HK1093070B - Imidazole derivatives as glutamate receptor antagonists - Google Patents

Description

Imidazole derivatives as glutamate receptor antagonists

The invention relates to imidazole derivatives having general formula I and pharmaceutically acceptable salts thereof,

wherein:

R¹represents halogen or cyano;

R²represents a lower alkyl group;

R³represents an aryl group or a heteroaryl group,

which is optionally substituted by one, two or three substituents selected from halogen, lower alkyl, cycloalkyl, lower alkyl-halogen, cyano, lower alkoxy, NR 'R',

or by 1-morpholinyl or by a pharmaceutically acceptable salt thereof,

or is optionally substituted by (CH)₂)_0，1OR substituted 1-pyrrolidinyl substituted with OR,

or is optionally substituted by (CH)₂)_0，1OR-substituted piperidinyl-substituted OR-substituted piperidinyl groups,

or by 1, 1-dioxo-thiomorpholinyl,

or by optionally lower alkyl or (CH)₂)_0，1-cycloalkyl-substituted piperazinyl substitution;

r is hydrogen, lower alkyl or (CH)₂)_0，1-a cycloalkyl group;

r 'and R' are independently from each other hydrogen, lower alkyl, (CH)₂)_0，1-cycloalkyl or (CH)₂)_nOR；

n is1 or 2;

R⁴is hydrogen, C (O) H or CH₂R⁵Wherein R is⁵Is hydrogen, OH, C₁-C₆-alkyl or C₃-C₁₂-a cycloalkyl group.

It has now been surprisingly found that: the compounds of formula I are metabotropic glutamate receptor antagonists. The compounds of formula I are distinguished by valuable therapeutic properties. They are useful for the treatment or prevention of mGluR5 receptor mediated disorders.

In the Central Nervous System (CNS), transmission of stimuli occurs through the interaction of neurotransmitters (emitted by neurons) with neuroreceptors.

Glutamate is the major excitatory neurotransmitter in the brain and plays a unique role in a variety of Central Nervous System (CNS) functions. Glutamate-dependent stimulus receptors are divided into two main classes. The first major type, the ionotropic receptors, forms ligand-controlled ion channels. Metabotropic glutamate receptors (mGluRs) belong to the second major class and, in addition, to the G-protein coupled receptor family.

Currently, eight different members of these mglurs are known, and some of them even have subtypes. These eight receptors can be subdivided into three subgroups based on their sequence homology, signaling mechanisms and agonist selectivity:

mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II, and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

Ligands of metabotropic glutamate receptors belonging to the first group are useful 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.

Other treatable indications in this context are restricted brain function caused by shunt surgery or grafts, insufficient blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Other treatable indications are ischemia, huntington's chorea, Amyotrophic Lateral Sclerosis (ALS), dementia caused by AIDS, eye trauma, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments and conditions which lead to glutamate deficiency functions, such as muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depression.

Disorders which are wholly or partly mediated 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, psychoses such as schizophrenia and anxiety, depression, pain and drug dependence (Expert opin. ther. patents (2002), 12, (12)).

Selective mGluR5 antagonists are particularly useful in the treatment of anxiety and pain.

The present invention relates to compounds of formula I and pharmaceutically acceptable salts thereof, to the above compounds as pharmaceutically active substances and to their production.

The invention also relates to a process for the preparation of compounds of general formula I according to the general process for the preparation of compounds of formula I as described above.

Furthermore, the invention relates to medicaments containing one or more compounds of the invention together with pharmaceutically acceptable excipients for the treatment and prevention of mGluR5 receptor mediated disorders, such as acute and/or chronic neurological disorders and in particular anxiety and chronic or acute pain.

The invention also relates to the use of the compounds of the invention and their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment and prevention of the above mGluR5 receptor mediated disorders.

The following definitions of the terms used in the present description apply regardless of whether the general terms appear alone or in combination. The term "lower alkyl" as used herein refers to a straight or branched chain saturated hydrocarbon group containing 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and the like.

The term "lower alkoxy" refers to a lower alkyl group having the foregoing definition attached through an oxygen atom. Examples of "lower alkoxy" include methoxy, ethoxy, isopropoxy, and the like.

The term "halogen" refers to fluorine, chlorine, bromine and iodine.

"aryl" means an aromatic carbocyclic group consisting of a single ring or one or more fused rings, wherein at least one ring is aromatic. A preferred aryl group is phenyl.

The term "heteroaryl" refers to an aromatic 5-or 6-membered ring containing one or more heteroatoms selected from nitrogen, oxygen or sulfur. Preferred are those heteroaryl groups selected from nitrogen. Examples of such heteroaryl groups are pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl.

The term "cycloalkyl" refers to a saturated carbocyclic group containing from 3 to 12 carbon atoms, preferably from 3 to 6 carbon atoms.

The term "pharmaceutically acceptable salt" refers to any salt derived from an inorganic or organic acid or base.

Included within the compounds of formula I are compounds of the general formula IA and pharmaceutically acceptable salts thereof,

wherein:

R¹represents halogen;

R²represents a lower alkyl group;

R³represents an aryl group or a heteroaryl group,

optionally substituted by one, two or three substituents selected from halogen, lower alkyl-halogen,

Cyano, NR 'R',

or by 1-morpholinyl or by a pharmaceutically acceptable salt thereof,

or is optionally substituted by (CH)₂)_0，1OR substituted 1-pyrrolidinyl substituted with OR,

or is optionally substituted by (CH)₂)_0，1OR-substituted piperidinyl-substituted OR-substituted piperidinyl groups,

or by 1, 1-dioxo-thiomorpholinyl,

or by optionally lower alkyl or (CH)₂)_0，1-cycloalkyl-substituted piperazinyl substitution;

r is hydrogen, lower alkyl or (CH)₂)_0，1-a cycloalkyl group;

r 'and R' are independently from each other hydrogen, lower alkyl, (CH)₂)_0，1-cycloalkyl or (CH)₂)_nOR；

n is1 or 2.

Preferred compounds of the formulae I and IA are those in which R¹Those that are chlorine or fluorine.

Especially preferred are compounds from the following group: wherein R is³Is unsubstituted or substituted heteroaryl, wherein the substituents are selected from the group consisting of fluorine, CF₃And lower alkyl groups, such as the following compounds:

2- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -4-trifluoromethyl-pyrimidine,

2- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -pyrazine,

2- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -6-trifluoromethyl-pyridine,

3- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -5-fluoro-pyridine,

4- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -2-trifluoromethyl-pyrimidine,

2- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -6-methyl-4-trifluoromethyl-pyridine, or

2- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -5-methyl-pyridine.

Especially preferred are also the following compounds: wherein R is³Is aryl substituted by one or more halogens, such as the following compounds:

2-chloro-4- [1- (4-fluoro-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine,

2-fluoro-4- [1- (4-fluoro-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine,

2-chloro-4- [1- (3, 5-difluoro-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine,

2-chloro-4- [1- (3, 5-difluoro-phenyl) -2, 5-dimethyl-1H-imidazol-4-ylethynyl ] -pyridine, or

2-chloro-4- [1- (4-fluoro-phenyl) -2, 5-dimethyl-1H-imidazol-4-ylethynyl ] -pyridine.

The compounds of formula I or IA of the present invention can be prepared by a process comprising

(a) Reacting a compound of formula II

Wherein R is¹、R²And R⁴As defined above, the above-mentioned,

with a compound of the formula III,

R³-Z(III)

wherein R is³As defined above and Z is halogen or B (OH)₂(ii) a Or

(b) Reacting a compound of formula IV

Wherein R is²、R³And R⁴As defined above, the above-mentioned,

with a compound of the formula V,

wherein R is¹As defined above and X is halogen; or

(c) Reacting a compound of formula VI

Wherein R is²、R³And R⁴As defined above and hal is halogen,

with a compound of the formula VII,

wherein R is¹As defined above and Y is trimethylsilyl or hydrogen.

The reaction as described in (a) can be carried out according to standard methods, for example by arylating a compound of formula II with an aromatic boronic acid and a copper catalyst in a solvent such as dichloromethane or tetrahydrofuran [ see, for example, 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 together with a base such as potassium carbonate or cesium carbonate in a solvent such as 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) can be carried out by reacting a compound of formula IV with a compound of formula V in, for example, CuI, (Ph)₃P)₂PdCl₂、Et₃By Sonogashira coupling in the presence of N in a solvent such as tetrahydrofuran or dimethylformamide [ Sonogashira et al, Synthesis777(1977)]. In one embodiment, the meaning of X in the compounds of formula V is bromine or iodine. The reaction as described in (c) above may be, for example, in CuI, (Ph)₃P)₂PdCl₂、Et₃N、n-Bu₄In the presence of F in a solvent such as tetrahydrofuran or dimethylformamide.

The salt forms can be prepared by standard methods known to the skilled artisan.

The compounds of formulae II, IV, VI and VII are novel and are likewise embodiments of the present invention.

The compounds of formulae III and V are commercially available or their preparation is known to the skilled artisan.

The compounds of formula II can be prepared as follows: reacting a compound of formula VIII

Wherein R is²And R⁴As defined above and hal is a halogen,

with the compound of formula VII above.

Compounds of formula VIII may be prepared as described, for example, in Cliff and Pyne (Synthesis 681-682 (1994)).

The compound of formula IV can be prepared as follows: reacting a compound of formula IX

Wherein R is²、R³And R⁴As defined above, the above-mentioned,

with (1-diazo-2-oxopropyl) dimethyl phosphate such as Ohira [ synth.comm.19: 561-564 (1989).

The compound of formula VI may be prepared by reacting a compound of formula VIII as described above with a compound of formula X,

R³-Z(X)

wherein R is³As defined above and Z is halogen or B (OH)₂。

The reaction may be carried out by arylation of a compound of formula VIII, either by usingAn aromatic boronic acid (compound of formula X) and a copper catalyst are reacted in a solvent such as dichloromethane or tetrahydrofuran under an oxygen atmosphere [ see, e.g., Colmann et al, org.lett.2: 1233(2000)]By reaction with R when Z is halogen³-Z is carried out with heating a base such as potassium carbonate or cesium carbonate in a solvent such as dimethylformamide or Pd-catalyzed according to Buchwald conditions [ see for example 8; buchwald et al, Tetrahedron Lett.40: 2657(1999)]。

The compound of formula VII may be prepared by reacting a compound of formula V as described above with a compound of formula XI:

the reaction is carried out, for example, at CuI, (Ph)₃P)₂PdCl₂、Et₃By Sonogashira coupling in the presence of N in a solvent such as tetrahydrofuran or dimethylformamide [ Sonogashira et al, Synthesis777(1977)]。

The compounds of formula IX can be prepared by oxidation of compounds of formula XII according to methods known to the skilled artisan:

the compounds of formula XII can be prepared by deprotecting compounds of formula XIII according to methods known to the skilled artisan:

the compounds of the formula XIII can be prepared by methods known to the skilled worker by using alkylating agents of the formula XVa

R²-hal(XVa)

By alkylating a compound of formula XIV.

The starting compounds of formula XVa are commercially available.

The compounds of formula XIV can be prepared by treating a compound of formula XV with tert-butyldimethylsilyl chloride according to methods known to the skilled worker:

the compounds of formula XV can be prepared by treating a compound of formula XVI with a reducing agent according to methods known to the skilled artisan:

the compounds of formula XVI can be prepared by hydrolysis of compounds of formula XVII according to methods known to the skilled artisan:

compounds of formula XVII can be prepared by treating compounds of formula XVIII with, for example, triethyl orthoformate, ethyl nitroacetate (ethyl nitrate), glacial acetic acid and iron powder according to methods known to the skilled person:

R³-NH₂(XVIII)。

compounds of formula XVIII are commercially available.

The compounds of the general formulae IA, I and their pharmaceutically acceptable salts can also be prepared by two general methods, which are described below for R¹Is chlorine, R²Is methyl and R³Scheme 1 for compounds that are 4-trifluoromethyl-pyrimidin-2-yl (see example 3) and for compounds in which R is¹Is chlorine, R²Is methyl and R³The compound, which is 4-fluoro-phenyl, is outlined in scheme 2 (see example 1), but both methods can be used for all compounds of formula I and IA, as follows:

a) reacting a compound of formula II

With R of the formula III³Z compound reaction, wherein R³As defined above and Z is halogen or B (OH)₂；

To give a compound of formula IA

Wherein R is¹、R²And R³As defined above and hal is preferably chlorine or fluorine, or

b) Reacting a compound of formula IV

With a compound of the formula V,

to give a compound of formula IA

Wherein R is¹、R²And R³As defined above, the above-mentioned,

and when R is⁴Other than hydrogen, the amount of hydrogen, if desired,

c) reacting a compound of formula IA with a compound of formula VI

R⁴Hal VI

To give the compound of the formula I

Wherein R is¹、R²、R³And R⁴As defined above, the above-mentioned,

and, if desired, converting the resulting compound into a pharmaceutically acceptable acid addition salt.

Method 1 is outlined in scheme 1.

The starting materials are known compounds or can be prepared according to methods known in the art.

Scheme 1

Step 1：

2-chloro-4-iodo-pyridine was dissolved in THF and triethylamine. Oxygen is then removed from the solution. Triphenylphosphine and bis (triphenylphosphine) palladium (II) chloride were added and the reaction mixture was stirred at room temperature for about 1 hour. Copper (I) iodide and trimethylsilylacetylene were added. The reaction mixture was stirred at room temperature overnight. After conventional work-up, the desired product, 2-chloro-4-trimethylsilylethynyl-pyridine, was obtained. This material was used in the next step without further purification.

Step 2：

Solution 1: 2-chloro-4-trimethylsilylethynyl-pyridine and 5-iodo-2-methyl-1H-imidazole (Synthesis: M.D.Cliff, S.G.Pyne, Synthesis1994, 681-682) were dissolved in THF and DMF. Oxygen is then removed from the solution.

Solution 2: triphenylphosphine, bis (triphenylphosphine) -palladium (II) chloride, copper (I) iodide and triethylamine were dissolved in THF. Oxygen is then removed from the solution.

Solution 2 was heated to 40 ℃ and solution 1 was added dropwise. The reaction mixture was heated to about 60 deg.C and tetrabutylammonium fluoride solution was added dropwise. The reaction was then stirred at room temperature overnight. After conventional work-up, the desired product, 2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine, was obtained.

Step 3：

2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine was dissolved in dimethylformamide. Potassium carbonate and 2-chloro-4-trifluoromethyl-pyrimidine were added and the reaction mixture was stirred at about 80 ℃ overnight. To obtain 2- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -4-trifluoromethyl-pyrimidine.

Method 2 is outlined in scheme 2.

Scheme 2

Step 1:

4-fluoroaniline was mixed with triethyl orthoformate, ethyl nitroacetate and glacial acetic acid at room temperature. The reaction mixture was refluxed for about 2 hours with mechanical stirring. Triethyl orthoformate and glacial acetic acid were added. Iron powder was added in 3 portions over a period of about 8 hours while maintaining the reaction mixture at reflux. Ethyl acetate was added and reflux continued. The crude 1- (4-fluoro-phenyl) -1H-imidazole-4-carboxylic acid ethyl ester was used in the next step without further purification.

Comprises the following steps of:

crude 1- (4-fluoro-phenyl) -1H-imidazole-4-carboxylic acid ethyl ester was dissolved in dioxane and sodium hydroxide solution. The reaction mixture was refluxed for about 2 hours. Activated carbon was added and the reflux continued. The desired compound 1- (4-fluoro-phenyl) -1H-imidazole-4-carboxylic acid was obtained.

And step 3:

1- (4-fluoro-phenyl) -1H-imidazole-4-carboxylic acid was dissolved in THF. A THF solution of borane-tetrahydrofuran complex was added dropwise. The reaction was refluxed for 2 hours and stirred at room temperature overnight. The reaction mixture was then cooled to 0 ℃ and methanol was added dropwise. The solvent was evaporated and the residue was dissolved in HCl and refluxed for 2 hours. The reaction mixture was then cooled to 0 ℃ and sodium hydroxide solution was added dropwise. The desired compound [1- (4-fluoro-phenyl) -1H-imidazol-4-yl ] -methanol was obtained.

And 4, step 4:

[1- (4-fluoro-phenyl) -1H-imidazol-4-yl ] -methanol was dissolved in DMF. Imidazole and tert-butyldimethylsilyl chloride were added. The reaction mixture was stirred at about 45 ℃ overnight. The desired compound 4- (tert-butyl-dimethyl-siloxymethyl) -1- (4-fluoro-phenyl) -1H-imidazole was obtained.

And 5:

4- (tert-butyl-dimethyl-silanyloxymethyl) -1- (4-fluoro-phenyl) -1H-imidazole was dissolved in THF and cooled to-78 ℃. A hexane solution of n-butyllithium was added dropwise, and the reaction mixture was warmed to-25 ℃ and held at-25 ℃ for 10 minutes, and then cooled again to-78 ℃. Methyl iodide was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred at room temperature overnight. The desired compound 4- (tert-butyl-dimethyl-siloxymethyl) -1- (4-fluoro-phenyl) -2-methyl-1H-imidazole was obtained.

Step 6:

4- (tert-butyl-dimethyl-silanyloxymethyl) -1- (4-fluoro-phenyl) -2-methyl-1H-imidazole was dissolved in THF. A THF solution of tetrabutylammonium fluoride was added and the reaction mixture was stirred at room temperature overnight. The desired compound [1- (4-fluoro-phenyl) -2-methyl-1H-imidazol-4-yl ] -methanol was obtained.

And 7:

[1- (4-fluoro-phenyl) -2-methyl-1H-imidazol-4-yl ] -methanol was dissolved in dichloromethane. Manganese (IV) oxide (mangan oxide) was added and the reaction mixture was stirred at room temperature for 3 days. The suspension was filtered through dicalite speed plus to obtain the desired compound (4-fluoro-phenyl) -2-methyl-1H-imidazole-4-carbaldehyde.

And 8:

(1-diazo-2-oxo-propyl) -phosphonic acid dimethyl ester was dissolved in methanol. Potassium carbonate was added. A solution of 1- (4-fluoro-phenyl) -2-methyl-1H-imidazole-4-carbaldehyde in methanol was added dropwise at room temperature. The reaction mixture was stirred at room temperature overnight. The desired compound 4-ethynyl-1- (4-fluoro-phenyl) -2-methyl-1H-imidazole was obtained.

And step 9:

2-chloro-4-iodopyridine was dissolved in THF. The mixture was evacuated and purged with argon several times to remove oxygen from the solution. Triphenylphosphine and bis (triphenylphosphine) palladium (II) chloride were added and the reaction mixture was stirred at room temperature for 1 hour. Copper (I) iodide and 4-ethynyl-1- (4-fluoro-phenyl) -2-methyl-1H-imidazole were added. The reaction mixture was stirred at room temperature for 3 days. The desired product 2-chloro-4- [1- (4-fluoro-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine was obtained.

Pharmaceutically acceptable salts of the compounds of formula I can be readily prepared according to methods known per se and taking into account the nature of the compound to be converted into a salt. Inorganic or organic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric or citric acid, formic, fumaric, maleic, acetic, succinic, tartaric, methanesulfonic, p-toluenesulfonic acid and the like are suitable for forming pharmaceutically acceptable salts of basic compounds of formula I. Compounds containing alkali or alkaline earth metals (e.g., sodium, potassium, calcium, magnesium, etc.), basic amines, or basic amino acids are suitable for forming pharmaceutically acceptable salts of acidic compounds.

As already mentioned above, the compounds of formula I and their pharmaceutically acceptable salts are metabotropic glutamate receptor antagonists, useful 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. Examples of treatable neurological disorders are 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 trauma, retinopathy, idiopathic parkinsonism or parkinsonism caused by drugs and disorders which lead to glutamate-deficiency functions, such as muscle spasms, convulsions, migraine, urinary incontinence, alcohol addiction, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, dyskinesia and depression. Other treatable indications are restricted brain function caused by shunt surgery or grafts, insufficient blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia.

The compounds of formula I and their pharmaceutically acceptable salts are particularly useful as analgesics. The types of pain that can be treated include inflammatory pain such as arthritis and rheumatoid diseases, vasculitis, neuropathic pain such as trigeminal or herpetic neuralgia, diabetic neuropathy, causalgia, hyperalgesia, severe chronic pain, post-operative pain, and pain associated with various conditions such as cancer, angina, renal colic or biliary colic, menstruation, migraine and gout.

The pharmacological activity of the compound was tested using the following method:

for the binding assay, the method described by Schlaeger and Christensen [ Cytotechnology 15: 1-13(1998)]cDNA encoding the human Glu5a receptor was transiently transfected into EBNA cells. Cell membrane homogenates were stored at-80 ℃ until the day of analysis, where they were thawed and resuspended and polytronised in binding buffer (15mM Tris-HCl, 120mM NaCl, 100mM KCl, 25mM CaCl₂、25mM MgCl₂Ph7.4), the final assay concentration was 20pg protein/well.

To these films were added [ 2 ] at a concentration of 12 at 4 ℃ ]³H]After 1 hour (final volume of 200. mu.l) of MPEP (0.04-100nM), the saturation isotherm was determined. Using a fixed concentration of³H]A competitive assay was performed in MPEP (2nM) and the IC of the test compounds was evaluated at 11 concentrations (0.3-10,000nM)₅₀The value is obtained. The incubation was carried out at 4 ℃ for 1 hour.

After the incubation was complete, the membrane was filtered with a Filtermate96 harvester (Packard BioScience) into a unifilter (96-well white microplate with a GF/C-bound filter, pretreated for 1 hour in washing buffer containing 0.1% PEI, Packard BioScience, Meriden, CT) and washed 3 times with cold 50mM Tris-HCl buffer (pH 7.4). Nonspecific binding was determined in the presence of 10 μ M MPEP. After adding 45 μ l microscint40(Canberra Packard S.A., Zurich, Switzerland) and shaking for 20 minutes, the calibration was quenched and the filter radioactivity was counted on a Packard Top-count microplate scintillation counter (3 minutes).

For functional analysis, methods described previously by Porter et al [ br.j. pharmacol.128: 13-20(1999)]Performing [ Ca ] on recombinant human Glu5a receptor in HEK-293 cells²⁺]_iAnd (4) measuring. Cells were loaded with dye using Fluo4-AM (obtained from FLUKA, 0.2. mu.M final concentration). Fluorescence imaging plate readers (FLIPR, Molecular Devices Corporation, La Jolla, CA,USA) [ Ca ]²⁺]_iAnd (4) measuring. The antagonist evaluation was performed after 5 minutes of preincubation with test compound and addition of the next largest agonist addition.

Fitting the inhibition (antagonist) curve to a four-parameter logistic equation using iterative nonlinear curve fitting software (Xcelfit) to obtain IC₅₀And a Hill coefficient.

For the binding assays, Ki values are given for the compounds tested. Ki values were calculated by the following formula:

Ki＝IC₅₀/[1+L/K_d]

wherein the IC₅₀The value is that of causing a competitive radioligand (,)³H]MPEP) concentration of test compound that inhibited 50%. L is the concentration of radioligand used in the binding assay, K of radioligand was determined experimentally for each batch of membranes prepared_dThe value is obtained.

The compounds of the invention are mGluR 5a receptor antagonists. The range of activity of compounds of formula I determined in the above assay is Ki < 70 nM.

The compounds of formula I and their pharmaceutically acceptable salts can be used as medicaments, for example in the form of pharmaceutical preparations. Pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, administration can also be effected rectally (e.g., in the form of suppositories) or parenterally (e.g., in the form of injection solutions).

The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic carriers to produce pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as 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, however, in the case of soft gelatin capsules, carriers are generally not required. 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 may, but are generally not necessary, be used in aqueous injection solutions of water-soluble salts of compounds of formula I. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

In addition, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for regulating the osmotic pressure, buffers, taste masking agents or antioxidants. They may also contain other therapeutically valuable substances.

As already mentioned above, medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient are likewise an object of the present invention, as are processes for the preparation thereof, which comprise bringing one or more compounds of formula I or a pharmaceutically acceptable salt thereof and, where appropriate, one or more other therapeutically valuable substances into a galenical form with one or more therapeutically inert carriers.

The dosage can vary within wide limits and can of course be adapted to the individual requirements in each particular case. For all the indications mentioned, an effective dose for oral or parenteral administration is generally 0.01 to 20 mg/kg/day, preferably 0.1 to 10 mg/kg/day. The daily dose for an adult weighing 70 kg is accordingly 0.7-1400 mg/day, preferably 7-700 mg/day.

The following examples serve to further illustrate the invention:

example 1

2-chloro-4- [1- (4-fluoro-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine

2-chloro-4-iodopyridine (1.39g, 5.8mmol) was dissolved in 50mL anhydrous THF. The mixture was evacuated and filled with argonGas was applied several times to remove oxygen from the solution. Triphenylphosphine (39mg, 0.15mmol) and bis (triphenylphosphine) palladium (II) chloride (170mg, 0.24mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper (I) iodide (28mg, 0.15mmol) and 4-ethynyl-1- (4-fluoro-phenyl) -2-methyl-1H-imidazole (970mg, 4.84mmol) were added. The reaction mixture was stirred at room temperature for 3 days. The solvent was evaporated. The residue was dissolved in 100mL of water and extracted three times with ethyl acetate (100 mL each). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated. The crude product is purified by flash chromatography on silica gel (gradient cyclohexane/ethyl acetate/triethylamine 1: 0- > 10: 1) and recrystallized from heptane and ethyl acetate. The desired product was obtained as a white solid (545mg, 36%), MS: 312.1(M + H)⁺)。

Example 2

2-fluoro-4- [1- (4-fluoro-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine

The title compound was prepared according to the general method of example 1 from 4-ethynyl-1- (4-fluoro-phenyl) -2-methyl-1H-imidazole and 2-fluoro-4-iodopyridine, MS: 296.1(M + H)⁺)。

Example 3

2- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -4-trifluoromethyl-pyrimidine

2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine (150mg, 0.69mmol) was dissolved in 5mL dimethylformamide. Potassium carbonate (190mg, 1.37mmol) and 2-chloro-4-trifluoromethyl-pyrimidine (189mg, 0.66mmol) were added and the reaction mixture was stirred at 80 ℃ overnight. The reaction mixture was poured into 70mL of water and extracted three times with ethyl acetate (100 mL each). The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was recrystallized from ether to give the desired compound as a white solid (190mg, 76%), MS: 364.1(M + H) M/e⁺)。

Example 4

2- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -pyrazine

The title compound was prepared according to the general method of example 3 from 2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine and 2-chloropyrazine, MS: 296.1(M + H)⁺)。

Example 5

2- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -6-trifluoromethyl-pyridine

The title compound was prepared according to the general method of example 3 from 2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine and 2-fluoro-6- (trifluoromethyl) pyridine, MS: 363.1.1(M + H)⁺)。

Example 6

3- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -5-fluoro-pyridine

The title compound was prepared according to the general method of example 3 from 2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine and 3, 5-difluoro-pyridine by the following general method: 313.1(M + H) M/e⁺)。

Example 7

2-chloro-4- [1- (4-chloro-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine

2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine (150mg, 0.69mmol) was dissolved in 30mL of dichloromethane. Powdered molecular sieves (3A, 200mg), 4-chlorobenzeneboronic acid (216mg, 1.38mmol) and [ Cu (OH) TMEDA were added]₂Cl₂(113mg, 0.24 mmol). Oxygen was bubbled through the reaction mixture for 5 minutes, and stirring was continued overnight at room temperature. The reaction mixture was filtered through a dicalite speed plus pad and washed with 50mL of dichloromethane. The filtrate was washed with 50ml of water, dried over magnesium sulphate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 100: 0- > 3: 2 gradient) and recrystallization from diisopropyl ether. The desired compound was obtained as a white solid (42mg, 19%), MS: m/e 329.2(M + H)⁺)。

Example 8

2-chloro-4- [1- (3, 4-dichloro-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine

The title compound was prepared according to the general method of example 7 from 2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine and 3, 4-dichlorophenylboronic acid, MS: 363.7(M + H)⁺)。

Example 9

2-chloro-4- [1- (4-fluoro-phenyl) -2-isopropyl-1H-imidazol-4-ylethynyl ] -pyridine fumarate

Step 1: 1- (4-fluoro-phenyl) -4-iodo-2-isopropyl-1H-imidazole

The title compound was prepared according to the general method of example 7 from 5-iodo-2-isopropyl-1H-imidazole and 4-fluorobenzeneboronic acid, MS: 331.1(M + H)⁺)。

Step 2: 2-chloro-4- [1- (4-fluoro-phenyl) -2-isopropyl-1H-imidazol-4-ylethynyl]-pyridine fumarate

The title compound was prepared according to the general method of example B, step 2, from 2-chloro-4-trimethylsilylethynyl-pyridine and 1- (4-fluoro-phenyl) -4-iodo-2-isopropyl-1H-imidazole and recrystallized from methanol and 1.05 equivalents of fumaric acid, MS: 340.1(M + H) M/e⁺)。

Example 10

4- [1- (4-fluoro-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine-2-carbonitrile

The title compound was prepared according to the general method of example 7 from 4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine-2-carbonitrile and 4-fluorobenzeneboronic acid, MS: m/e 303.1(M + H)⁺)。

4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine-2-carbonitrile

Triphenylphosphine (126mg, 0.48mmol), bis (triphenylphosphine) palladium (II) chloride (1.01g, 1.44mmol) and triethyl phosphineThe amine (3.65g, 101.2mmol) was dissolved in 40ml of anhydrous THF. The mixture was evacuated and purged with argon several times to remove oxygen from the solution. 4-iodo-2-methyl-1H-imidazole [ tetrahedron letters30(11), 1409(1989)](5.0g, 20.8mmol), 4-trimethylsilylethynyl-pyridine-2-carbonitrile (4.43g, 22.1mmol) and copper (I) iodide (46mg, 0.24mmol), the mixture was warmed to 60 ℃. A1M solution of tetrabutylammonium fluoride (24ml, 24.0mmol) was added dropwise over 30 minutes. After the addition was complete, the reaction mixture was stirred at 60 ℃ for an additional 1 hour. The solvent was evaporated. The residue was dissolved in 200mL of water and extracted three times with 200mL of ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (methanol/dichloromethane 5: 95). The desired product was obtained as a pale yellow solid (1.06g, 21%). MS: 208.9 (M/e)⁺)。

4-trimethylsilylethynyl-pyridine-2-carbonitrile

A mixture of 4-bromo-2-pyridinecarbonitrile [ Cesko-Slovenska Farmacie25(5), 181(1976)](0.73g, 4.0mmol) was dissolved in 18mL of anhydrous THF. The mixture was evacuated and purged with argon several times to remove oxygen from the solution. Triphenylphosphine (31mg, 0.12mmol) and bis (triphenylphosphine) palladium (II) chloride (141mg, 0.20mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper (I) iodide (23mg, 0.12mmol) and trimethylsilyl-acetylene (590mg, 6.0mmol) were added. The reaction mixture was stirred at room temperature for 3 days. The solvent was evaporated. The residue was dissolved in 100mL of water and extracted three times with 100mL of ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/dichloromethane 1: 2). The desired product was obtained as a yellow oil (329mg, 41%), MS: m/e is 201.3(M + H)⁺)。

Example 11

2-chloro-4- [1- (2, 4-difluoro-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine

The title compound was prepared according to the general method of example 7 from 2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine and 2, 4-difluorophenylboronic acidSubstance, MS: 330.4(M + H) M/e⁺)。

Example 12

2-chloro-4- [1- (3, 4-difluoro-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine

The title compound was prepared according to the general method of example 7 from 2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine and 3, 4-difluorophenylboronic acid, MS: 330.4(M + H) M/e⁺)。

Example 13

4- [1- (3, 4-difluoro-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine-2-carbonitrile

The title compound was prepared according to the general method of example 7 from 4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine-2-carbonitrile and 3, 4-fluorobenzeneboronic acid, MS: 321.5(M + H)⁺)。

Example 14

2-chloro-4- [1- (3-fluoro-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine

The title compound was prepared according to the general method of example 7 from 2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine and 3-fluorobenzeneboronic acid, MS: 312.5(M + H)⁺)。

Example 15

2-chloro-4- [1- (3, 5-difluoro-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine

The title compound was prepared according to the general method of example 7 from 2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine and 3, 5-difluorophenylboronic acid, MS: 330.3(M + H) M/e⁺)。

Example 16

4- [1- (3, 5-difluoro-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine-2-carbonitrile

According to the general procedure of example 7, starting from 4- (2-methyl-1)H-imidazol-4-ylethynyl) -pyridine-2-carbonitrile and 3, 5-fluorobenzeneboronic acid the title compound was prepared, MS: 321.4(M + H)⁺)。

Example 17

2-chloro-4- [1- (3-fluoro-4-methyl-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine

The title compound was prepared according to the general method of example 7 from 2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine and 3-fluoro-4-methyl-phenylboronic acid, MS: 326.4(M + H)⁺)。

Example 18

2-chloro-4- [1- (4-fluoro-3-methyl-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine

The title compound was prepared according to the general method of example 7 from 2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine and 4-fluoro-3-methyl-phenylboronic acid, MS: 326.4(M + H)⁺)。

Example 19

2-chloro-4- [1- (3-chloro-4-fluoro-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine

The title compound was prepared according to the general method of example 7 from 2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine and 3-chloro-4-fluoro-phenylboronic acid, MS: 347.2(M + H)⁺)。

Example 20

2-chloro-4- [1- (4-methyl-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine

The title compound was prepared according to the general method of example 7 from 2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine and 4-methyl-phenylboronic acid, MS: 308.8(M + H) M/e⁺)。

Example 21

2-chloro-4- [1- (3-methoxy-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine

The title compound was prepared according to the general method of example 7 from 2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine and 3-methoxy-phenylboronic acid, MS: 324.8(M + H) M/e⁺)。

Example 22

2-chloro-4- [1- (4-methoxy-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine

The title compound was prepared according to the general method of example 7 from 2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine and 4-methoxy-phenylboronic acid, MS: 324.8(M + H) M/e⁺)。

Example 23

3- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -benzonitrile

The title compound was prepared according to the general method of example 7 from 2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine and 3-cyano-phenylboronic acid, MS: 319.8(M + H) M/e⁺)。

Example 24

2- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -pyrimidine

The title compound was prepared according to the general method of example 3 from 2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine and 2-chloro-pyrimidine, MS: 296.5(M + H) M/e⁺)。

Example 25

2- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -4-methyl-pyrimidine

The title compound was prepared according to the general method of example 3 from 2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine and 2-chloro-4-methyl-pyrimidine, MS: 310.4(M + H)⁺)。

Example 26

2- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -4-methoxy-pyrimidine

The title compound was prepared according to the general method of example 3 from 2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine and 2-chloro-4-methoxy-pyrimidine, MS: 326.5(M + H)⁺)。

Example 27

2- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -5-fluoro-pyrimidine

The title compound was prepared according to the general method of example 3 from 2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine and 2-chloro-5-fluoro-pyrimidine, MS: 314.5(M + H) M/e⁺)。

Example 28

4- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -2-trifluoromethyl-pyrimidine

The title compound was prepared according to the general method of example 3 from 2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine and 4-chloro-2-trifluoromethyl-pyrimidine, MS: 364.5(M + H)⁺)。

Example 29

2- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -6-methyl-pyridine

The title compound was prepared according to the general method of example 3 from 2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine and 2-fluoro-6-methyl-pyridine, MS: 309.5(M + H)⁺)。

Example 30

2- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -5-methyl-pyridine

The title compound was prepared according to the general method of example 3 from 2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine and 2-fluoro-5-methyl-pyridine, MS: 309.5(M + H)⁺)，。

Example 31

4- [1- (6-chloro-pyridin-3-yl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine-2-carbonitrile

The title compound was prepared according to the general method of example 7 from 4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine-2-carbonitrile and 6-chloro-3-pyridinyl-boronic acid, MS: 320.0, 322.1(M + H)⁺)。

Example 32

2-chloro-4- [1- (6-chloro-pyridin-3-yl) -2-isopropyl-1H-imidazol-4-ylethynyl ] -pyridine

Step 1: 2-chloro-5- (4-iodo-2-isopropyl-imidazol-1-yl) -pyridine

The title compound was prepared according to the general method of example 7 from 5-iodo-2-isopropyl-1H-imidazole and 4-chloropyridine-5-boronic acid, MS: 348.4(M + H)⁺)。

Step 2: 2-chloro-4- [1- (6-chloro-pyridin-3-yl) -2-isopropyl-1H-imidazol-4-ylethynylpyridin

The title compound was prepared according to the general method of example B, step 2, from 2-chloro-4-trimethylsilylethynyl-pyridine and 2-chloro-5- (4-iodo-2-isopropyl-imidazol-1-yl) -pyridine, MS: 358.1(M + H) M/e⁺)。

Example 33

5- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -2-cyclopropyl-pyridine

Step 1: 2-chloro-5- (4-iodo-2-methyl-imidazol-1-yl) -pyridine

The title compound was prepared according to the general method of example 7 from 4-iodo-2-methyl-1H-imidazole and 4-chloropyridine-5-boronic acid, MS: 320.2(M + H) M/e⁺)。

Step 2: 2-chloro-5- (2-methyl-4-trimethylsilylethynyl-imidazol-1-yl) -pyridine

The title compound was prepared according to the general method of example B, step 1 from 2-chloro-5- (4-iodo-2-methyl-imidazol-1-yl) -pyridine and trimethylsilylacetylene, MS: 290.6(M + H)⁺)。

And step 3: 2-cyclopropyl-5- (2-methyl-4-trimethylsilylethynyl-imidazol-1-yl) -pyridine

2-chloro-5- (2-methyl-4-trimethylsilylethynyl-imidazol-1-yl) -pyridine (425mg, 1.47mmol) was dissolved in 0.4M zinc cyclopropylchloride in THF (7.33mL, 0.4M in THF) and tetrakis (triphenylphosphine) palladium (34mg, 0.03mmol) was added. The reaction mixture was refluxed for 16 hours and poured into 50mL of saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate (50 mL each). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 100: 0- > 1: 1 gradient) to afford the desired product as a pale yellow solid (395mg, 91%), MS: 296.2(M + H)⁺)。

And 4, step 4: 2-chloro-4- [1- (6-cyclopropyl-pyridin-3-yl) -2-isopropyl-1H-imidazol-4-ylethynyl]-pyridine Pyridine (I)

The title compound was prepared according to the general method of example B, step 2, from 2-cyclopropyl-5- (2-methyl-4-trimethylsilylethynyl-imidazol-1-yl) -pyridine and 2-chloro-4-iodo-pyridine, MS: 335.6(M + H)⁺)。

Example 34

2-chloro-4- [1- (3, 5-difluoro-phenyl) -2, 5-dimethyl-1H-imidazol-4-ylethynyl ] -pyridine

2-chloro-4- [1- (3, 5-difluoro-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine (200mg, 0.607mmol) was dissolved in 10mL THF and cooled to-75 ℃.

Lithium diisopropylamide (0.45ml, 0.91mmol) was added and the mixture stirred at-75 ℃ for 15 min. Methyl iodide (0.05ml, 0.85) was addedmmol) was added and stirring was continued at-75 ℃ for 2 hours. The reaction mixture was saturated NaHCO₃The solution was quenched and extracted with water and ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 90: 10- > 20: 80 gradient) and recrystallization from ethyl acetate. The desired compound was obtained as a white solid (40mg, 19%), MS: 344.5(M + H) M/e⁺)。

Example 35

2-chloro-4- [1- (4-fluoro-phenyl) -2, 5-dimethyl-1H-imidazol-4-ylethynyl ] -pyridine

Following the general method of example 34, from 2-chloro-4- [1- (4-fluoro-phenyl) -2-methyl-1H-imidazol-4-ylethynyl]Pyridine preparation of the title compound, MS: 326.5(M + H)⁺)。

Example 36

2- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -6-methyl-4-trifluoromethyl-pyridine

Step 1: 2- (4-iodo-2-methyl-imidazol-1-yl) -6-methyl-4-trifluoromethyl-pyridine

The title compound was prepared according to the general method of example 3 from 5-iodo-2-methyl-1H-imidazole and 2-chloro-6-methyl-4- (trifluoromethyl) -pyridine, MS: 368.0(M + H)⁺)。

Step 2: 2- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl]-6-methyl-4-trifluoromethyl- Pyridine compound

The title compound was prepared according to the general method of example B, step 2, from 2-chloro-4-trimethylsilylethynyl-pyridine and 2- (4-iodo-2-methyl-imidazol-1-yl) -6-methyl-4-trifluoromethyl-pyridine, MS: 377.2(M + H)⁺)，。

Synthesis of intermediates

Example A

4-ethynyl-1- (4-fluoro-phenyl) -2-methyl-1H-imidazole

Step 1: 1- (4-fluoro-phenyl) -1H-imidazole-4-carboxylic acid ethyl ester

4-fluoroaniline (20.0g, 175mmol) was combined at room temperature with triethyl orthoformate (35.4g, 233mmol), ethyl nitroacetate (28.5g, 210mmol) and 4mL glacial acetic acid. The reaction mixture was refluxed for 2 hours with mechanical stirring. Triethyl orthoformate (200mL) and glacial acetic acid (200mL) were added. Iron powder (100g, 1.79mol) was added in 3 portions over 8 hours while stirring the reaction mixture at reflux. Ethyl acetate (700mL) was added and reflux continued for an additional 2 hours. The reaction mixture was filtered through dicalite speed plus pad and washed with 500mL ethyl acetate. The solvent was evaporated and the crude product was used in the next step without further purification.

Step 2: 1- (4-fluoro-phenyl) -1H-imidazole-4-carboxylic acid

Crude 1- (4-fluoro-phenyl) -1H-imidazole-4-carboxylic acid ethyl ester (175mmol) was dissolved in 450mL dioxane and 450mL 2N sodium hydroxide solution. The reaction mixture was refluxed for 2 hours. Activated charcoal (1g, Norit SA II) was added and refluxing continued for another 20 minutes. The mixture was filtered while hot and washed with 50mL of 2N sodium hydroxide solution. The filtrate was treated with 550mL of 2N HCl and stirred at room temperature overnight. The solid material is filtered off and dried at 50 ℃ and 15 mbar. The desired compound was obtained as an off-white solid (28g, 78%), MS: and M/e is 205.1 (M-H).

And step 3: [1- (4-fluoro-phenyl) -1H-imidazol-4-yl]-methanol

1- (4-fluoro-phenyl) -1H-imidazole-4-carboxylic acid (18g, 87mmol) was dissolved in 90mL anhydrous THF. Borane tetrahydrofuran complex (174mL, 1M in THF, 174mmol) was added dropwise. The reaction was refluxed for 2 hours atStir at room temperature overnight. The reaction mixture was cooled to 0 ℃ and 100mL of methanol was added dropwise. The solvent was evaporated. The residue was dissolved in 100mL of 2N HCl and refluxed for 2 hours. The reaction mixture was then cooled to 0 ℃ and 120mL of 2N sodium hydroxide solution was added dropwise. The solid material is filtered off and dried at 50 ℃ and 15 mbar. The desired compound was obtained as a white solid (13g, 78%), MS: m/e 193.2(M + H)⁺。

And 4, step 4: 4- (tert-butyl-dimethyl-silanyloxy) -1- (4-fluoro-phenyl) -1H-imidazole

Reacting [1- (4-fluoro-phenyl) -1H-imidazol-4-yl]Methanol (13g, 67.5mmol) was dissolved in 65mL DMF. Imidazole (11g, 162mmol) and tert-butyldimethylsilyl chloride (12.2g, 81mmol) were added. The reaction mixture was stirred at 45 ℃ overnight and poured into 500mL of water. The aqueous phase was extracted three times with ethyl acetate (200mL each). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated. The crude product was purified by silica gel column chromatography (dichloromethane/methanol 98: 2) to afford the desired compound as a light brown oil (20g, 96%), MS: m/e 291.2 (M-CH)₃) And M/e is 249.1 (M-tert-butyl).

And 5: 4- (tert-butyl-dimethyl-silanyloxymethyl) -1- (4-fluoro-phenyl) -2-methyl-1H-imidazole

4- (tert-butyl-dimethyl-silanyloxymethyl) -1- (4-fluoro-phenyl) -1H-imidazole (18.2g, 59.2mmol) was dissolved in 600mL anhydrous THF and cooled to-78 ℃. N-butyllithium (55.5mL, 1.6M in hexane, 88.8mmol) was added dropwise. The reaction mixture was warmed to-25 ℃, held at-25 ℃ for 10 minutes and then cooled again to-78 ℃. Methyl iodide (7.4mL, 11.8mmol) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred at room temperature overnight. The solvent was evaporated. The residue was dissolved in 300mL of water and extracted three times with ethyl acetate (200mL each). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated. The crude product was purified by silica gel column chromatography (cyclohexane/ethyl acetate 50: 50- > 20: 80 gradient) to afford the desired compound as an orange oil (14.7g, 77%), MS: 321.1(M + H)⁺)。

Step 6: [1- (4-fluoro-phenyl) -2-methyl-1H-imidazol-4-yl]-methanol

4- (tert-butyl-dimethyl-silanyloxymethyl) -1- (4-fluoro-phenyl) -2-methyl-1H-imidazole (14.7g, 45.7mmol) was dissolved in 200mL THF. Tetrabutylammonium fluoride (91mL, 1M THF solution, 91mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was dissolved in 200mL of water and extracted three times with ethyl acetate (200mL each). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated. The crude product was suspended in 150mL of ethyl acetate, filtered and dried. The desired compound was obtained as a white solid (7.16g, 76%), MS: 207.1(M + H) M/e⁺)。

And 7: 1- (4-fluoro-phenyl) -2-methyl-1H-imidazole-4-carbaldehyde

Reacting [1- (4-fluoro-phenyl) -2-methyl-1H-imidazol-4-yl]Methanol (7.16g, 34.7mmol) was dissolved in 2.3 liters of dichloromethane. Manganese (IV) oxide (26.8g, 278mmol) was added and the reaction mixture was stirred at room temperature for 3 days. The suspension was filtered through a dicalite speed plus pad and washed with 1 l dichloromethane. The solvent was evaporated to give the desired compound as a white solid (5.87g, 83%), MS: 205.1(M + H)⁺)。

And 8: 4-ethynyl-1- (4-fluoro-phenyl) -2-methyl-1H-imidazole

(1-diazo-2-oxo-propyl) -phosphonic acid dimethyl ester (6.51g, 33.9mmol) was dissolved in 100mL of methanol. Potassium carbonate (7.81g, 56.5mmol) was added. A solution of 1- (4-fluoro-phenyl) -2-methyl-1H-imidazole-4-carbaldehyde (5.77g, 45mmol) in 100mmol of methanol was added dropwise at room temperature. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was dissolved in 150mL of water and extracted three times with ethyl acetate (150 mL each). The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 100: 0- > 0: 100 gradient) to afford the desired compound as a white solid (3.81g, 67%), MS: and m/e is 200.1(M⁺)。

Example B

2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine

Step 1: 2-chloro-4-trimethylsilylethynyl-pyridine

2-chloro-4-iodo-pyridine (10.0g, 41.8mmol) was dissolved in 200mL anhydrous THF and 17.5mL triethylamine. The mixture was evacuated and purged with argon several times to remove oxygen from the solution. Triphenylphosphine (329mg, 1.25mmol) and bis (triphenylphosphine) palladium (II) chloride (1.47g, 2.09mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper (I) iodide (239mg, 1.25mmol) and trimethylsilylacetylene (6.28g, 6.39mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was dissolved in 500mL of water and extracted three times with ethyl acetate (500 mL each). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated. The crude product is purified by chromatography on silica gel (cyclohexane/ethyl acetate 80: 20). The desired product was obtained as a light brown semi-solid (10g, > 100%). This material was used in the next step without any further purification.

Step 2: 2-chloro-4- (2-methyl-1H-imidazol-4-ylethynyl) -pyridine

Solution 1: 2-chloro-4-trimethylsilylethynyl-pyridine (8.9g, purity < 100%, as indicated in step 1) and 5-iodo-2-methyl-1H-imidazole (13.24g, 64mmol, Synthesis: M.D. Cliff, S.G. Pyne, Synthesis1994, 681-. The mixture was evacuated and purged with argon several times to remove oxygen from the solution.

Solution 2: triphenylphosphine (223mg, 0.85mmol), bis (triphenylphosphine) palladium (II) chloride (1.79g, 2.55mmol), copper (I) iodide (81mg, 0.43mmol) and triethylamine (8.87mL, 64mmol) were dissolved in 75mL anhydrous THF. The mixture was also evacuated and purged with argon several times to remove oxygen from the solution.

Solution 2 was heated to 40 ℃ and solution 1 was added dropwise. The reaction mixture was heated to 60 ℃ and tetrabutylammonium fluoride solution (1M THF solution, 55mL, 55mmol) was added dropwise over 45 minutes. The reaction was then stirred at room temperature overnight. The solvent was evaporated. The residue was dissolved in 200mL of water and extracted three times with ethyl acetate (200mL each). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated. The crude product is purified by chromatography on silica gel (dichloromethane/methanol 95: 5) and recrystallized from a mixture of dichloromethane and ethyl acetate. The desired product was obtained as a light brown solid (2.89g, 31%):

example C

4-chloro-2-trifluoromethyl-pyrimidine

The compound was prepared as described in s.inoue, a.j.saggiomo, e.a.nodiff, j.org.chem.1961, 26, 4504.

Preparation of pharmaceutical compositions

Example I

Tablets of the following composition were produced according to conventional methods:

mg/tablet

Active ingredient 100

Powdered lactose 95

White corn starch 35

Polyvinylpyrrolidone 8

Sodium carboxymethylcellulose 10

Magnesium stearate 2

Tablet weight250

Example II

Tablets of the following composition were produced according to conventional methods:

mg/tablet

Active ingredient 200

Powdered lactose 100

White corn starch 64

Polyvinylpyrrolidone 12

Sodium carboxymethylcellulose 20

Magnesium stearate 4

Tablet weight400

Example III

Capsules producing the following composition:

mg/granule capsule

Active ingredient 50

Crystalline lactose 60

Microcrystalline cellulose 34

Talc powder 5

Magnesium stearate 1

Capsule fill weight150

The active ingredient having a suitable particle size, crystalline lactose and microcrystalline cellulose are mixed uniformly with one another, sieved, and then incorporated with talc and magnesium stearate. The final mixture is filled into hard gelatin capsules of suitable size.

Claims (13)

1. A compound of the general formula I or a pharmaceutically acceptable salt thereof,

wherein:

R¹represents halogen or cyano;

R²is represented by C₁-C₆-an alkyl group;

R³represents phenyl or contains one or moreAn aromatic 5-or 6-membered ring of heteroatoms selected from nitrogen, oxygen or sulfur,

it is optionally substituted by one, two or three groups selected from halogen, C₁-C₆Alkyl radical, C₃-C₆-cycloalkyl, C₁-C₆Alkyl-halogen, cyano, C₁-C₆-alkoxy, NR 'R' wherein R 'and R' are independently of each other hydrogen, C₁-C₆Alkyl radical, C₃-C₆-cycloalkyl, (CH)₂)-C₃-C₆-cycloalkyl or (CH)₂)_nOR；

R is hydrogen, C₁-C₆Alkyl radical, C₃-C₆-cycloalkyl or (CH)₂)-C₃-C₆-a cycloalkyl group;

n is1 or 2;

R⁴is hydrogen, C (O) H or CH₂R⁵Wherein R is⁵Is hydrogen, OH, C₁-C₆-alkyl or C₃-C₁₂-a cycloalkyl group.

2. A compound of claim 1 having the structure of formula IA,

wherein:

R¹represents halogen;

R²is represented by C₁-C₆-an alkyl group;

R³represents phenyl or an aromatic 5-or 6-membered ring containing one or more heteroatoms selected from nitrogen, oxygen or sulphur,

it is optionally substituted by one, two or three groups selected from halogen, C₁-C₆Alkyl radical, C₁-C₆-alkyl-halogen, cyano, NR 'R',

r 'and R' are independently of each other hydrogen, C₁-C₆Alkyl radical, C₃-C₆-cycloalkyl, (CH)₂)-C₃-C₆-cycloalkyl or (CH)₂)_nOR；

R is hydrogen, C₁-C₆Alkyl radical, C₃-C₆-cycloalkyl or (CH)₂)-C₃-C₆-a cycloalkyl group;

n is1 or 2.

3. A compound of formula I according to claim 1, wherein R is¹Is chlorine or fluorine.

4. A compound of formula I according to claim 3, wherein R is³Is an aromatic 5-or 6-membered ring containing one or more heteroatoms selected from nitrogen, oxygen or sulfur, optionally substituted with one, two or three substituents selected from fluorine, CF₃And C₁-C₆-an alkyl group.

5. A compound of formula I according to claim 4, or a pharmaceutically acceptable salt thereof, wherein said compound is:

2- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -4-trifluoromethyl-pyrimidine,

2- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -pyrazine,

2- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -6-trifluoromethyl-pyridine,

3- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -5-fluoro-pyridine,

4- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -2-trifluoromethyl-pyrimidine,

2- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -6-methyl-4-trifluoromethyl-pyridine, or

2- [4- (2-chloro-pyridin-4-ylethynyl) -2-methyl-imidazol-1-yl ] -5-methyl-pyridine.

6. A compound of formula I according to claim 3, wherein R is³Is taken by one, two or three halogensA substituted phenyl group.

7. A compound of formula I according to claim 6, or a pharmaceutically acceptable salt thereof, wherein said compound is:

2-chloro-4- [1- (4-fluoro-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine,

2-fluoro-4- [1- (4-fluoro-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine,

2-chloro-4- [1- (3, 5-difluoro-phenyl) -2-methyl-1H-imidazol-4-ylethynyl ] -pyridine,

2-chloro-4- [1- (3, 5-difluoro-phenyl) -2, 5-dimethyl-1H-imidazol-4-ylethynyl ] -pyridine,

2-chloro-4- [1- (4-fluoro-phenyl) -2, 5-dimethyl-1H-imidazol-4-ylethynyl ] -pyridine.

8. A process for the preparation of a compound of formula I as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein said pharmaceutically acceptable salt is a pharmaceutically acceptable acid addition salt, which process comprises

(a) Reacting a compound of formula II

Wherein R is¹、R²And R⁴As defined in the corresponding claims,

with a compound of the formula III,

R³-Z (III)

wherein R is³As defined in the corresponding claims and Z is halogen or B (OH)₂(ii) a Or

(b) Reacting a compound of formula IV

Wherein R is²、R³And R⁴As defined in the corresponding claims,

with a compound of the formula V,

wherein R is¹As defined in the corresponding claims and X is halogen; or

(c) Reacting a compound of formula VI

Wherein R is²、R³And R⁴As defined in the corresponding claims and hal is halogen,

with a compound of the formula VII,

wherein R is¹As defined in the corresponding claims and Y is trimethylsilyl or hydrogen; and optionally converting the resulting compound into a pharmaceutically acceptable acid addition salt.

9. A process for the preparation of a compound of formula I as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein said pharmaceutically acceptable salt is a pharmaceutically acceptable acid addition salt, which process comprises

a) Reacting a compound of formula II

With R of the formula III³Z compound reaction, wherein R₃As defined in the corresponding claims and Z is halogen or B (OH)₂；

To give a compound of formula IA

Wherein R is¹、R²And R³As defined in the respective claims, or

b) Reacting a compound of formula IV

With a compound of the formula V,

to give a compound of formula IA

Wherein R is¹、R²And R³As defined in the corresponding claims, and when R is⁴In the case where it is not hydrogen,

c) reacting a compound of formula IA with a compound of formula VI wherein Hal is halogen

R⁴Hal VI

To give the compound of the formula I

Wherein R is¹、R²、R³And R⁴As defined in the corresponding claims, and optionally, converting the resulting compound into a pharmaceutically acceptable acid addition salt.

10. A medicament containing one or more compounds as claimed in any one of claims 1 to 7 together with pharmaceutically acceptable excipients for the treatment and prevention of mGluR5 receptor mediated disorders.

11. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment and prevention of mGluR5 receptor mediated disorders.

12. Use according to claim 11 for the manufacture of a medicament for the treatment and prevention of mGluR5 receptor mediated acute and/or chronic neurological disorders, or for the treatment of mGluR5 receptor mediated chronic and acute pain, or for the treatment of mGluR5 receptor mediated urinary incontinence.

13. Use according to claim 12, in the manufacture of a medicament for the treatment and prevention of mGluR5 receptor mediated anxiety.