -Csalko y include mefhoxy, methoxyethyl and methoxyethoxy.
- Examples for halogenmethoxy include trifluoromethoxy.
- Examples for C 2 -C ⁇ heterocycloaIkyl include pyrrolidinyl, morpholinyl and thiomorpho- linyl.
- Examples for -Csalkylamino include methylamino and ethylamino.
- Examples for di- - C 6 al_kylamino include dimethylamino.
- Examples for -Cealkoxyamino include methoxy- ethylamino.
- Examples for (C 1 -C 6 alkoxy)C 1 -C 6 aIkylamino include (methoxyethyl)methyl- amino.
- Examples for methoxycycloalkylamino include cyclopropylamino.
- halogen denotes fluorine, chlorine, bromine and iodine.
- Aryl represents an aromatic carbocyclic group consisting of one individual ring, or one or more fused rings in which at least one ring is aromatic in nature. Examples for aryl in- elude phenyl. Examples for substituted aryl include fluorophenyl, difluorophenyl, chloro- phenyl, dichlorophenyl, chlorofluorophenyl, cyanophenyl, methylphenyl, methoxyphenyl, fluoromethylphenyl, trifluoromethylphenyl and trifluoromethoxyphenyl.
- heteroaryl refers to an aromatic 5- or 6-membered ring or one or more fused rings containing one or more heteroatoms selected from nitrogen, oxygen or sulphur.
- heteroaryl groups are pyrimidinyl, pyrazinyl, pyridazinyl, pyridinyl and indolyl, e.g. pyridin-4-yl, pyridin-2-yl, pyrazin-2-yl and pyrimidin-2-yl.
- substituted heteroaryl examples include methylpyrimidinyl, dimethylpyrimidinyl, trifluoromethylpyri- midinyl, mefhoxypyrimidinyl, methoxyethoxypyrimidinyl, ethylpyrimidinyl, fluoropyri- midinyl, chloropyrimidinyl, bromopyrimidinyl, methylsulfanylpyrimidinyl, cyclopropyl- pyrimidinyl, methylpyrazinyl, cyclopropylpyrazinyl, chloropyrazinyl, methoxypyrazinyl, methoxyethoxypyrazinyl, methylaminopyrazinyl, dimethylaminopyrazinyl, cyclopropyl- aminopyrazinyl, morpholinylpyrazinyl, fluoropyridinyl, chloropyridinyl, bromopyridinyl, iodopyridin
- pharmaceutically acceptable salt refers to any salt derived from an inorganic or organic acid.
- “Pharmaceutically acceptable salts” of a compound means salts that are pharmaceutically acceptable, which are generally safe, non-toxic, and neither biologically nor otherwise undesirable, and that possess the desired pharmacological activity of the parent compound. These salts are derived from an inorganic or organic acid. If possible, compounds of formula I may be converted into pharmaceutically acceptable salts.
- references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) of the same acid addition salt.
- Examples for pharmaceutically acceptable acid addition salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucohep tonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaph- thoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluene-sulfonic acid, trimethylacetic acid, trifluoro
- Preferred compounds of formula I* are those, in which R 1 and R 2 are both methyl.
- R 3 is substituted phenyl, wherein the substitution is fluoro, chloro, cyano or CF 3 .
- Examples of compounds, wherein the substitution is cyano are as follows: 4- [2-methyl-4- (2-methyl-pyridin-4-ylethynyl) -imidazol- 1 -yl] -benzonitrile, or 3-[2-methyl-4-(2-mefhyl-pyridin-4-ylethynyl)-imidazol-l-yl]-benzonitrile.
- R 1 and R 2 are both methyl and R 3 is pyrimidinyl, for example the following compound: 2- [2-methyl-4- (2-methyl-pyridin-4-ylethynyl) -imidazol- 1 -yl] -pyrimidine.
- the present invention provides a compound of formula I wherein R 1 is methyl, and R 2 , R 3 and R 4 independently are as defined above or hereinafter.
- the present invention provides a compound of formula I wherein R 2 is Ci-Cgalkyl. In another embodiment the present invention provides a compound of formula I wherein R 2 is methyl or isopropyl. In another embodiment the present invention provides a compound of formula I wherein R 2 is cyclopropyl. In all the above embodiments R , R 3 and R 4 independently are as defined above or hereinafter.
- the present invention provides a compound of formula I wherein R 3 is unsubstituted aryl or aryl substituted by one, two or three substituents selected from halo- gen, C C ⁇ alkyl, S-Ci-Cgalkyl, Ci-C 6 aIkyl-halogen, C ⁇ -C 6 alkoxy, halogen-Ci-Cealkoxy, C 3 - C 12 cycloalkyl, C 2 -Cnheterocycloalkyl, CrCgalkylamino, di- -C ⁇ alkylamino, CrCgalkoxy- amino, (C 1 -C6alkoxy)C 1 -C 6 alkylamino, C 3 -C ⁇ 2 cycloaIkylamino, benzylamino and cyano.
- R 3 is unsubstituted aryl or aryl substituted by one, two or three substituents selected from halo- gen, C C ⁇ alkyl
- the present invention provides a compound of formula I wherein R 3 is phenyl or phenyl substituted by one, two or three substituents selected from halogen, Ci-Cgalkyl, S- -Cgalkyl, Ci-Cgalkyl-halogen, Ci-C 6 alkoxy, halogen- -Cgalkoxy, C 3 -
- the present invention provides a compound of formula I wherein R 3 is phenyl or phenyl substituted by one or two substituents selected from halogen, C Cgalkyl, CrCgalkyl-halogen, -Cgalkoxy, halogen- -Cgalkoxy and cyano.
- the present invention provides a compound of formula I wherein R 3 is phenyl substituted by one or two substituents selected from halogen, -Cgalkyl, - C 6 alkyl-halogen, Ci-Cgalkoxy, halogen-Ci-C 6 aIkoxy and cyano.
- R 3 is phenyl substituted by one or two substituents selected from fluoro, chloro, methyl, trifluoromethyl, methoxy, trifluoromethoxy and cyano.
- the present invention provides a compound of formula I wherein R 3 is fluorophenyl, difluorophenyl, chlorophenyl, di- chlorophenyl, cyanophenyl, trifluoromethylphenyl, fluoro-methylphenyl, chloro-fluoro- phenyl, methylphenyl, methoxyphenyl or trifluoromethoxyphenyl.
- R 3 is fluorophenyl, difluorophenyl, chlorophenyl, di- chlorophenyl, cyanophenyl, trifluoromethylphenyl, fluoro-methylphenyl, chloro-fluoro- phenyl, methylphenyl, methoxyphenyl or trifluoromethoxyphenyl.
- the present invention provides a compound of formula I wherein R 3 is unsubstituted heteroaryl or heteroaryl substituted by one, two or three substituents selected from the group consisting of halogen, Ci-Cgalkyl, S-Ci-Cgalkyl, -Cgalkyl-halo- gen, Ci-Cgalkoxy, halogen-CrCgalkoxy, C 3 -C ⁇ 2 cycloaIkyl, C 2 -C ⁇ heterocycloalkyl, Q- Cgalkylamino, di-Ci-Cgalkylamino, Ci-Cgalkoxyamino, (Ci-Cgalkoxy)C ⁇ -C 6 alkylamino, C 3 -Ci 2 cycloalkylamino, benzylamino and cyano.
- substituents selected from the group consisting of halogen, Ci-Cgalkyl, S-Ci-Cgalkyl, -Cgalkyl-halo- gen, Ci-
- the present invention provides a compound of formula I wherein R 3 is unsubstituted pyrimidinyl, unsubstituted pyrazinyl or unsubstituted pyridinyl.
- R 3 is heteroaryl selected from pyrimi- dinyl, pyrazinyl, pyridinyl and indolyl wherein the heteroaryl is substituted by one or two substituents selected from halogen, Ci-Cgalkyl, S-CrCgalkyl, Ci-Cgalkyl-halogen, Q- Cgalkoxy, C 3 -C 12 cycloalkyl, C 2 -Cnheterocycloalkyl, -Cgalkylamino, di- -Cgalkylamino, CrCgalkoxyamino, (Ci-Cgalkoxy)C ⁇ -Cgalkylamino, C 3 -C ⁇ 2 cycloalkylamino and
- the present invention provides a compound of formula I wherein R 3 is pyrimidinyl substituted by one or two substituents selected from halogen, Ci-Cgalkyl, S-Ci-C ⁇ alkyl, Ci-Cgalkyl-halogen, -Cgalkoxy and C 3 -C ⁇ 2 cycloalkyl; or pyrazinyl substituted by one substituent selected from halogen, Ci-Cgalkyl, Ci-Cgalkoxy, C 3 -C 12 cycloalkyl, C 2 -C ⁇ heterocycloalkyl, Ci-Cgalkylamino, di-Ci-Cgalkylamino and C 3 - C 12 cycloalkylamino; or pyridinyl substituted by one or two substituents selected from halogen, d-Cgalkyl, CrCgalkyl-halogen, Q-Cgalkoxy, C 3 -C 12 cycloalkyl, C 2 -C ⁇ hetero-
- the present invention provides a compound of formula I wherein R 3 is methylpyrimidinyl, ethylpyrimidinyl, dimethylpyrimidinyl, trifluoromethylpyrimidinyl, methoxypyrimidinyl, methoxyethoxypyrimidinyl, fluoropyrimidinyl, chloropyrimidinyl, bromopyrimidinyl, methylsulfanylpyrimidinyl, cyclopropylpyrimidinyl, methylpyrazinyl, cyclopropylpyr- azinyl, mefhoxypyrazinyl, chloropyrazinyl, methylaminopyrazinyl, dimethylaminopyr- azinyl, cyclopropylpyrazinyl, mefhylpyridinyl, butylpyridinyl, fluoropyridinyl, chloro- pyridinyl, bromopyridinyl, io
- the present invention provides a compound of formula I wherein R 4 is hydrogen, C(O)H or CH 3 . In another embodiment the present invention provides a compound of formula I wherein R 4 is hydrogen. In all the above embodiments R 1 , R 2 and R 3 independently are as defined above or hereinafter.
- the present invention provides a compound of formula I wherein R 1 is methyl
- R 2 is Ci-Cgalkyl or C 3 -C 12 cycloalkyl
- R 3 is aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted by one, two or three substituents selected from halogen, CrCgalkyl, S-CrCgalkyl, - Cgalkyl-halogen, CrCgalkoxy, halogen-CrCgalkoxy, C 3 -C 12 cycloalkyl, C 2 -
- R 4 is hydrogen, C(O)H or CH 2 R 5 wherein R 5 is hydrogen, OH, CrCgalkyl or C 3 -
- the present invention provides a compound of formula I wherein R 1 is methyl
- R 2 is methyl, isopropyl or cyclopropyl
- R 3 is aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted by one, two or three substituents selected from halogen, CrCgalkyl, S-Ci-Cgalkyl, - Cgalkyl-halogen, CrCgalkoxy, halogen-CrCgalkoxy, C 3 -C 12 cycloalkyl, C 2 -
- R 4 is hydrogen, C(O)H or CH 2 R 5 wherein R 5 is hydrogen, OH, CrCgalkyl or C 3 -
- R 1 is methyl
- R 2 is methyl, isopropyl or cyclopropyl
- R 3 is aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted by one, two or three substituents selected from halogen, CrCgalkyl, S-CrCgalkyl, Ci-
- Cgalkyl-halogen Ci-Cgalkoxy, halogen-CrCgalkoxy, C 3 -C ⁇ 2 cycloalkyl, C 2 - C ⁇ heterocycloalkyl, CrCgalkylamino, di-Ci-Cgalkylamino, CrCgalkoxyamino, (Ci- Cgalkoxy) CrCgalkylamino, C 3 -Ci 2 cycloal_kylamino, benzylamino and cyano; and
- R 4 is hydrogen, C(O)H or methyl.
- R 1 is methyl
- R 2 is methyl, isopropyl or cyclopropyl
- R 3 is aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted by one, two or three substituents selected from halogen, Ci-Cgalkyl, S-Ci-Cgalkyl, Q- C 6 alkyl-halogen, Ci-Cgalkoxy, halogen-Ci-Cgalkoxy, C 3 -C ⁇ 2 cycloalkyl, C 2 - Ciiheterocycloalkyl, CrCgalkylamino, di-Ci-Cgalkylamino, Ci-Cgalkoxyamino, (Q- Cgalkoxy)C ⁇ -Cgalkylamino, Q-Cncydoalkylamino, benzylamino and cyano; and R is hydrogen.
- R and R are methyl
- R 3 is aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted by one, two or three substituents selected from halogen, Ci-Cgalkyl, S-CrCgalkyl, Q- Cgalkyl-halogen, Q-Cgalkoxy, halogen-Q-Cgalkoxy, C 3 -C 12 cycloalkyl, C 2 -
- R 1 and R 2 are methyl
- R 3 is unsubstituted aryl or aryl substituted by one, two or three substituents selected from halogen, Q-Cgalkyl, S-CrCgalkyl, Q-Cgalkyl-halogen, Ci-Cgalkoxy, halogen-Q- Cgalkoxy, Q-Cncycloalkyl, C 2 -Qiheterocycloalkyl, Ci-Cgalkylamino, di-Q-Cgalkyl- amino, CrCgalkoxyamino, (CrCgalkoxy)Q-Cgalkylamino, C3-C ⁇ 2 cycloalkylamino, benzylamino and cyano; and R 4 is hydrogen.
- the present invention provides a compound of formula I wherein R 1 and R 2 are methyl;
- R 3 is phenyl or phenyl substituted by one, two or three substituents selected from halogen, Ci-Cgalkyl, S-Ci-Cgalkyl, Q-Cgalkyl-halogen, Ci-Cgalkoxy, halogen-Ci- Cgalkoxy, C 3 -Q 2 cycloalkyl, -Qiheterocycloalkyl, Q-Cgalkylamino, di-Q-Cgalkyl- amino, CrCgalkoxyamino, (Q-Cgalkoxy)Ci-Cgalkylamino, C 3 -C ⁇ 2 cycloalkylamino, benzylamino and cyano; and
- R 4 is hydrogen
- R 1 and R 2 are methyl;
- R 3 is phenyl or phenyl substituted by one or two substituents selected from halogen, Q-
- R 1 and R 2 are methyl
- R 3 is phenyl substituted by one or two substituents selected from fluoro, chloro, methyl, trifluoromethyl, methoxy, trifluoromethoxy and cyano; and R 4 is hydrogen.
- R 1 and R 2 are methyl
- R 3 is fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, cyanophenyl, tri- fluoromethylphenyl, fluoro-methylphenyl, chloro-fluorophenyl, methylphenyl, mefh- oxyphenyl or trifluoromethoxyphenyl;
- R 4 is hydrogen
- R 1 and R 2 are methyl;
- R 3 is unsubstituted heteroaryl or heteroaryl substituted by one, two or three substituents selected from the group consisting of halogen, Ci-Cgalkyl, S-Q-Cgalkyl, Ci-Cgalkyl- halogen, CrCgalkoxy, halogen-Ci-Cgalkoxy, Q-Cncycloalkyl, C -Q ⁇ heterocycloalkyl, Q-Cgalkylamino, di-Q-Cgalkylamino, Q-Cgalkoxyamino, (Q-CgalkoxyJQ-Cgalkyl- amino, C 3 -Q 2 cycloalkylamino, benzylamino and cyano; and R 4 is hydrogen.
- R 1 and R 2 are methyl
- R 3 is unsubstituted pyrimidinyl, unsubstituted pyrazinyl or unsubstituted pyridinyl; and R 4 is hydrogen.
- R 1 and R 2 are methyl;
- R 3 is heteroaryl selected from pyrimidinyl, pyrazinyl, pyridinyl and indolyl wherein the heteroaryl is substituted by one or two substituents selected from halogen, Q-Cgalkyl, S-Q-Cgalkyl, Q-Cgalkyl-halogen, Q-Cgalkoxy, C 3 -C ⁇ 2 cycloalkyl, Q-Qiheterocyclo- alkyl, Q-Cgalkylamino, di-Q-Cgalkylamino, Q-Cgalkoxyamino, (Q-Cgalkoxy) Q- Cgalkylamino, C 3 -C ⁇ 2 cycloalkylamino and benzylamino; and
- R 4 is hydrogen
- R 1 and R 2 are methyl;
- R 3 is pyrimidinyl substituted by one or two substituents selected from halogen, Ci- Cgalkyl, S-Q-Cgalkyl, Ci-Cgalkyl-halogen, Q-Cgalkoxy and C 3 -C 12 cycloalkyl; or pyrazinyl substituted by one substituent selected from halogen, Q-Cgalkyl, Ci-Cgalkoxy, C 3 -Q 2 cycloalkyl, C 2 -Q ⁇ heterocycloalkyl, Q-Cgalkylamino, di-Q-Cgalkylamino and C 3 -Q 2 cycloalkylarnino; or pyridinyl substituted by one or two substituents selected from halogen, Q-Cgalkyl, Q-Cgalkyl-halogen, Ci-Cgalkoxy, Q-C ⁇ cycloalkyl,
- R 4 is hydrogen
- R 1 and R 2 are methyl
- R 3 is methylpyrimidinyl, ethylpyrimidinyl, dimethylpyrimidinyl, trifluoromethylpyri- midinyl, methoxypyrimidinyl, methoxyethoxypyrimidinyl, fluoropyrimidinyl, chloropyrimidinyl, bromopyrimidinyl, methylsulfanylpyrimidinyl, cyclopropylpyrimidinyl, methylpyrazinyl, cyclopropylpyrazinyl, methoxypyrazinyl, chloropyrazinyl, methyl- aminopyrazinyl, dimethylaminopyrazinyl, cyclopropylpyrazinyl, methylpyridinyl, butylpyridinyl, fluoropyridinyl, chloropyridinyl, bromopyridinyl, iodopyridinyl, tri- fluoromethylpyridinyl, (triflu
- R 4 is hydrogen
- Examples of compounds of formula I include 4-[l-(4-fluoro-phenyl)-2-methyl-lH-imidazol-4-ylethynyl] -2-methyl-pyridine, -[l-(3,4-dichloro-phenyl)-2-methyl-lH-imidazol-4-ylethynyl] -2-methyl-pyridine hydro- chloride, -[l-(2,4-difluoro-phenyl)-2-methyl-lH-imidazol-4-ylethynyl]-2-methyl-pyridine, - [l-(3,4-difluoro-phenyl)-2-methyl-lH-imidazol-4-ylethynyl] -2-methyl-pyridine, -[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-l-yl]-benzonitrile, -[2-methyl-4-(2-methyl-pyridin-4-
- the present invention also provides a process for the production of a compound of formula I
- R 1 is Q-Cgalkyl
- R 2 is Ci-Cgalkyl or C 3 -C 12 cycloaIkyl
- R 3 is unsubstituted aryl or aryl substituted by one, two or three substituents selected from halogen, Q-Cgalkyl, S-Q-Cgalkyl, Ci-Cgalkyl-halogen, Q-Cgalkoxy, halogen-Ci- Cgalkoxy, C 3 -Q 2 cycloalkyl, Q-Qiheterocycloalkyl, Q-Cgalkylamino, di-Q-Cgalkylamino, CrCgalkoxyamino, (Q-Cgalkoxy)CrCgalkylamino, Q-C ⁇ cycloalkylamino, benzylamino and cyano, unsubstituted heteroaryl or heteroaryl substituted by one, two or three substituents selected from the group consisting of halogen, Q-Cgalkyl, S- Q
- R 3 -Z (III) wherein R 3 has the meanings as defined above and Z is halogen or B(OH) 2 ; or (b) a compound of formula IV
- R 1 has the meanings as defined above and X is halogen; or (c) a compound of formula VI
- R 1 has the meaning as defined above and Y is trimethylsilyl or hydrogen.
- the reaction as described in (a) maybe carried out in accordance with standard procedures, e.g. by arylation of a compound of formula II using an aromatic boronic acid and a copper catalyst in a solvent like dichloromethane or tetrahydrofurane [see e.g. Colmann et al., Org. Lett. 2:1233 (2000)] or by heating a compound of formula II and a compound of formula III wherein Z is halogen with a base like potassium carbonate or cesium carbonate in a solvent like dimethylformamide, or Pd catalyzed according to Buchwald conditions [see e.g. Example 8; Buchwald et al., Tetrahedron Lett. 40:2657 (1999)] .
- the reaction as described in (b) may be carried out by a Sonogashira coupling of a compound of formula IV and a compound of formula V in the presence of, e.g., Cul, (Ph 3 P) 2 PdCl , Et ⁇ N in a solvent like tetrahydrofuran or dimethylformamide [Sonogashira et al, Synthesis 777 (1977)].
- the meaning X in compounds of formula V is bromine or iodine.
- the reaction as described in (c) above may, e.g. be carried out in the presence of Cul, (Ph. 3 P) 2 PdCl 2 , Et 3 N, n-Bu F in a solvent like tetrahydrofuran or dimethylformamide.
- the compounds of formula II may be prepared by reacting a compound of formula VIII wherein R 2 and R 4 have the above meanings and hal is halogen, with a compound of formula VII as above.
- the compounds of formula VIII may be prepared as described e.g. in Cliff and Pyne [Synthesis 681-682 (1994)].
- the compounds of formula IV maybe prepared by reacting a compound of formula IX
- R 3 R 4 wherein R 2 , R 3 and R 4 have the meanings as defined above, with dimethyl (l-diazo-2-oxopropyl)phosphonate as described in Ohira [Synth. Comm. 19:561-564 (1989)].
- R 3 -B(OH) 2 (X) wherein R 3 has the meanings as defined above.
- the reaction may take place by arylation of a compound of formula VIII using an aromatic boronic acid (compound of formula X) and a copper catalyst in a solvent like dichloromethane or tetrahydrofurane under an oxygen atmosphere [see e.g. Colmann et al., Org.Lett. 2:1233 (2000)].
- the reaction may take place by a Sonogashira coupling in the presence of eg. Cul, (Ph 3 P) 2 PdCl 2 , EtaN in a solvent like tetrahydrofuran or dimethylformamide [Sonogashira et al., Synthesis 777 (1977)].
- Compounds of formula XV may be prepared by treating a compound of formula XVI with a reducing agent according to methods known to the skilled artisan.
- R 3 -NH 2 (XVIII) with e.g. triethyl orthoformate, ethylnitro acetate, glacial acetic acid and iron powder according to methods known to the skilled artisan.
- the compounds of general formula I* and their pharmaceutically acceptable salts can be manufactured by two general procedures, which procedures are outlined below for compounds wherein R 1 is methyl and R 2 is methyl, but which procedures are applicable for all compounds according to Formula I*.
- the invention also relates to a process for preparing a compound according to general formula I* following the general procedures as outlined above for compounds of formula I* wherein R 1 is methyl and R 2 is methyl (R 3 and R 1 are designated Ar and Ar', respectively, in Scheme 2).
- the invention relates also medicaments containing one or more compounds of the present invention and pharmaceutically acceptable excipients for the treatment and. prevention of mGluR5 receptor mediated disorders, such as acute and/ or chronic neurological disorders, in particular anxiety and chronic or acute pain.
- the invention also relates to the use of a compound in accordance with the present invention as well as its pharmaceutically acceptable salt for the manufacture of medicaments for the treatment and prevention of mGluR5 receptor mediated disorders as outlined above.
- Pharmaceutically acceptable salts of compounds of formula I can be manufactured readily according to methods known per se and taking into consideration the nature of the compound to be converted into a salt.
- Inorganic or organic acids such as, e.g., hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like are suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula I.
- Compounds which contain the alkali metals or alkaline earth metals, for example sodium, potassium, calcium, magnesium or the like, basic amines or basic amino acids are suitable for the formation of pharmaceutically acceptable salts of acidic compounds.
- the compounds of formula I and their pharmaceutically acceptable salts are, as already mentioned above, metabotropic glutamate receptor antagonists and can be used for the treatment or prevention of mGluR5 receptor mediated disorders, such as acute and/or chronic neurological disorders, cognitive disorders and memory deficits, as well as acute and chronic pain.
- Treatable neurological dis- orders are for instance epilepsy, schizophrenia, anxiety, acute, traumatic or chronic degenerative processes of the nervous system, such as Alzheimer's disease, senile dementia, Huntington's chorea, ALS, multiple sclerosis, dementia caused by AIDS, eye injuries, re- tinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficient functions, such as e.g. muscle spasms, con- vulsions, migraine, urinary incontinence, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, dyskinesia and depression.
- glutamate-deficient functions such as e.g. muscle spasms, con- vulsions, migraine, urinary incontinence, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, dyskinesia and depression.
- Treatable kinds of pain include inflammatory pain such as arthritis and rheumatoid disease, vasculitis, neuropathic pain such as trigeminal or herpetic neuralgia, diabetic neuropathy pain, causalgia, hyper- algesia, severe chronic pain, post-operative pain and pain associated with various condi- tions like cancer, angina, renal or billiay colic, menstruation, migraine and gout.
- cDNA encoding human mGlu 5a receptor was transiently trans- fected into EBNA cells using a procedure described by Schlaeger and Christensen [Cyto- technology 15:1-13 (1998)].
- Cell membrane homogenates were stored at -80°C until the day of assay where upon they were thawed and resuspended and polytronised in 15 mM Tris-HCl, 120 mM NaCl, 100 mM KC1, 25 mM CaCl 2 , 25 mM MgCl 2 binding buffer at pH 7.4 to a final assay concentration of 20 ⁇ g protein/ well.
- membranes were filtered onto unifilter (96-well white micro- plate with bonded GF/C filter preincubated 1 h in 0.1% PEI in wash buffer, Packard Bio- Science, Meriden, CT) with a Filtermate 96 harvester (Packard BioScience) and washed 3 times with cold 50 mM Tris-HCl, pH 7.4 buffer. Nonspecific binding was measured in the presence of 10 ⁇ M MPEP. The radioactivity on the filter was counted (3 min) on a Packard Top-count microplate scintillation counter with quenching correction after addition of 45 ⁇ l of microscint 40 (Canberra Packard S.A., Zurich, Switzerland) and shaking for 20 min.
- Ki value is defined by the following formula:
- Ki IC 50 / [l + L / K d ]
- IC 50 values are those concentrations of the compounds tested which cause 50 % inhibition of the competing radioligand ([ 3 H]MPEP).
- L is the concentration of radioligand used in the binding experiment and the Ka value of the radioligand is empiri- cally determined for each batch of membranes prepared.
- Pharmaceutical Compounds are mGluR 5a receptor antagonists.
- the activities of Pharmaceutical Compounds as measured in the assay described above are in the range of Kj ⁇ 150 nM.
- the Vogel conflict drinking test is a procedure that has been widely used as a screening method for anxiolytics.
- the water intake of thirsty rats is measured under conditions where water intake is suppressed by electric shock.
- rats are water-restricted for 23h during three consecutive days. One day after the first water restriction, they are allowed to freely drink for one hour in their home-cage. The second day, they are allowed to lick from a drinking spout in the operant box for 15 min, after which they are allowed to freely drink in their home cage for one hour.
- Pharmaceutical Compounds can be used as medicaments, e.g. in the form of pharmaceutical preparations.
- the pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emul- sions or suspensions.
- the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
- Pharmaceutical Compounds can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations.
- Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, e.g., as such carriers for tablets, coated tablets, dragees and hard gelatine capsules.
- Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules.
- Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.
- Adjuvants such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula I, but as a rule are not necessary.
- Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
- the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
- medicaments containing a Pharmaceutical Compound and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such medicaments which comprises bringing one or more Pharmaceutical Compound and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.
- the dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case.
- the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/ kg/day being preferred for all of the indications described.
- Step 1 2-Methyl- 1 - (2-trimethylsilanyl-ethoxymethyl) - lH-imidazole-4-carbaldehyde and
- Step 2 4-Ethynyl-2-methyl-l-(2-frimemylsflanyl-etfroxymethyl)-lH-imidazole and 5- ethynyl-2-methyl-l-(2-trimethylsilanyl-ethoxymefhyl)-lH-imidazole (l-Diazo-2-oxo-propyl)- ⁇ hosphonic acid dimethyl ester (10.4 g, 54 mmol) was dissolved in 150 mL methanol. Potassium carbonate (12.6 g, 90 mmol) was added.
- Step 4 2-Methyl-4-(2-methyl-lH-imidazol-4-ylethynyl -pyridine 2-Methyl-4-[2-me1 ⁇ yl-l-(2-trimethylsflanyl-ethoxymethyl)-lH-imidazol-4-ylethynyl]- pyridine and 2-methyl-4- [2-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4- ylethynyl] -pyridine (2.85 g, 8.7 mmol) were dissolved in 50 mL EtOH saturated with HCl. The reaction mixture was stirred at RT overnight. The solvent was evaporated.
- Step 1 4-Iodo-2-methyl-pyridine 4-Chloropicoline (10 g, 78 mmol), sodium iodide (17.8 g, 118 mmol) and hydroiodic acid (57%, 26 mL, 196 mmol) were heated in a sealed class tube at 140°C for 7 days. The reaction mixture was poured into ice water and neutralized by addition of sodium hydroxide. This mixture was extracted three times with dichloromethane (300 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The desired product was obtained as an off-white solid (14.7 g, 85%) and used without any further purification for the next step. Sje ⁇ 2-Methyl-4-trimethylsilanylethynyl-pyridine
- the reaction mixture was stirred at RT overnight. The solvent was evaporated. The residue was taken up in 500 mL water and extracted three times with ethyl acetate (500 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate gradient 100:0 — 0:100). The desired product was obtained as a light brown liquid (8.18 g, 99%).
- Step 3 2-Methyl-4-(2-methyl-lH-imidazol-4-ylethynyl -pyridine Solution 1: 2-Mefhyl-4-trimethylsilanylethynyl-pyridine (12 g, 74 mmol) and 5-iodo-2- methyl- lH-imidazole (13.24 g, 64 mmol, synthesis: Cliff and Pyne, Synthesis 681-682
- Solution 2 Triphenylphosphine (223 mg, 0.85 mmol), bis (triphenylphosphine) -palladi- um(II) chloride (1.79 g, 2.55 mmol), copper(I)iodide (81 mg, 0.43 mmol) and triethyl amine (8.87 mL, 64 mmol) were dissolved in 75 mL dry THF. This mixture was also evacuated and backfilled with argon several times to remove oxygen from the solution. Solution 2 was heated to 40°C and solution 1 was added dropwise.
- the reaction mixture was heated to 60°C and tetrabutylammonium fluoride solution (1M in THF, 55 mL, 55 mmol) was added dropwise during 45 min. The reaction was than stirred at RT overnight. The solvent was evaporated. The residue was taken up in 200 mL water and extracted three times with ethyl acetate (200 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by chromatography on silica gel (methylene chloride/methanol 95:5) and recrystallized from a mixture of methylene chloride and ethyl acetate. The desired product was obtained as a light brown solid (7.44 g, 59%).
- Example III- 1 2-Chloro-5-methyl-pyrazine (III-l) 2-Hydroxy-5-methylpyrazine (0.984g, 8.94 mmol) was refluxed in 15 mL phosphoroxy- chloride for 1.5h. The reaction mixture was slowly poured into ice and adjusted to pH6 by addition of sodium carbonate. The mixture was extracted six times with ethyl acetate (50 mL each). The combined organic extracts were dried with sodium sulfate, filtered and eva- porated. The crude product was used without any further purification for the next step.
- This compound was prepared according to WO 92/11,241.
- Example IV- 1 4-Emynyl-l-(4-fluoro-phenyl)-2-methyl-lH-imidazole (IV-1)
- Step 1 l-(4-Fluoro-phenyl)-lH-imidazole-4-carboxylic acid ethyl ester 4-Fluoroaniline (20.0 g, 175 mmol) was mixted at RT with triethyl orthoformate (35.4 g, 233 mmol), ethylnitro acetate (28.5 g, 210 mmol) and 4 mL glacial acetic acid. The reaction mixture was refluxed with mechanical stirring for 2h. More triethyl orthoformate (200 mL) and glacial acetic acid (200 mL) were added. Iron powder (100 g, 1.79 mol) was added in 3 portions during 8h while maintaining the reaction mixture at reflux.
- Step 2 l-(4-Fluoro-phenyl)-lH-imidazole-4-carboxylic acid
- Step 3 [l-(4-Fluoro-phenyl)-lH-imidazol-4-yl]-methanol l-(4-Fluoro-phenyl)-lH-imidazole-4-carboxylic acid (18 g, 87 mmol) was dissolved in 90 mL dry THF. Borane tetrahydrofuran complex (174 mL, 1M in THF, 174 mmol) was added dropwise. The reaction was refluxed for 2h and stirred at RT overnight.
- Step 6 [l-(4-Fluoro-phenyl)-2-methyl-lH-imidazol-4-yl1 -methanol 4- (tert-Butyl-dimethyl-silanyloxymethyl) - 1- (4-fluoro-phenyl) -2-methyl- lH-imidazole (14.7 g, 45.7 mmol) was dissolved in 200 mL THF. Tetrabutyl ammoniumfluoride (91 mL, IM in THF, 91 mmol) was added and the reaction mixture was stirred at RT overnight. The solvent was evaporated. The residue was taken up in 200 mL water and extracted three times with ethyl acetate (200 mL each).
- Step 8 4-Ethynyl- 1 - (4-fluoro -phenyl) -2-methyl- lH-imidazole
- Example 1 4- [ 1 - (4-Fluoro-phenyl) -2-methyl- lH-imidazol-4-ylethynyl] -2-methyl- pyridine (1)
- Example 2 2- [2-Methyl-4-(2-meth.yl-pyridin-4-ylethynyl)-imidazol- 1-yl] -pyrimidine (8) 2-Methyl-4- (2-methyl- lH-imidazol-4-ylethynyl) -pyridine (II-l) (87 mg, 0.44 mmol) was dissolved in 3 mL dimethyl formamide. Potassium carbonate (122 mg, 0.88 mmol) and 2- chloro-pyrimidine (76 mg, 0.66 mmol) were added and the reaction mixture was refluxed overnight. The reaction mixture was poured into 60 mL water and extracted three times with ethyl acetate (50 mL each).
- the foUowing compounds were prepared in analogy to the method as described above:
- triphenylphosphine (4 mg, 0.01 mmol), bis(triphenylphosphine)-paUadium(II)chloride (16 mg, 0.02 mmol), copper(I)- iodide (1 mg, 0.01 mmol) and triethyl amine (0.10 mL, 0.69 mmol) were dissolved in 2 mL dry THF. This mixture was also evacuated and backfiUed with argon several times to remove oxygen from the solution.
- 2-CUoro-6-[2-methyl-4-(2-me1i ⁇ yl-pyridin-4-ylethynyl)-imidazol-l-yl]-pyrazine (27)(300 mg, 0.968 mmol) was dissolved in 5 mL dry tetrahydrofuran. Dimethylzinc (1.2 mL, 2M in toluene) and tetrakis(triphenylphosphin)paUadium (23 mg, 0.02 mmol) were added. The reaction mixture was refluxed for 2h and poured into 50 mL sat. sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate (50 mL each).
- the foUowing compounds were prepared in analogy to the method as described above:
- Diisopropylamine (0.260 mg, 2.6 mmol) was dissolved in 5 mL dry tetrahydrofurane, n- butyUithium (1.6 mL, 1.6 M in hexane, 2.6 mmol) were added at -78°C and the mixture was kept at -78°C for 10 min.
- 4-[l-(4-Fluoro-phenyl)-2-methyl-lH-imidazol-4-ylethyn- yl] -2-methyl-pyridine (1) 500 mg, 1.72 mmol
- 5 mL dry tetrahydrofurane was added at -78°C and stirring was continued for 45 min at this temperature.
- Tablets of the foUowing composition are produced in a conventional manner: mg/Tablet Active ingredient 100
- Tablets of the foUowing composition are produced in a conventional manner: mg/Tablet Active ingredient 200
- Capsules of the foUowing composition are produced: - 44 - mg/Capsule
- the active ingredient having a suitable particle size, the crystaUine lactose and the microcrystaUine ceUulose are homogeneously mixed with one another, sieved and thereafter talc and magnesium stearate are admixed.
- the final mixture is filled into hard gelatine capsules of suitable size.
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Abstract
Description
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DK04717578T DK1606277T3 (en) | 2003-03-10 | 2004-03-05 | Imidazol-4-yl-ethynyl-pyridine derivatives |
AU2004220382A AU2004220382B2 (en) | 2003-03-10 | 2004-03-05 | Imidazol-4-yl-ethynyl-pyridine derivatives |
EP04717578A EP1606277B8 (en) | 2003-03-10 | 2004-03-05 | Imidazol-4-yl-ethynyl-pyridine derivatives |
BRPI0408093-9A BRPI0408093A (en) | 2003-03-10 | 2004-03-05 | imidazol-4-yl-ethynyl-pyridine derivatives. |
ES04717578T ES2305739T3 (en) | 2003-03-10 | 2004-03-05 | DERIVATIVES OF IMIDAZOL-4-IL-ETINIL-PIRIDINA. |
PL04717578T PL1606277T3 (en) | 2003-03-10 | 2004-03-05 | Imidazol-4-yl-ethynyl-pyridine derivatives |
SI200430735T SI1606277T1 (en) | 2003-03-10 | 2004-03-05 | Imidazol-4-yl-ethynyl-pyridine derivatives |
NZ541643A NZ541643A (en) | 2003-03-10 | 2004-03-05 | Imidazol-4-yl-ethynyl-pyridine derivatives |
JP2006504558A JP4404896B2 (en) | 2003-03-10 | 2004-03-05 | Imidazole-4-yl-ethynyl-pyridine derivatives |
DE602004013746T DE602004013746D1 (en) | 2003-03-10 | 2004-03-05 | Imidazole-4-YL-ETHYNYL-PYRIDINE DERIVATIVES |
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