Title of Invention	IMIDAZOL-4-YL-ETHYNYL-PYRIDINE DERIVATIVES
Abstract	4-[ 1 -Aryl-imidazol-4-yIethynyl]-2-alkyl-pyridine and 1 -heteroaryl-imidazol-4-ylethynyl]-2-alkyl-pyridine derivatives and pharmaceutically acceptable salts thereof for the treatment or prevention of disorders mediated full or in part by metabotropic glutamate receptor 5, e.g. 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.

Title of Invention

IMIDAZOL-4-YL-ETHYNYL-PYRIDINE DERIVATIVES

Abstract

4-[ 1 -Aryl-imidazol-4-yIethynyl]-2-alkyl-pyridine and 1 -heteroaryl-imidazol-4-ylethynyl]-2-alkyl-pyridine derivatives and pharmaceutically acceptable salts thereof for the treatment or prevention of disorders mediated full or in part by metabotropic glutamate receptor 5, e.g. 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.

Full Text	Imidazol-4-yl-ethynvl-pyridine derivatives The present invention relates to novel imidazole derivatives, to proC6sses for their production their use as pharmaC6uticals and to pharmaC6utical compositions comprising them. More particularly the present invention provides in a first aspect novel 4-[l-aryl and 1-heteroaryl-imidazol-4-ylethynyl]-2-alkyl-p'5Tidine derivatives as well as pharmaC6utical^ acC6ptable salts thereof. More particularly the present invention provides a compound of formula I wherein R1 is C1-C6alkyl; R2 is C1-C6alkyl or C5-C12cycloalkyl; R3 is aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted by one, two or three substituents selected from halogen, Q-C6alkyl, S-C1~C6alkyl, C1-C6alkyl-halogen, C1-C6alkoxy, halogen-C1-C6alkoxy, Cs-Cncycloalkyl, C2~ Cnheterocycloalkyl, Q-C6alkylamino, di-C1-C6alkylamino, C1-C6alkoxyamino, (Q-C6alko^C1-C6alkylamino, C3-C12cycloalkylamino, benzylamino and cyano; and R4 is hydrogen, C(0)H or CH2R5 wherein R5 is hydrogen, OH, Q-C6alkyl or C3-C12cycloalkyk In one embodiment the present invention provides a compound of formula Ist (I) wherein R1 signifies lower alkyl; R signifies lower alkyl; R signifies aryi 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 pharmaC6utically acC6ptable salts thereof. It has now surprisingly been found that the compounds of general formula I are metabo-tropic glutamate reC6ptor 5 antagonists. Compounds of formula I are distinguished by having valuable therapeutic properties. They can be used in the treatment or prevention of mGluR5 reC6ptor mediated disorders. In the C6ntral nervous system (CNS) the transmission of stimuli takes plaC6 by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreC6ptor. Glutamate is the major exC1tatory neurotransmitter in the brain and plays a unique role in a. variety of C6ntral nervous system (CNS) functions. The glutamate-dependent stimulus reC6ptors are divided into two main groups. The first main group, namely the ionotropic reC6ptors, forms ligand-controlled ion channels. The metabotropic glutamate reC6ptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein coupled reC6ptors. At present, eight different members of these mGluR are known and of these some even have sub-types. According to their sequenC6 homology, signal transduction mechanisms and agonist selectivity, these eight reC6ptors can be sub-divided into three sub-groups: mGluRl and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluRS belong to group III. Ligands of metabotropic glutamate reC6ptors 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 defiC1ts, as well as chronic and acute pain. Other 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, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-defiC1ency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinenC6, drug abuse/dependanC6 such as nicotine addiction, opiate addiction, and alcohol abuse, anxiety, vomiting, dyskinesia and depressions. Disorders mediated full or in part by mGluR5 are for example acute, traumatic and chronic degenerative proC6sses 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 espeC1ally useful for the treatment of anxiety and pain. Objects of the present invention are compounds of formula I and their pharmaC6utically acC6ptable salts, the above-mentioned compounds as pharmaC6utically active substanC6s and their production. Further objects of the invention are medicaments based on a compound in accordanC6 with the invention and their manufacture as well as the use of the compounds in the control or prevention of mGluR5 reC6ptor mediated disorders, and, respectively, for the production of corresponding medicaments. The following definitions of general terms used in the present desC1-iption apply irrespective of whether the terms in question appear alone or in combination. The term "lower alkyl11 used in the present desC1-iption 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 „cycloaIkyl" used in the present desC1-iption denotes cyclic saturated hydrocarbon residues "with 3 to 12 carbon atoms. Examples for cycloallcyl include cyclopropyl, cyclobutyl and cyclopentyl. Examples for Q-C6alkoxy include methoxy, methoxyethyl and methoxyethoxy. Examples for halogenmethoxy include trifluoromethoxy. Examples for C2-Cnheterocycloalkyl include pyrrolidinyl, morpholinyl and thiomorpho-linyl. Examples for C1-C6alkylamino include methylamino and ethylamino. Examples for di-C1-C6alkylamino include dimethylamino. Examples for Q-Csalkoxyamino include methoxy-ethylamino. Examples for (C1-C6alkoxy)C1-C6aIkylamino include (methoxyethyl)methyl-amino. Examples for methoxycycloalkylamino include cyclopropylamino. The term "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 include phenyl. Examples for substituted aryl include fluorophenyl, difluorophenyl, chloro-phenyl, dichlorophenyi, chlorofluorophenyl, cyanophenyl, methylphenyl, methoxyphenyl, fluoromethylphenyl, trifluoromethylphenyl and trifluoromethoxyphenyl. The term "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. Examples of such heteroaryl groups are p}Timidinyl, pyrazinyl, p)T:ida2iinyl, pyridinyl and indolyl, e.g. pyridin-4-yl, pyridin-2-yl, pyrazin-2-yl and pyrimidin-2-yl. Examples for substituted heteroaryl include methylpyrimidinyl, dimefhylp^imidinyl, trifluoromethylpyri-midinyl, methoxypyrimidinyl, methoxyethoxypyrimidinyl, ethylpyrimidinyl, fluoropyri-midinyl, chloropyrimidinyl, bromopyrimidinyl, methylsulfanylimidinyl? cyclopropyl-pyrimidinyl, methylpyrasinyl, cydopropylpyrazinyl, chloropyrazinyl, methoxypyrasinyl, methoxypyrazinyl, methylaminopyrazinyl, dimethylaminopyrazinyl, q^clopropyl-aminopyrazinyl, morpholinylpyrazinyl, fluoropyridinyl, chloropyridinyl, bromopyridinyl, iodopyridinyl, methylpyridinyl, trifluoromethylpyridinyl, Mfluoromethylmethylpyridinyl, cyclopropylpyridinyl, butylp)nridinyl, methoxypyridinyl, dimethylaminoppridinyl, methyl-aminopyridinyl, eth}daminopyridinyl, pyrrolidinylpyridinyl, morpholinylpyridinyl, thio-morpholinylpyridinyl, (methoxyethyl)methylaminopyridinyl, methoxyethylaminopyri-dinyl, benzylaminopyridinyl and methyl-IH-indolyl. The term "pharmaC6utically acC6ptable salt" refers to any salt derived from an inorganic or organic aC1d. "PharmaC6utically acC6ptable salts" of a compound means salts that are pharmaC6utically acC6ptable, 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 acd. If possible, compounds of formula I maybe converted into pharmaC6utically acC6ptable salts. It should be understood that all referenC6s to pharmaC6utically acC6ptable salts include solvent addition forms (solvates) or c-ystal forms (polymorphs) of the same acd addition salt. Examples for pharmaC6utically acC6ptable acd addition salts include acd addition salts formed with inorganic acds such as hydrochloric acd, hydrobromic acd, sulfuric acd, nitric acd, phosphoric acd, and the like; or formed with organic acds such as aC6tic acd, benzenesulfonic a cid, benzoic, camphorsulfonic acd, ctric acd, ethanesulfonic acd, fumaric acid, glucoheptonic acd, gluconic acid, glutamic acd, glycolic acd, hydroxynaph-thoic acd, 2-hydroxyethanesulfonic acd, lactic acd, maleic acd, malic acd, mandelic acid, methanesulfonic acd, muconic acd, 2-naphthalenesulfonic acd, propionic acd, salicylic acd, succnic acd, dibenzoyH-tartaric acd, tartaric acd, p-toluene-sulfonic acd, trimethylaC6tic acd, trifluoroaC6tic acd, and the like. Preferred compounds of formula I are those, in which R and R are both methyl. Especally preferred are those compounds from this group, in which R is substituted phenyl, wherein the substitution is fluoro, chloro, cyano or CF3. The following are examples of compounds, wherein the substitution is fluoro or chloro: 4- [ 1 - (4-fluoro-phenyl) -2-methyl- lH-imidazol-4-ylethynyl] -2-methyl-pyridine» 4- [ 1 - (3,4-dichloro-phenyl) -2-mefhyl- lH4midazol-4-ylethynyl] -2-methyl-pyridine, HCl 4-[ 1 -(2,4-difiuoro-phenyl)-2-methyl-lH-imidazol-4-ylethynyl] -2-methyl-pyridine, or 4-[l-(3,4-difiuoro-phenyl)-2-methyl^ Examples of compounds, wherein the substitution is cyano, are as follows: 4- [2-methyl-4-(2-methyl-p)rridin-4-ylethynyl) -imidazol-1 -yl] -benzonitrile, or 3- [2-methyl-4-(2-methyl-pyridin-4-ylethynyl) -imidazol-1 -yl] -benzonitrile., The following is an example of compounds, wherein the substitution is CF3: 2-methyl-4- [2-methyl-1 - (3-trifluoromethyl-phenyl) - lH-imidazol-4-ylethynyl]-pyridine. Especally preferred are further those compounds, wherein R and R2 are both methyl and R is pyrimidinyl, for example the following compound: 2- [2-methyl-4- (2-methyl-pyridin-4-ylethynyl) -imidazol-1 -yl] -pyrimidine. (c) a compound of formula VI (VI) wherein R , R and R have the meanings as defined above and hal is halogen, with a compound of formula VII (VII) wherein R1 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 lilce 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, (Ph3P)2PdCl2> Et3N in a solvent like tetrahydrofuran or dimethylformamide [Sonogashira et al., Synthesis 777 (1977)]. In one embodiment 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, (Ph3P)2PdCl2, Et3N, n-Bu4 F in a solvent like tetrahydrofuran or dimethylformamide. The salt forms are made by standard procedures known to the skilled artisan. The compounds of formulae II, IV, VI und VII are novel and also an embodiment 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 may be prepared by reacting a compound of formula VIII (VIII) wherein R2 and R4 have the above meanings and hal is halogen, with a compound of formula VII as above. The compounds of formula VIII maybe prepared as desC1-ibed e.g. in Cliff and Pyne [Synthesis 681-682 (1994)]. The compounds of formula IV may be prepared by reacting a compound of formula IX (IX) wherein R , R and R have the meanings as defined above, with dimethyl (l-diazo-2-oxopropyl)phosphonate as desC1-ibed in Ohira [Synth.Comm. 19:561-564(1989)]. Compounds of formula VI maybe prepared by reacting a compound of formula VIII as above with a compound of formula X R3-B(OH)2 (X) wherein R"1 has the meanings as defined above. The reaction may take plaC6 by arylation of a compound of formula VIII using an aromatic boronic aC1d (compound of formula X) and a copper catalyst in a solvent like dichloromethane or tetrahydrofarane under an oxygen atmosphere [see e.g. Colmann et aL, Org.Lett. 2:1233 (2000)]. Compounds of formula VII may be prepared by reacting a compound of formula V as above with a compound of formula XI Y^ (XI) The reaction may take plaC6 by a Sonogashira coupling in the presenC6 of eg. Cul, (PhaP)2PdCl2 Et3N in a solvent like tetrahydrofiiran or dimethylformamide [Sonogashira et aL, Synthesis 777 (1977)]. Compounds of formula IX may be prepared by oxidizing a compound of formula XII (XII) according to methods known to the skilled artisan. Compounds of formula XII may be prepared by deprotecting a compound of formula XIII (XIII) i according to methods known to the skilled artisan. Compounds of formula XIII may be prepared by alkylating a compound of formula XIV (XIV) with an alkylating agent of formula XVa R2-hal (XVa) according to methods known to the skilled artisan-Starting compounds of formula XVa are commerC1ally available. Compounds of formula XIV maybe prepared by treating a compound of formula XV (XV) with tert.-butyl dimethyl silyl chloride according to methods known to the skilled artisan. Compounds of formula XV may be prepared by treating a compound of formula XVI (XVI) with a reduC1ng agent according to methods known to the skilled artisan. Compounds of formula XVI may be prepared by hydrolysing a compound of formula. XVII (XVII) according to methods known to the skilled artisan. Compounds of formula XVII may be prepared by treating a compound of formula XVIII R3-NH2 (xvni) with e.g. triethyl orthoformate, ethylnitro aC6tate, glaC1al aC6tic aC1d and iron powder according to methods known to the skilled artisan. Compounds of formula XVIII are commerC1ally available. The compounds of general formula I* and their pharmaC6utically acC6ptable salts can be manufactured by two general proC6dures, which proC6dures are outlined below for compounds wherein R1 is methyl and R2 is methyl, but which proC6dures are applicable for all compounds according to Formula I. I wherein R is methyl and R2 is methyl (R3 and R1 are designated Ar and Ai?, respectively, in Scheme 2). Moreover the invention relates also medicaments containing one or more compounds of the present invention and pharmaC6utically acC6ptable exC1pients for the treatment and. prevention of mGluR5 reC6ptor 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 accordanC6 with the present invention as well as its pharmaC6utically acC6ptable salt for the manufacture of medicaments for the treatment and prevention of mGluRS reC6ptor mediated disorders as outlined above. PharmaC6utically acC6ptable 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 aC1ds such as, e.g., hydrochloric aC1d, hydrobromic aC1d, sulphuric aC1d, nitric aC1d, phosphoric aC1d or C1tric aC1d, formic aC1d, fumaric aC1d, maleic aC1d, aC6tic aC1d, sucC1nic aC1d, tartaric aC1d, methanesulphonic aC1d, p-toluenesulphonic aC1d and the like are suitable for the formation of pharmaC6utically acC6ptable salts of basic compounds of formula I. Compounds which contain the alkali metals or alkaline earth metals, for example sodium, potassium, calC1um, magnesium or the like, basic amines or basic amino aC1ds are suitable for the formation of pharmaC6utically acC6ptable salts of aC1dic compounds. The compounds of formula I and their pharmaC6utically acC6ptable salts (hereinafter: PharmaC6utical Compounds) are, as already mentioned above, metabotropic glutamate reC6ptor antagonists and can be used for the treatment or prevention of mGluRS reC6ptor mediated disorders, such as acute and/or chronic neurological disorders, cognitive disorders and memory defiC1ts, as well as acute and chronic pain. Treatable neurological disorders are for instanC6 epilepsy, schizophrenia, anxiety, acute, traumatic or chronic degenerative proC6sses of the nervous system, such as Alzheimer's disease, senile dementia, Huntington's chorea, ALS, multiple sclerosis, dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-defiC1ent functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinenC6, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, dyskinesia and depression. Other treatable indications 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 hypoglyC6mia. PharmaC6utical Compounds are espeC1ally useful as analgesics. 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, hyperalgesia, severe chronic pain, post-operative pain and pain assoC1ated with various conditions like canC6r, angina, renal or bifliay colic, menstruation, migraine and gout. The pharmacological activity of PharmaC6utical Compounds was tested using the following method: For binding experiments, cDNA encoding human mGlu 5a reC6ptor was transiently trans-fected into EBNA C6lls using a proC6dure desC1-ibed by Schlaeger and Christensen [Cyto-technology 15:1-13 (1998)]. C6ll 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 CaCl2, 25 mM MgCl2 binding buffer at pH 7.4 to a final assay conC6ntration of 20 \ig protein/ well. Saturation isotherms were determined by addition of twelve [ H]MPEP conC6ntrations (0.04-100 nM) to these membranes (in a total volume of 200 \xl) for 1 h at 4°C. Compe-tition experiments were performed with a feed conC6ntration of [TijMPEP (2nM) and IC50 values of test compounds evaluated using 11 conC6ntrations (0.3-10,000nM). Incubations were performed for 1 h at 4° C. At the end of the incubation, membranes were filtered onto unifilter (96-well white miC1-o-plate with bonded GF/C filter preincubated 1 h in 0.1% PEI in wash buffer, Packard Bio-SC1enC6, Meriden, CT) with a Filtermate 96 harvester (Packard BioSC1enC6) and washed 3 times with cold 50 mM Tris-HCl, pH 7.4 buffer. NonspeC1fic binding was measured in the presenC6 of 10 μM MPEP. The radioactivity on the filter was counted (3 min) on a Packard Top-count miC1-oplate sC1ntillation counter with quenching correction after addition of 45 μ-1 of miC1-osC1nt 40 (Canberra Packard S.A., Zurich, Switzerland) and shaking for 20 min. For functional assays, [Ca2+]i measurements were performed as desC1-ibed previously by Porter et al. [Br. J. Pharmacol. 128:13-20 (1999)] on recombinant human mGlu 5a reC6ptors in HEK-293 C6lls. The C6lls were dye loaded using Fluo 4-AM (obtainable by FLUKA, 0.2j-iM final conC6ntration). [Ca ]i measurements were performed using a ' fluorometric imaging plate reader (FLIPR, Molecular DeviC6s Corporation, La Jolla, CA, USA). Antagonist evaluation was performed following a 5 min preincubation with the test compounds followed by the addition of a submaximal addition of agonist. The inhibition (antagonists) curves were fitted with a four parameter logistic equation giving IC5o, and Hill coeffiC1ent using an iterative non linear curve fitting software (XC6l at). For binding experiments the Ki values of the compounds tested are given. The Ki value is defined by the following formula: Ki = IC50 / [l + L/Kd] in which the IC50 values are those conC6ntrations of the compounds tested which cause 50 % inhibition of the competing radioligand ([ H]MPEP). L is the conC6ntration of radioligand used in the binding experiment and the Kd value of the radioligand is empirically determined for each batch of membranes prepared. PharmaC6utical Compounds are mGluR 5a reC6ptor antagonists. The activities of PharmaC6utical Compounds as measured in the assay desC1-ibed above are in the range of Ki Activity data Activity speC1fically as anxiolytic agents maybe demonstrated in acordanC6 with standard test methods, e.g. as desC1-ibed in the Vogel conflict drinking test [see e.g. review of Mfllan, Progress in Neurobiology 70:83-244 (2003)]: The Vogel conflict drinking test is a proC6dure that has been widely used as a sC1-eening method for anxiolytics. In this proC6dure, the water intake of thirsty rats is measured under conditions where water intake is suppressed by electric shock. In our version of the test, 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. On the third -test - day, they are allowed to lick again from a drinking spout for 10 min, but now they reC6ive a 0.5 mA electric stimulus for 0.5 sec every sec that they lick (counted as an interruption of an infrared beam in front of the spout). The electric stimulus suppresses the time that the animals spend drinking, and treatment with PharmaC6utical Compounds partially or completely reinstates normal drinking duration. PharmaC6utical Compounds can be used as medicaments, e.g. in the form of pharmaC6utical preparations. The pharmaC6utical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions. PharmaC6utical Compounds can be proC6ssed with pharmaC6utically inert, inorganic or organic carriers for the production of pharmaC6utical preparations. Lactose, corn starch or derivatives thereof, talc, stearic aC1d 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 substanC6 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, suC1-ose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glyC6rol, 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 neC6ssary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like. In addition, the pharmaC6utical 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 substanC6s. As mentioned earlier, medicaments containing a PharmaC6utical Compound and a therapeutically inert exC1pient are also an object of the present invention, as is a proC6ss for the production of such medicaments which comprises bringing one or more PharmaC6utical Compound and, if desired, one or more other therapeutically valuable substanC6s 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. In general, 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 desC1-ibed. The daily dosage for an adult human being weighing 70 kg accordingly lies between 0.7-1400 mg per day, preferably between 7 and 700 mg per day. The following examples are provided to further eluC1date the invention: Preparation of the starting compounds Example II-1: 2-Methyl-4-(2-methyl-lH-imidazol-4-ylethynyl)-pyridine (II-1) Method Al: Step 1: 2-Methyl-l-(2-trimethylsfo and 2-methyl-3-(2-1ximethylsilanyl-ethoxyTnethyl)-3H-imidazole-4-carbaldehyde A solution of 2-methyl-lH-imidazol-4-carbaldehyde (5.0 g, 45 mmol) in 125 mL dry DMF was added dropwise at 0°C to suspension of sodium hydride (1.98 g, 45 mmol) in dry DMF. The reaction mixture was stirred at RT for 2h. A solution of 2-(trimethylsilyl)eth- oxymefhyl chloride (7.97 g, 45 mmol) in 50 mL dry THF was added dropwise at 0°C. The reaction mixture was stirred at RT overnight. Water (100 mL) was added carefully and the solvents were evaporated. The residue was taken up in 150 mL water and extracted three times with ethyl aC6tate (150 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The C1-ude product (mixture of 2 isomers, 12.5 g) was used without any farther purification for the next step, MS: m/e = 241.2 (M+H+). Step 2:4-Ethynyl-2~methyl-l-(2-trimethyls^ and 5- etliynyl-2-methyl-l-(2-1ximethylsilanyl-ethoxjrmethyl)-lH-imidazole (l-Diazo-2-oxo-propyl)-phosphonic aC1d dimethyl ester (10.4 g, 54 mmol) was dissolved in 150 mL methanol. Potassium carbonate (12.6 g, 90 mmol) was added. A solution of C1-ude 2-methyl-l-(2-trimethylsilanyl-ethox)miethyl)-lH-imidazole-4-carbaldehyde and 2-metiyl-3-(2-trimethylsilanyl-ethox5naeth.yl)-3H-imidazole-4-carbaldehyde (45 mmol) in 150 mmol methanol was added dropwise at RT. The reaction mixture was stirred at RT overnight. The solvent was evaporated. The residue was taken up in 150 mL water and extracted three times with ethyl aC6tate (150 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The C1-ude product was purified by column chromatography on silica gel (qclohexane / ethyl aC6tate 1:1) and the desired compound was obtained as a mixture of 2 isomers (8.36 g, 78%), MS: m/e = 237.0 (M+H+). 2-Hydroxy-5-methylpyrazine (0.984g> 8.94 mmol) was refluxed in 15 ml pftospnoroxy-chloride fox 1.5h. The reaction mixture was slowly poured into iC6 and adjusted to pH6 by addition of sodium carbonate. The mixture was extracted six times with ethyl aC6tate (50 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The C1-ude product was used without any further purification for the next step. Example III-2: 4-Chloro-2-trifluoromethyl-pyrimidine (III-2) This compound was prepared according to Inoue et al., J. Org. Chem. 26:4504 (1961). Example III-3; 2-Bromo-6-fluoro-pyridine (III-3) This compound was prepared according to WO 92/11,241. Example IV-1: 4-Ethynyl-l-(4-fluoro-phenyl)-2-methyl-lH-iinidazole (TV-1) Step 1: l-(4-Fluoro-phenyl)-lH-imidazole-4-carboxylk aC1d ethyl ester 4-Fluoroaniline (20.0 g, 175 mmol) was mixted at RT with triethyl orthoformate (35,4 g, 233 mmol), ethylnitro aC6tate (28.5 g, 210 mmol) and 4 mL glaC1al aC6tic aC1d. The reaction mixture was refluxed with mechanical stirring for 2h. More triethyl orthoformate (200 mL) and glaC1al aC6tic aC1d (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. Ethyl aC6tate (700 mL) was added and reflux was continued for another 2h. The reaction mixture was filtered through a dicalite speed plus pad and washed with 500 mL ethyl aC6tate. The solvents were evaporated and the C1-ude product was used without any further purification for the next step. Step 2: l-(4-Fluoro-phenyl)-lH-imidazole-4-carbox)?lic aC1d C1-ude l-(4-fiuoro-phenyl)-lH-imidaz;ole-4-carboxylic aC1d ethyl ester (175 mmol) was dissolved in 450 mL dioxane and 450 mL 2N sodium hydroxide solution. The reaction mixture was refluxed for 2h. Charcoal (1 g, Norit SAII) was added and reflux was continued for another 20 min. The mixture was filtered hot and washed with. 50 mL 2N sodium hydroxide solution. The filtrate was treated with 550 mL 2N HC1 and stirred at RT overnight. The solid material was filtered off and dried at 50°C and 15 mbar. The desired compound was obtained as an off-white solid (28 g, 78%)> MS: m/e = 205.1 (M-H). Step 3: [l-(4-Fluoro-phenyl)-lH-imidazol-4-yl]-methanol ) l-(4-Pluoro-phenyl)-lH-imidazole-4-carboxylic aC1d (18 g, 87 mmol) was dissolved in 90 mL dry THF. Borane tetrahydrofuran complex (174 mL, 1M in THE, 174 mmol) was added dropwise. The reaction was refluxed for 2h and stirred at RT overnight. The reaction mixture was cooled to 0°C and 100 mL methanol were added dropwise. The solvents were evaporated. The residue was taken up in 100 mL 2N HC1 and refiuxed for 2h. The reaction mixture was then cooled to 0°C and 120 mL 2N sodium hydroxide solution were added dropwise. The solid material was filtered off and dried at 50°C and 15 mbar. The desired compound was obtained as a white solid (13 g, 78%), MS: m/e = 193.2 (M+H)+. Stei^4-(tert-Butyl-dimethyl-sik^ [l-(4-Fluoro-phen7l)-lH-imidazol-4-7l]-methanol (13 g, 67.5 mmol) was dissolved 65 mL DMF. Imidazole (11 g, 162 mmol) and tert. butyldimethyl chlorosilane (12.2 g, 81 mmol) were added. The reaction mixture was stirred at 45°C overnight and poured into 500 mL water. The aqueous phase was extracted three times with ethyl aC6tate (200 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The C1-ude product was purified by column chromatography on silica gel (methylene chloride / methanol 98:2) and the desired compound was obtained as a light brown oil (20 g, 96%), MS: m/e = 291.2 (M-CH3)> m/e = 249.1 (M-tert. butyl). Step 5:4-(tert-ButyI-dimetfayl^ imidazole 4-(tert-Butyl-dimethyl-silanyloxjTn^^ (18.2 g, 59.2 mmol) was dissolved in 600 mL dry THF and cooled to -78°C. n- Butyl lithium (55.5 mL, 1.6M in hexane, 88.8 mmol) was added dropwise. The reaction mixture was warmed up to -25°C, kept at -25°C for lOmin and then cooled again to -78°C. Iodomethane (7.4 mL, 11.9 mmol) was added dropwise. The reaction mixture was slowly warmed up to RT and stirred at RT overnight The solvent was evaporated. The residue was taken up in 300 mL water and extracted three times with ethyl aC6tate (200 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The C1-ude product was purified by column chromatography on silica gel (cyclohexane / ethyl aC6tate 50:50 -> 20:80 gradient) and the desired compound was obtained as an orange oil (14.7 g, 77%)> MS: m/e = 321.1 (M+H+). Step 6: [l-(4-Fluoro-phenyl)-2-methyl-lH-imidazol-4-yl] -methanol 4-(tert-Butyl-dimethyl-silanyloxy^ (14.7 g, 45.7 mmol) was dissolved in 200 mL THF. Tetrabutyl ammoniumfluoride (91 mL, 1M 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 aC6tate (200 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The C1-ude product was suspended in 150 mL ethyl aC6tate, filtered and dried. The desired compound was obtained as a white solid (7.16 g, 76%), MS: m/e = 207.1 (M+H+). Step 7: l-(4-Fluoro-phenyl)-2-methyl-lH-imidazole-4-carbaldehyde [l-(4-Fluoro-phenyl)-2-methyl-lH-imidazol-4-yl] -methanol (7.16 g, 34.7 mmol) was dissolved in 2.3 L methylene chloride. Mangan (IV) oxid (26.8 g5 278 mmol) was added and the reaction mixture was stirred at RT for 3 days. The suspension was filtered through a dicalite speed plus pad and washed with 1L methylene chloride. The solvents were evaporated and the desired compound was obtained as a white solid (5.87 g, 83%), MS: m/e = 205.1 (M+H). Step 8:4-Ethynyl-1 - (4-fluoro-phenyl) -2-methyl- lH-imidazole (l-Diazo-2-oxo-propyi)-phosphonic aC1d dimethyl ester (6.51 g3 33.9 mmol) was dissolved in 100 mL methanol. Potassium carbonate (7.81 g5 56.5 mmol) was added. A solution of !-(4-fluoro-phenyl)-2-methyl-lH-imidazoIe-4-carbaldehyde (5.77 g, 45 mmol) in 100 mmol methanol was added dropwise at RT. The reaction mixture was stirred at RT overnight. The solvent was evaporated. The residue was taken up in 150 mL water and extracted three times with ethyl aC6tate (150 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The C1-ude product was purified by flash chromatography on silica gel (heptane / ethyl aC6tate 100:0 -> 0:100 gradient) and the desired compound was obtained as a white solid (3.81 g, 67%), MS: m/e = 200.1 (M""). lK3>4-Dichloro-phenyl)'4-eth)myl-2-methyl-lH-imida2ole (IV-2) [MS: m/e = 252.1 (M+)] was prepared in accordanC6 with the method of example IV-1 from 3,4-dichloroaniline. Example V-1: 2-Cyclopropyl-1-(4-fluoro-phenyl)-4-iodo-iH-imidasole (V-1) Stepjj: 2-Cyclopropyl-4)5-diiodo- IH-imidazole 2-Cyclopropyl-lH-imidazole (2500 mg, 23.12 mmol) was suspended in 46 ml 2N NaOH. A solution of iodine (11.74 g, 46.23 mmol) in 45 ml dichloromethane was added dropwise to the suspension within 15 min. The two-layer-mixture was stirred vigorously at RT over night. The aqueous layer was separated, neutralized with aC6tic aC1d and saturated Na2S203-solution was added until the solution remained colorless. The suspension was stirred for 10 min, filtered and the solid was dried over night at 50°C under reduC6d pressure ( 42%). Step 2: 2-Cyclopropyl-4-iodo-lH-imidazole Na2S03 (10.42 g, 82.65 mmol) was suspended in 40 ml water and 20 ml ethanol. 2-Cyclo- propyl-4,5-diiodo-lH-imidazole (3500 mg, 9.72 mmol) was added and the mixture was stirred at reflux for 16 hours. The reaction mixture was conC6ntrated to 20 ml and then filtered. The solid was dried for 5 hours at 50°C under reduC6d pressure ( 2-Cyclopropyl-4~iodo-lH-imidazole (500 mg, 2.14 mmol) was dissolved in 20 ml THF. 4-Fluorobenzeneboronic aC1d (613 mg, 4.38 mmol) and [Cu(OH)TMEDA]2Cl2 (347 mg, 0.75 mmol) were added Oxygen was bubbled through the reaction mixture for 60 min and stirring was continued under an oxygen atmosphere at RT overnight. The reaction mixture was filtered through a dicalite speed plus pad and washed with 30 mL ethyl aC6tate. After drying the C1-ude product was purified by flash chromatography on silica gel (heptane / ethyl aC6tate 90:10 -> 50:50 gradient) to get the desired compound as a white solid (320 mg, 46%), MS: m/e = 329.1 (M+H+). Preparation of the compounds of formula I Example 1: 4- [ 1 - (4-Fluoro-phenyl)-2-methyl- lH-imidazol-4-ylethynyl] -2-methyl-pyridine (1) Method A: 2-Methyl-4-(2-methyl-lH-irnidazol-4-yleth)rnyl)-p}T:idine (II-l) (200 mg, 1.01 mmol) was dissolved in 10 mL dichloromethane. Powdered molecular sieves (3 A, 200 mg), 4-fluoro-benzene boronic aC1d (284 mg, 2.02 mmol) and [Cu(OH)TMEDA]2Cl2 (47 mg, 0.10 mmol) were added. Oxygen was bubbled through the reaction mixture for 5 min and stirring was continued at RT overnight. The reaction mixture was filtered through a dicalite speed plus pad and washed with 50 mL dichloromethane. The filtrate was washed with 50 ml water, dried with magnesium sulfate, filtered and evaporated. The C1-ude product was purified by flash chromatography on silica gel (dichloromethane / methanol 100:0 -> 85:15 gradient) and a mixture of 2 regioisomers was isolated. The desired compound was obtained by reC1-ystallization from diethylether as a white solid (151 mg, 51%), mp ^ 151°C, MS: m/e = 292.1 (M+H). Method B: 4-Iodo-2-methyl-pyridine (656 mg, 3.0 mmol) was dissolved in 10 mL dry THF and 10 mL piperidine. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (20 mg, 0.07 mmol) and bis(triphenyl-phosphin)palladium(II)chloride (175 mg, 0.10 mmol) were added and the reaction mixture was stirred at RT for Ih. Copper(I)iodide (14 mg, 0.07 mmol) and 4-ethynyl-l-(4-fluoro-phenyl)-2-methyl-lH-hnidazole (IV-1) (500 mg, 2.5 mmol) were added. The reaction mixture was then refluxed for 3h. 'The solvent was evaporated. The residue was taken up in 30 mL water and extracted three times "with ethyl aC6tate (50 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The C1-ude product was purified by flash chromatography on silica gel (dichloromethane / methanol 100:0 -» 90:10 gradient) and reC1-ystallization from diethylether and the desired 5 product was obtained as a light yellow solid (250 mg> 34%), mp = 151°C, MS: m/e = 292.1 (M+H+). 4-[l-(3>4-DicUoro-phenyl)-2-me hydrochloride (2) [MS: m/e = 341.9 (M+H+)] was prepared in analogy to the mettod as desC1-ibed in Example 1 Method B starting from l-(3,4-dicHoro-phenyl)-4~ethynyl-2-) methyl-lH-imidazole (IV-2) and 4-iodo-2-methyl-pyridine. For further purification the compound was preC1pitated as its HC1 salt from an etheral solution. Method C: 4-Iodo-2-methyl-lH-imidazoIe (200 mg, 1.0 mmol), 4-fluorophenylboronic aC1d (215 mg, L6 mmol), copper(II)aC6tate (210 mg, 1.2 mmol) and EtjN (0.16 ml, 1.2 mmol) were suspended in 10 ml THF and oxygen was bubbled through the reaction mixture for 40 min. The reaction mixture was stirred for 48 hours at RT and then filtrated over dicalit. The filtrate was conC6ntrated and then purified by flash chromatography to yield l-(4-fluoro-phenyl)-4~iodo-2~methyl-lH-imidazole (120 mg, 0.40 mmol, 41 %). A solution of l-(4-fluoro-phenyl)-4-iodo-2-methyl-lH-imidazole (5,0g, 17mmol) and 2-methyl»4-trimethylsilanyleth}myl-p}ddine (3.2 g, 17 mmol, prepared from 4-iodo-2-methyi pyridine and commerC1ally available eth)myl-trimethyl-silane in a Sonogashira reaction) in 15ml THF was transferred to a mixture of triphenylphosphine (88 mg, 0.34 mmol), bis(tri-phenylphosphin)palladium(II)chloride (705 mg, 1.0 mmol) and Et3N (3.5 ml. 25 mmol) in 80 ml THF. Copper(I)iodide (32 mg, 0.17 mmol) was added and the reaction mixture was heated under argon atmosphere to 40°C and a solution of tetrabutylammoniumfluoride (1 M in THF, 25.1 ml) was added over a period of 40 min. The reaction mixture was stirred for three hours at 40°C and then for 48 hours at RT. After aqueous work up and purification by chromatography over silica gel and C1-ystallization from ethylaC6tate and hexane the desired product was obtained as a light yellow solid (2.8 g, 57%, mp = 151°C, MS: m/e = 292.1 (M+H+)). The following compounds were prepared in analogy to the method as desC1-ibed in the above Method A: Compound name and number Compound of MS: m/e I I ... .,-1 1 . —» * prepared according to De Lang and Brandsma, Synthetic Communications 28:225-232 (1998) Example 5: 2-Butyl-6- [2-methyl-4-(2-metiiyl-pyridin-4-yIeliiyiiyl)-imidazol- 1-yl]-pyridine (65) 5 The title compound, MS: m/e = 33 L3 (M+H) was obtained as a by-product in the synthesis of 2~cyclopropyl~6- [2-metliyl-4-(2-metiiyl-p^T:idin-4--ylethynyl) -imidazol- 1-yi] -pyridine (57) due to n-butyllithium impurities in the cyclopropylzinc chloride solution. Example 6: 2-ButyI-5-[2-metkyI-4-(2-m pyridine (66) 10 The title compound, MS: m/e = 331.1 (M+H+) was obtained as a by-product in the synthesis of2-qrclopropyl-5-[2-methyl-4-(2-metiiyl-pyTidin-4-ylethynyl)-imidazol-l-yl]-pyridine (59) due to n-butyllithium impurities in the cyclopropylzinc chloride solution. Example?: 2-Methoxy-6-[2-metbyl-4-(2-methyl-pyridin-4-ylethynyl)-iim pyrazine (67) Example 10: 2-(2-Methoxy-etho:^)-6-[2-methyl-4^ imidaEol-l-ylj-pyrazine (86) The title compound, MS: m/e = 350.4 (M+H) was prepared by treatment of 100 mg 0.32 mmol) 2-chloro-6-[2-methyl~4-(2-metkyl-pyridin^ 1-yl]-pyrazine (27) with 3 equiv. of 2-methoxyethanol and 3 equiv. of sodium hydride in 5 ml of THF (lh> 50°C). The compound, after extraction with methylene chloride / water, was purified by chromatography. Yield: 45 mg (0.13 mmol, 40%). 2- (2-Methory-ethoxy)-6- [2-methyl-4-(2-methyl-p)Tidin-4-ylethynyl)-imidasol-l-yl] -pyridine (87) [MS: m/e = 349.3 (M+H+)] was prepared in analogy to the method as desC1-ibed above from 6-fluoro-2-[2-melhiyl"4-(2-melhyl-p)rridin-4-yleth)myl)-imidazol-l-yl]-pyridine(33). Example 11: 4-[l-(4-Huoro-phenyl)-2,5-dime&yl~lH-im pyridine (88) Diisopropylamine (0.260 mg, 2.6 mmol) was dissolved in 5 mL dry tetrahydrofurane, n-butyllithium (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) in 5 mL dry tetrahydro&rane was added at -78°C and stirring was continued for 45 min at this temperature. Methyl iodide (410 mg, 2.9 mmol) was added at -78°C and the reaction mixture was si owly warmed to RT. The reaction mixture was quenched by addition of 50 mL water and extracted three times with iiethylether (100 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The C1-ude product was purified by column chromatography on silica gel (methylenchloride/methanol 9:1) and the desired compound was obtained as a white solid (325 mg, 62%), MS: m/e = 306.4 (M+H+). 3-(4-Fluoro-phenyl)-2-methyl-5-(2-methyl-pyridin-4-ylelhynyl)-3H"imidazole-4-carb-aldehyde (89) [MS: m/e = 320.4 (M+)] was prepared in analogy to the method as above from 4-[l-(4-Fluoro-phenyl)-2-methyl-lH-imidazol-4-ylethynyl]-2-methyl-pyridine (1) and N,N~dimethyl-formamide. Preparation of the pharmaC6utical compositions: Example I: Tablets Tablets of the following composition are produC6d in a conventional manner: mg/Tablet Active ingredient 100 Powdered, lactose 95 White corn starch 35 P olynnylpyrrolidone 8 Na carboxymethylstarch 10 Magnesium stearate ' 2 Tablet weight 250 Example II: Tablets Tablets of the following composition are produC6d in a conventional manner: mg/Tablet Active ingredient 200 Powdered, lactose 100 White corn starch 64 Polyvinylpyrrolidone 12 Na carboxymethylstarch 20 Magnesium stearate 4 Tablet weight 400 Example III: Capsules Capsules of the following composition are produC6d: mg/Capsule Active ingredient 50 c-ystalline, lactose 60 Micro-oc-ystalline C6llulose 34 Talc 5 Magnesium stearate 1 Capsule fill weight 150 The active ingredient having a suitable particle size, the c-ystalline lactose and the mic-o c-ystalline C6llulose are homogeneously mixed with one another, sieved and i thereafter talc and magnesium stearate are admixed. The final mixture is filled into hard gelatine capsules of suitable size. CLAIMS 1. A hydrocarbon fluids container comprising: a pouch made of polymer lam inate having at least three layers comprising: an outer layer of a first; polyalkylene or a first oriented nylon; at least one inner layer of a second oriented nylon or aluminum with the proviso that when the outer layer is a first polyalkylene the at least one inner layer is an oriented nylion; and an inside layer of a second polyalkylene; and a rigid outer box having one or more feces; wherein the pouch is disposed wi:hin the rigid box. 2. The container according to claim 1 further comprising a valve or a quill affixed to the pouch and extending outwardly therefrom and a valve opening in a face of the box.. 3 r The container according to claim 2 wherein the valve opening is located on the top fe.ce of the box where the pouch is placed inside the box: 4. The container according to any one of claims 1-3 wherein the box is made of a cellulosic material 5. The container according to any one of claims 1-4 wherein the box is made of cardboard. 6. The container according to claim !5 wherein the cardboard is coated with a fire retardant and/or water-repellant 7. The container according to any of claims 1-7 wherein the first polyalkylene is selected from the group of cast polypropylene linear low density polyethylene, low density polyethylene, ultra low density po lyethylene, high density polyethylene, polyethylene, polyethylene terephthalate, oriented and cross larpinated high density polyethylene and ethylene vinyl alcohol-linear (or density polyethylene copolymer. 8. The container according to any of claims 1-S wherein the second polyalkylene is selected from the group of cast polypropylene linear low density polyethylene, low density polyethylene, ultra low density polyethylene, high density polyethylene, polyethylene, polyethylene terephlhalate, oriented and cross laminated high density polyethylene and ethylene vinyl aJ cohol-linear (or density polyethylene copolymer. 9. The container according to any of claims 1-9 wherein the oriented nylon is selected from the'group of uniaxially oriented nylon and biaxially oriented nylon. 10. The container accordingto any one of claims 1-10 where the total laminate thickness is from 15 microns to 260 microns,, the first layer is between 5:and 225 microns thick; the inner oriented nylon layer is between 50 and 250 microns thick, the third layer is between 5 and 225 microns thick;, and the aluminum layer is between 0.0001 and 0.00070 inches thick 11. The container according to claim 1 wherein the container comprises an additional inner layer of an ethylene vinyl alcohol polymer layer. [" 12. A hydrocarbon fluids container comprising: [ a pouch of oriented and crosfi laminated high density polyethylene; and a rigid box having at least onu fece, wherein the pouch is disposed within the rigid box. 13. The container according to claim 12 wherein the flexible bag is between 50 to 200 microns thick. 14. The container according to claim 12 or 13 further comprising a valve affixed to the pouch and extending outwardly tkercfrom. 15. The container according to claim 14 further comprising a valve opening in a face of the box. 16. The container according to any o ne of claims 14 wherein the valve opening is located on the top face of lie box where the pouch is placed inside the box. wherein R1 has the meaning as defined above. 12. A pharmaceutical composition, in particular for use as an anxiolytic comprising a compound according to any one of claims 1 to 9 and a therapeutically inert carrier, 13. The use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment and prevention of mGluR5 receptor mediated disorders, in particular anxiety. 14. A method for the treatment or prevention of a disease or condition in which metabo-tropic glutamate receptor subtype 5 activation plays a role or is implicated comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to claim 1.

Full Text

Imidazol-4-yl-ethynvl-pyridine derivatives
The present invention relates to novel imidazole derivatives, to proC6sses for their production their use as pharmaC6uticals and to pharmaC6utical compositions comprising them.
More particularly the present invention provides in a first aspect novel 4-[l-aryl and 1-heteroaryl-imidazol-4-ylethynyl]-2-alkyl-p'5Tidine derivatives as well as pharmaC6utical^ acC6ptable salts thereof.
More particularly the present invention provides a compound of formula I
wherein
R1 is C1-C6alkyl;
R2 is C1-C6alkyl or C5-C12cycloalkyl;
R3 is aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted by one, two or three substituents selected from halogen, Q-C6alkyl, S-C1~C6alkyl, C1-C6alkyl-halogen, C1-C6alkoxy, halogen-C1-C6alkoxy, Cs-Cncycloalkyl, C2~ Cnheterocycloalkyl, Q-C6alkylamino, di-C1-C6alkylamino, C1-C6alkoxyamino, (Q-C6alko^C1-C6alkylamino, C3-C12cycloalkylamino, benzylamino and cyano; and
R4 is hydrogen, C(0)H or CH2R5 wherein R5 is hydrogen, OH, Q-C6alkyl or C3-C12cycloalkyk
In one embodiment the present invention provides a compound of formula Ist

(I*)
wherein
R1 signifies lower alkyl;
R signifies lower alkyl;
R signifies aryi 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 pharmaC6utically acC6ptable salts thereof.
It has now surprisingly been found that the compounds of general formula I are metabo-tropic glutamate reC6ptor 5 antagonists. Compounds of formula I are distinguished by having valuable therapeutic properties. They can be used in the treatment or prevention of mGluR5 reC6ptor mediated disorders.
In the C6ntral nervous system (CNS) the transmission of stimuli takes plaC6 by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreC6ptor.
Glutamate is the major exC1tatory neurotransmitter in the brain and plays a unique role in a. variety of C6ntral nervous system (CNS) functions. The glutamate-dependent stimulus reC6ptors are divided into two main groups. The first main group, namely the ionotropic reC6ptors, forms ligand-controlled ion channels. The metabotropic glutamate reC6ptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein coupled reC6ptors.
At present, eight different members of these mGluR are known and of these some even have sub-types. According to their sequenC6 homology, signal transduction mechanisms and agonist selectivity, these eight reC6ptors can be sub-divided into three sub-groups:
mGluRl and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluRS belong to group III.
Ligands of metabotropic glutamate reC6ptors 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 defiC1ts, as well as chronic and acute pain.
Other 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, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-defiC1ency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinenC6, drug abuse/dependanC6 such as nicotine addiction, opiate addiction, and alcohol abuse, anxiety, vomiting, dyskinesia and depressions.
Disorders mediated full or in part by mGluR5 are for example acute, traumatic and chronic degenerative proC6sses 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 espeC1ally useful for the treatment of anxiety and pain.
Objects of the present invention are compounds of formula I and their pharmaC6utically acC6ptable salts, the above-mentioned compounds as pharmaC6utically active substanC6s and their production. Further objects of the invention are medicaments based on a compound in accordanC6 with the invention and their manufacture as well as the use of the compounds in the control or prevention of mGluR5 reC6ptor mediated disorders, and, respectively, for the production of corresponding medicaments.
The following definitions of general terms used in the present desC1-iption apply irrespective of whether the terms in question appear alone or in combination. The term "lower alkyl11 used in the present desC1-iption 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 „cycloaIkyl" used in the present desC1-iption denotes cyclic saturated hydrocarbon residues "with 3 to 12 carbon atoms. Examples for cycloallcyl include cyclopropyl, cyclobutyl and cyclopentyl.
Examples for Q-C6alkoxy include methoxy, methoxyethyl and methoxyethoxy. Examples for halogenmethoxy include trifluoromethoxy.

Examples for C2-Cnheterocycloalkyl include pyrrolidinyl, morpholinyl and thiomorpho-linyl.
Examples for C1-C6alkylamino include methylamino and ethylamino. Examples for di-C1-C6alkylamino include dimethylamino. Examples for Q-Csalkoxyamino include methoxy-ethylamino. Examples for (C1-C6alkoxy)C1-C6aIkylamino include (methoxyethyl)methyl-amino. Examples for methoxycycloalkylamino include cyclopropylamino.
The term "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 include phenyl. Examples for substituted aryl include fluorophenyl, difluorophenyl, chloro-phenyl, dichlorophenyi, chlorofluorophenyl, cyanophenyl, methylphenyl, methoxyphenyl, fluoromethylphenyl, trifluoromethylphenyl and trifluoromethoxyphenyl.
The term "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. Examples of such heteroaryl groups are p}Timidinyl, pyrazinyl, p)T:ida2iinyl, pyridinyl and indolyl, e.g. pyridin-4-yl, pyridin-2-yl, pyrazin-2-yl and pyrimidin-2-yl. Examples for substituted heteroaryl include methylpyrimidinyl, dimefhylp^imidinyl, trifluoromethylpyri-midinyl, methoxypyrimidinyl, methoxyethoxypyrimidinyl, ethylpyrimidinyl, fluoropyri-midinyl, chloropyrimidinyl, bromopyrimidinyl, methylsulfanylimidinyl? cyclopropyl-pyrimidinyl, methylpyrasinyl, cydopropylpyrazinyl, chloropyrazinyl, methoxypyrasinyl, methoxypyrazinyl, methylaminopyrazinyl, dimethylaminopyrazinyl, q^clopropyl-aminopyrazinyl, morpholinylpyrazinyl, fluoropyridinyl, chloropyridinyl, bromopyridinyl, iodopyridinyl, methylpyridinyl, trifluoromethylpyridinyl, Mfluoromethylmethylpyridinyl, cyclopropylpyridinyl, butylp)nridinyl, methoxypyridinyl, dimethylaminoppridinyl, methyl-aminopyridinyl, eth}daminopyridinyl, pyrrolidinylpyridinyl, morpholinylpyridinyl, thio-morpholinylpyridinyl, (methoxyethyl)methylaminopyridinyl, methoxyethylaminopyri-dinyl, benzylaminopyridinyl and methyl-IH-indolyl.
The term "pharmaC6utically acC6ptable salt" refers to any salt derived from an inorganic or organic aC1d.
"PharmaC6utically acC6ptable salts" of a compound means salts that are pharmaC6utically acC6ptable, 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 acd. If possible, compounds of formula I maybe converted into pharmaC6utically acC6ptable salts.
It should be understood that all referenC6s to pharmaC6utically acC6ptable salts include solvent addition forms (solvates) or c-ystal forms (polymorphs) of the same acd addition salt.
Examples for pharmaC6utically acC6ptable acd addition salts include acd addition salts formed with inorganic acds such as hydrochloric acd, hydrobromic acd, sulfuric acd, nitric acd, phosphoric acd, and the like; or formed with organic acds such as aC6tic acd, benzenesulfonic a cid, benzoic, camphorsulfonic acd, ctric acd, ethanesulfonic acd, fumaric acid, glucoheptonic acd, gluconic acid, glutamic acd, glycolic acd, hydroxynaph-thoic acd, 2-hydroxyethanesulfonic acd, lactic acd, maleic acd, malic acd, mandelic acid, methanesulfonic acd, muconic acd, 2-naphthalenesulfonic acd, propionic acd, salicylic acd, succnic acd, dibenzoyH-tartaric acd, tartaric acd, p-toluene-sulfonic acd, trimethylaC6tic acd, trifluoroaC6tic acd, and the like.
Preferred compounds of formula I* are those, in which R and R are both methyl.
Especally preferred are those compounds from this group, in which R is substituted phenyl, wherein the substitution is fluoro, chloro, cyano or CF3.
The following are examples of compounds, wherein the substitution is fluoro or chloro:
4- [ 1 - (4-fluoro-phenyl) -2-methyl- lH-imidazol-4-ylethynyl] -2-methyl-pyridine»
4- [ 1 - (3,4-dichloro-phenyl) -2-mefhyl- lH4midazol-4-ylethynyl] -2-methyl-pyridine, HCl
4-[ 1 -(2,4-difiuoro-phenyl)-2-methyl-lH-imidazol-4-ylethynyl] -2-methyl-pyridine, or
4-[l-(3,4-difiuoro-phenyl)-2-methyl^
Examples of compounds, wherein the substitution is cyano, are as follows: 4- [2-methyl-4-(2-methyl-p)rridin-4-ylethynyl) -imidazol-1 -yl] -benzonitrile, or 3- [2-methyl-4-(2-methyl-pyridin-4-ylethynyl) -imidazol-1 -yl] -benzonitrile.,
The following is an example of compounds, wherein the substitution is CF3: 2-methyl-4- [2-methyl-1 - (3-trifluoromethyl-phenyl) - lH-imidazol-4-ylethynyl]-pyridine.
Especally preferred are further those compounds, wherein R and R2 are both methyl and R is pyrimidinyl, for example the following compound: 2- [2-methyl-4- (2-methyl-pyridin-4-ylethynyl) -imidazol-1 -yl] -pyrimidine.

(c) a compound of formula VI
(VI)
wherein R , R and R have the meanings as defined above and hal is halogen, with a compound of formula VII
(VII)
wherein R1 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 lilce 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, (Ph3P)2PdCl2> Et3N in a solvent like tetrahydrofuran or dimethylformamide [Sonogashira et al., Synthesis 777 (1977)]. In one embodiment 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, (Ph3P)2PdCl2, Et3N, n-Bu4 F in a solvent like tetrahydrofuran or dimethylformamide.
The salt forms are made by standard procedures known to the skilled artisan.
The compounds of formulae II, IV, VI und VII are novel and also an embodiment 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 may be prepared by reacting a compound of formula VIII

(VIII)
wherein R2 and R4 have the above meanings and hal is halogen, with a compound of formula VII as above.
The compounds of formula VIII maybe prepared as desC1-ibed e.g. in Cliff and Pyne [Synthesis 681-682 (1994)].
The compounds of formula IV may be prepared by reacting a compound of formula IX
(IX)
wherein R , R and R have the meanings as defined above,
with dimethyl (l-diazo-2-oxopropyl)phosphonate as desC1-ibed in Ohira [Synth.Comm.
19:561-564(1989)].
Compounds of formula VI maybe prepared by reacting a compound of formula VIII as above with a compound of formula X
R3-B(OH)2 (X)
wherein R"1 has the meanings as defined above.
The reaction may take plaC6 by arylation of a compound of formula VIII using an aromatic boronic aC1d (compound of formula X) and a copper catalyst in a solvent like dichloromethane or tetrahydrofarane under an oxygen atmosphere [see e.g. Colmann et aL, Org.Lett. 2:1233 (2000)].
Compounds of formula VII may be prepared by reacting a compound of formula V as above with a compound of formula XI
Y^ (XI)
The reaction may take plaC6 by a Sonogashira coupling in the presenC6 of eg. Cul, (PhaP)2PdCl2 Et3N in a solvent like tetrahydrofiiran or dimethylformamide [Sonogashira et aL, Synthesis 777 (1977)].
Compounds of formula IX may be prepared by oxidizing a compound of formula XII

(XII)
according to methods known to the skilled artisan.
Compounds of formula XII may be prepared by deprotecting a compound of formula XIII
(XIII)
i according to methods known to the skilled artisan.
Compounds of formula XIII may be prepared by alkylating a compound of formula XIV
(XIV)
with an alkylating agent of formula XVa
R2-hal (XVa)
according to methods known to the skilled artisan-Starting compounds of formula XVa are commerC1ally available. Compounds of formula XIV maybe prepared by treating a compound of formula XV
(XV)
with tert.-butyl dimethyl silyl chloride according to methods known to the skilled artisan. Compounds of formula XV may be prepared by treating a compound of formula XVI

(XVI)
with a reduC1ng agent according to methods known to the skilled artisan.
Compounds of formula XVI may be prepared by hydrolysing a compound of formula. XVII
(XVII)
according to methods known to the skilled artisan.
Compounds of formula XVII may be prepared by treating a compound of formula XVIII
R3-NH2 (xvni)
with e.g. triethyl orthoformate, ethylnitro aC6tate, glaC1al aC6tic aC1d and iron powder according to methods known to the skilled artisan.
Compounds of formula XVIII are commerC1ally available.
The compounds of general formula I* and their pharmaC6utically acC6ptable salts can be manufactured by two general proC6dures, which proC6dures are outlined below for compounds wherein R1 is methyl and R2 is methyl, but which proC6dures are applicable for all compounds according to Formula I*.

I wherein R is methyl and R2 is methyl (R3 and R1 are designated Ar and Ai?, respectively, in Scheme 2).
Moreover the invention relates also medicaments containing one or more compounds of the present invention and pharmaC6utically acC6ptable exC1pients for the treatment and. prevention of mGluR5 reC6ptor 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 accordanC6 with the present invention as well as its pharmaC6utically acC6ptable salt for the manufacture of medicaments for the treatment and prevention of mGluRS reC6ptor mediated disorders as outlined above.
PharmaC6utically acC6ptable 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 aC1ds such as, e.g., hydrochloric aC1d, hydrobromic aC1d, sulphuric aC1d, nitric aC1d, phosphoric aC1d or C1tric aC1d, formic aC1d, fumaric aC1d, maleic aC1d, aC6tic aC1d, sucC1nic aC1d, tartaric aC1d, methanesulphonic aC1d, p-toluenesulphonic aC1d and the like are suitable for the formation of pharmaC6utically acC6ptable salts of basic compounds of formula I. Compounds which contain the alkali metals or alkaline earth metals, for example sodium, potassium, calC1um, magnesium or the like, basic amines or basic amino aC1ds are suitable for the formation of pharmaC6utically acC6ptable salts of aC1dic compounds.
The compounds of formula I and their pharmaC6utically acC6ptable salts (hereinafter: PharmaC6utical Compounds) are, as already mentioned above, metabotropic glutamate reC6ptor antagonists and can be used for the treatment or prevention of mGluRS reC6ptor mediated disorders, such as acute and/or chronic neurological disorders, cognitive disorders and memory defiC1ts, as well as acute and chronic pain. Treatable neurological disorders are for instanC6 epilepsy, schizophrenia, anxiety, acute, traumatic or chronic degenerative proC6sses of the nervous system, such as Alzheimer's disease, senile dementia, Huntington's chorea, ALS, multiple sclerosis, dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-defiC1ent functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinenC6, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, dyskinesia and depression. Other treatable indications 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 hypoglyC6mia.

PharmaC6utical Compounds are espeC1ally useful as analgesics. 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, hyperalgesia, severe chronic pain, post-operative pain and pain assoC1ated with various conditions like canC6r, angina, renal or bifliay colic, menstruation, migraine and gout.
The pharmacological activity of PharmaC6utical Compounds was tested using the following method:
For binding experiments, cDNA encoding human mGlu 5a reC6ptor was transiently trans-fected into EBNA C6lls using a proC6dure desC1-ibed by Schlaeger and Christensen [Cyto-technology 15:1-13 (1998)]. C6ll 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 CaCl2, 25 mM MgCl2 binding buffer at pH
7.4 to a final assay conC6ntration of 20 \ig protein/ well.
Saturation isotherms were determined by addition of twelve [ H]MPEP conC6ntrations (0.04-100 nM) to these membranes (in a total volume of 200 \xl) for 1 h at 4°C. Compe-tition experiments were performed with a feed conC6ntration of [TijMPEP (2nM) and IC50 values of test compounds evaluated using 11 conC6ntrations (0.3-10,000nM). Incubations were performed for 1 h at 4° C.
At the end of the incubation, membranes were filtered onto unifilter (96-well white miC1-o-plate with bonded GF/C filter preincubated 1 h in 0.1% PEI in wash buffer, Packard Bio-SC1enC6, Meriden, CT) with a Filtermate 96 harvester (Packard BioSC1enC6) and washed 3 times with cold 50 mM Tris-HCl, pH 7.4 buffer. NonspeC1fic binding was measured in the
presenC6 of 10 μM MPEP. The radioactivity on the filter was counted (3 min) on a Packard Top-count miC1-oplate sC1ntillation counter with quenching correction after addition of 45 μ-1 of miC1-osC1nt 40 (Canberra Packard S.A., Zurich, Switzerland) and shaking for 20 min.
For functional assays, [Ca2+]i measurements were performed as desC1-ibed previously by Porter et al. [Br. J. Pharmacol. 128:13-20 (1999)] on recombinant human mGlu 5a reC6ptors in HEK-293 C6lls. The C6lls were dye loaded using Fluo 4-AM (obtainable by
FLUKA, 0.2j-iM final conC6ntration). [Ca ]i measurements were performed using a ' fluorometric imaging plate reader (FLIPR, Molecular DeviC6s Corporation, La Jolla, CA, USA). Antagonist evaluation was performed following a 5 min preincubation with the test compounds followed by the addition of a submaximal addition of agonist.

The inhibition (antagonists) curves were fitted with a four parameter logistic equation giving IC5o, and Hill coeffiC1ent using an iterative non linear curve fitting software (XC6l
at).
For binding experiments the Ki values of the compounds tested are given. The Ki value is defined by the following formula:
Ki = IC50 / [l + L/Kd]
in which the IC50 values are those conC6ntrations of the compounds tested which cause 50 % inhibition of the competing radioligand ([ H]MPEP). L is the conC6ntration of radioligand used in the binding experiment and the Kd value of the radioligand is empirically determined for each batch of membranes prepared.
PharmaC6utical Compounds are mGluR 5a reC6ptor antagonists. The activities of PharmaC6utical Compounds as measured in the assay desC1-ibed above are in the range of Ki Activity data

Activity speC1fically as anxiolytic agents maybe demonstrated in acordanC6 with standard test methods, e.g. as desC1-ibed in the Vogel conflict drinking test [see e.g. review of Mfllan, Progress in Neurobiology 70:83-244 (2003)]:
The Vogel conflict drinking test is a proC6dure that has been widely used as a sC1-eening method for anxiolytics. In this proC6dure, the water intake of thirsty rats is measured under conditions where water intake is suppressed by electric shock. In our version of the test, 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. On the third -test - day, they are allowed to lick again from a drinking spout for 10 min, but now they reC6ive a 0.5 mA electric stimulus for 0.5 sec every sec that they lick (counted as an interruption of an infrared beam in front of the spout). The electric stimulus suppresses the time that the animals spend drinking, and treatment with PharmaC6utical Compounds partially or completely reinstates normal drinking duration.
PharmaC6utical Compounds can be used as medicaments, e.g. in the form of pharmaC6utical preparations. The pharmaC6utical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
PharmaC6utical Compounds can be proC6ssed with pharmaC6utically inert, inorganic or organic carriers for the production of pharmaC6utical preparations. Lactose, corn starch or derivatives thereof, talc, stearic aC1d 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 substanC6 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, suC1-ose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glyC6rol, 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 neC6ssary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
In addition, the pharmaC6utical 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 substanC6s.
As mentioned earlier, medicaments containing a PharmaC6utical Compound and a therapeutically inert exC1pient are also an object of the present invention, as is a proC6ss for the production of such medicaments which comprises bringing one or more PharmaC6utical Compound and, if desired, one or more other therapeutically valuable substanC6s 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. In general, 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 desC1-ibed. The daily dosage for an adult human being weighing 70 kg accordingly lies between 0.7-1400 mg per day, preferably between 7 and 700 mg per day.
The following examples are provided to further eluC1date the invention:
Preparation of the starting compounds
Example II-1: 2-Methyl-4-(2-methyl-lH-imidazol-4-ylethynyl)-pyridine (II-1)
Method Al:
Step 1: 2-Methyl-l-(2-trimethylsfo and
2-methyl-3-(2-1ximethylsilanyl-ethoxyTnethyl)-3H-imidazole-4-carbaldehyde
A solution of 2-methyl-lH-imidazol-4-carbaldehyde (5.0 g, 45 mmol) in 125 mL dry DMF
was added dropwise at 0°C to suspension of sodium hydride (1.98 g, 45 mmol) in dry
DMF. The reaction mixture was stirred at RT for 2h. A solution of 2-(trimethylsilyl)eth-
oxymefhyl chloride (7.97 g, 45 mmol) in 50 mL dry THF was added dropwise at 0°C. The
reaction mixture was stirred at RT overnight. Water (100 mL) was added carefully and the
solvents were evaporated. The residue was taken up in 150 mL water and extracted three
times with ethyl aC6tate (150 mL each). The combined organic extracts were dried with
sodium sulfate, filtered and evaporated. The C1-ude product (mixture of 2 isomers, 12.5 g)
was used without any farther purification for the next step, MS: m/e = 241.2 (M+H+).
Step 2:4-Ethynyl-2~methyl-l-(2-trimethyls^ and 5-
etliynyl-2-methyl-l-(2-1ximethylsilanyl-ethoxjrmethyl)-lH-imidazole (l-Diazo-2-oxo-propyl)-phosphonic aC1d dimethyl ester (10.4 g, 54 mmol) was dissolved in 150 mL methanol. Potassium carbonate (12.6 g, 90 mmol) was added. A solution of C1-ude 2-methyl-l-(2-trimethylsilanyl-ethox)miethyl)-lH-imidazole-4-carbaldehyde and 2-metiyl-3-(2-trimethylsilanyl-ethox5naeth.yl)-3H-imidazole-4-carbaldehyde (45 mmol) in 150 mmol methanol was added dropwise at RT. The reaction mixture was stirred at RT overnight. The solvent was evaporated. The residue was taken up in 150 mL water and extracted three times with ethyl aC6tate (150 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The C1-ude product was purified by column chromatography on silica gel (qclohexane / ethyl aC6tate 1:1) and the desired compound was obtained as a mixture of 2 isomers (8.36 g, 78%), MS: m/e = 237.0 (M+H+).

2-Hydroxy-5-methylpyrazine (0.984g> 8.94 mmol) was refluxed in 15 ml pftospnoroxy-chloride fox 1.5h. The reaction mixture was slowly poured into iC6 and adjusted to pH6 by addition of sodium carbonate. The mixture was extracted six times with ethyl aC6tate (50 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The C1-ude product was used without any further purification for the next step.
Example III-2: 4-Chloro-2-trifluoromethyl-pyrimidine (III-2)
This compound was prepared according to Inoue et al., J. Org. Chem. 26:4504 (1961).
Example III-3; 2-Bromo-6-fluoro-pyridine (III-3)
This compound was prepared according to WO 92/11,241.
Example IV-1: 4-Ethynyl-l-(4-fluoro-phenyl)-2-methyl-lH-iinidazole (TV-1)
Step 1: l-(4-Fluoro-phenyl)-lH-imidazole-4-carboxylk aC1d ethyl ester 4-Fluoroaniline (20.0 g, 175 mmol) was mixted at RT with triethyl orthoformate (35,4 g, 233 mmol), ethylnitro aC6tate (28.5 g, 210 mmol) and 4 mL glaC1al aC6tic aC1d. The reaction mixture was refluxed with mechanical stirring for 2h. More triethyl orthoformate (200 mL) and glaC1al aC6tic aC1d (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. Ethyl aC6tate (700 mL) was added and reflux was continued for another 2h. The reaction mixture was filtered through a dicalite speed plus pad and washed with 500 mL ethyl aC6tate. The solvents were evaporated and the C1-ude product was used without any further purification for the next step.
Step 2: l-(4-Fluoro-phenyl)-lH-imidazole-4-carbox)?lic aC1d
C1-ude l-(4-fiuoro-phenyl)-lH-imidaz;ole-4-carboxylic aC1d ethyl ester (175 mmol) was dissolved in 450 mL dioxane and 450 mL 2N sodium hydroxide solution. The reaction mixture was refluxed for 2h. Charcoal (1 g, Norit SAII) was added and reflux was continued for another 20 min. The mixture was filtered hot and washed with. 50 mL 2N sodium hydroxide solution. The filtrate was treated with 550 mL 2N HC1 and stirred at RT overnight. The solid material was filtered off and dried at 50°C and 15 mbar. The desired compound was obtained as an off-white solid (28 g, 78%)> MS: m/e = 205.1 (M-H). Step 3: [l-(4-Fluoro-phenyl)-lH-imidazol-4-yl]-methanol ) l-(4-Pluoro-phenyl)-lH-imidazole-4-carboxylic aC1d (18 g, 87 mmol) was dissolved in 90 mL dry THF. Borane tetrahydrofuran complex (174 mL, 1M in THE, 174 mmol) was added dropwise. The reaction was refluxed for 2h and stirred at RT overnight. The reaction mixture was cooled to 0°C and 100 mL methanol were added dropwise. The solvents

were evaporated. The residue was taken up in 100 mL 2N HC1 and refiuxed for 2h. The reaction mixture was then cooled to 0°C and 120 mL 2N sodium hydroxide solution were added dropwise. The solid material was filtered off and dried at 50°C and 15 mbar. The desired compound was obtained as a white solid (13 g, 78%), MS: m/e = 193.2 (M+H)+. Stei^4-(tert-Butyl-dimethyl-sik^
[l-(4-Fluoro-phen7l)-lH-imidazol-4-7l]-methanol (13 g, 67.5 mmol) was dissolved 65 mL DMF. Imidazole (11 g, 162 mmol) and tert. butyldimethyl chlorosilane (12.2 g, 81 mmol) were added. The reaction mixture was stirred at 45°C overnight and poured into 500 mL water. The aqueous phase was extracted three times with ethyl aC6tate (200 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The C1-ude product was purified by column chromatography on silica gel (methylene chloride / methanol 98:2) and the desired compound was obtained as a light brown oil (20 g, 96%), MS: m/e = 291.2 (M-CH3)> m/e = 249.1 (M-tert. butyl). Step 5:4-(tert-ButyI-dimetfayl^ imidazole
4-(tert-Butyl-dimethyl-silanyloxjTn^^ (18.2 g, 59.2
mmol) was dissolved in 600 mL dry THF and cooled to -78°C. n- Butyl lithium (55.5 mL, 1.6M in hexane, 88.8 mmol) was added dropwise. The reaction mixture was warmed up to -25°C, kept at -25°C for lOmin and then cooled again to -78°C. Iodomethane (7.4 mL, 11.9 mmol) was added dropwise. The reaction mixture was slowly warmed up to RT and stirred at RT overnight The solvent was evaporated. The residue was taken up in 300 mL water and extracted three times with ethyl aC6tate (200 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The C1-ude product
was purified by column chromatography on silica gel (cyclohexane / ethyl aC6tate 50:50 ->
20:80 gradient) and the desired compound was obtained as an orange oil (14.7 g, 77%)>
MS: m/e = 321.1 (M+H+).
Step 6: [l-(4-Fluoro-phenyl)-2-methyl-lH-imidazol-4-yl] -methanol
4-(tert-Butyl-dimethyl-silanyloxy^
(14.7 g, 45.7 mmol) was dissolved in 200 mL THF. Tetrabutyl ammoniumfluoride (91 mL,
1M 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 aC6tate (200 mL each). The combined organic extracts were dried with
magnesium sulfate, filtered and evaporated. The C1-ude product was suspended in 150 mL
ethyl aC6tate, filtered and dried. The desired compound was obtained as a white solid (7.16
g, 76%), MS: m/e = 207.1 (M+H+).
Step 7: l-(4-Fluoro-phenyl)-2-methyl-lH-imidazole-4-carbaldehyde

[l-(4-Fluoro-phenyl)-2-methyl-lH-imidazol-4-yl] -methanol (7.16 g, 34.7 mmol) was dissolved in 2.3 L methylene chloride. Mangan (IV) oxid (26.8 g5 278 mmol) was added and the reaction mixture was stirred at RT for 3 days. The suspension was filtered through a dicalite speed plus pad and washed with 1L methylene chloride. The solvents were evaporated and the desired compound was obtained as a white solid (5.87 g, 83%), MS: m/e = 205.1 (M+H*).
Step 8:4-Ethynyl-1 - (4-fluoro-phenyl) -2-methyl- lH-imidazole
(l-Diazo-2-oxo-propyi)-phosphonic aC1d dimethyl ester (6.51 g3 33.9 mmol) was dissolved in 100 mL methanol. Potassium carbonate (7.81 g5 56.5 mmol) was added. A solution of !-(4-fluoro-phenyl)-2-methyl-lH-imidazoIe-4-carbaldehyde (5.77 g, 45 mmol) in 100 mmol methanol was added dropwise at RT. The reaction mixture was stirred at RT overnight. The solvent was evaporated. The residue was taken up in 150 mL water and extracted three times with ethyl aC6tate (150 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The C1-ude product was purified by flash
chromatography on silica gel (heptane / ethyl aC6tate 100:0 -> 0:100 gradient) and the desired compound was obtained as a white solid (3.81 g, 67%), MS: m/e = 200.1 (M"*").
lK3>4-Dichloro-phenyl)'4-eth)myl-2-methyl-lH-imida2ole (IV-2) [MS: m/e = 252.1 (M+)] was prepared in accordanC6 with the method of example IV-1 from 3,4-dichloroaniline.
Example V-1: 2-Cyclopropyl-1-(4-fluoro-phenyl)-4-iodo-iH-imidasole (V-1)
Stepjj: 2-Cyclopropyl-4)5-diiodo- IH-imidazole
2-Cyclopropyl-lH-imidazole (2500 mg, 23.12 mmol) was suspended in 46 ml 2N NaOH.
A solution of iodine (11.74 g, 46.23 mmol) in 45 ml dichloromethane was added dropwise
to the suspension within 15 min. The two-layer-mixture was stirred vigorously at RT over
night. The aqueous layer was separated, neutralized with aC6tic aC1d and saturated
Na2S203-solution was added until the solution remained colorless. The suspension was
stirred for 10 min, filtered and the solid was dried over night at 50°C under reduC6d
pressure (
42%).
Step 2: 2-Cyclopropyl-4-iodo-lH-imidazole
Na2S03 (10.42 g, 82.65 mmol) was suspended in 40 ml water and 20 ml ethanol. 2-Cyclo-
propyl-4,5-diiodo-lH-imidazole (3500 mg, 9.72 mmol) was added and the mixture was
stirred at reflux for 16 hours. The reaction mixture was conC6ntrated to 20 ml and then

filtered. The solid was dried for 5 hours at 50°C under reduC6d pressure ( 2-Cyclopropyl-4~iodo-lH-imidazole (500 mg, 2.14 mmol) was dissolved in 20 ml THF. 4-Fluorobenzeneboronic aC1d (613 mg, 4.38 mmol) and [Cu(OH)TMEDA]2Cl2 (347 mg, 0.75 mmol) were added Oxygen was bubbled through the reaction mixture for 60 min and stirring was continued under an oxygen atmosphere at RT overnight. The reaction mixture was filtered through a dicalite speed plus pad and washed with 30 mL ethyl aC6tate. After drying the C1-ude product was purified by flash chromatography on silica gel (heptane / ethyl aC6tate 90:10 -> 50:50 gradient) to get the desired compound as a white solid (320 mg, 46%), MS: m/e = 329.1 (M+H+).
Preparation of the compounds of formula I
Example 1: 4- [ 1 - (4-Fluoro-phenyl)-2-methyl- lH-imidazol-4-ylethynyl] -2-methyl-pyridine (1)
Method A:
2-Methyl-4-(2-methyl-lH-irnidazol-4-yleth)rnyl)-p}T:idine (II-l) (200 mg, 1.01 mmol) was dissolved in 10 mL dichloromethane. Powdered molecular sieves (3 A, 200 mg), 4-fluoro-benzene boronic aC1d (284 mg, 2.02 mmol) and [Cu(OH)TMEDA]2Cl2 (47 mg, 0.10 mmol) were added. Oxygen was bubbled through the reaction mixture for 5 min and stirring was continued at RT overnight. The reaction mixture was filtered through a dicalite speed plus pad and washed with 50 mL dichloromethane. The filtrate was washed with 50 ml water, dried with magnesium sulfate, filtered and evaporated. The C1-ude product was purified by flash chromatography on silica gel (dichloromethane / methanol
100:0 -> 85:15 gradient) and a mixture of 2 regioisomers was isolated. The desired compound was obtained by reC1-ystallization from diethylether as a white solid (151 mg, 51%), mp ^ 151°C, MS: m/e = 292.1 (M+H*).
Method B:
4-Iodo-2-methyl-pyridine (656 mg, 3.0 mmol) was dissolved in 10 mL dry THF and 10 mL piperidine. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (20 mg, 0.07 mmol) and bis(triphenyl-phosphin)palladium(II)chloride (175 mg, 0.10 mmol) were added and the reaction mixture was stirred at RT for Ih. Copper(I)iodide (14 mg, 0.07 mmol) and 4-ethynyl-l-(4-fluoro-phenyl)-2-methyl-lH-hnidazole (IV-1) (500 mg, 2.5 mmol) were added. The reaction mixture was then refluxed for 3h. 'The solvent was evaporated. The residue was

taken up in 30 mL water and extracted three times "with ethyl aC6tate (50 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The C1-ude product was purified by flash chromatography on silica gel (dichloromethane / methanol 100:0 -» 90:10 gradient) and reC1-ystallization from diethylether and the desired 5 product was obtained as a light yellow solid (250 mg> 34%), mp = 151°C, MS: m/e = 292.1 (M+H+).
4-[l-(3>4-DicUoro-phenyl)-2-me
hydrochloride (2) [MS: m/e = 341.9 (M+H+)] was prepared in analogy to the mettod as desC1-ibed in Example 1 Method B starting from l-(3,4-dicHoro-phenyl)-4~ethynyl-2-) methyl-lH-imidazole (IV-2) and 4-iodo-2-methyl-pyridine. For further purification the compound was preC1pitated as its HC1 salt from an etheral solution.
Method C:
4-Iodo-2-methyl-lH-imidazoIe (200 mg, 1.0 mmol), 4-fluorophenylboronic aC1d (215 mg, L6 mmol), copper(II)aC6tate (210 mg, 1.2 mmol) and EtjN (0.16 ml, 1.2 mmol) were suspended in 10 ml THF and oxygen was bubbled through the reaction mixture for 40 min. The reaction mixture was stirred for 48 hours at RT and then filtrated over dicalit. The filtrate was conC6ntrated and then purified by flash chromatography to yield l-(4-fluoro-phenyl)-4~iodo-2~methyl-lH-imidazole (120 mg, 0.40 mmol, 41 %).
A solution of l-(4-fluoro-phenyl)-4-iodo-2-methyl-lH-imidazole (5,0g, 17mmol) and 2-methyl»4-trimethylsilanyleth}myl-p}ddine (3.2 g, 17 mmol, prepared from 4-iodo-2-methyi pyridine and commerC1ally available eth)myl-trimethyl-silane in a Sonogashira reaction) in 15ml THF was transferred to a mixture of triphenylphosphine (88 mg, 0.34 mmol), bis(tri-phenylphosphin)palladium(II)chloride (705 mg, 1.0 mmol) and Et3N (3.5 ml. 25 mmol) in 80 ml THF. Copper(I)iodide (32 mg, 0.17 mmol) was added and the reaction mixture was heated under argon atmosphere to 40°C and a solution of tetrabutylammoniumfluoride (1 M in THF, 25.1 ml) was added over a period of 40 min. The reaction mixture was stirred for three hours at 40°C and then for 48 hours at RT. After aqueous work up and purification by chromatography over silica gel and C1-ystallization from ethylaC6tate and hexane the desired product was obtained as a light yellow solid (2.8 g, 57%, mp = 151°C, MS: m/e = 292.1 (M+H+)).
The following compounds were prepared in analogy to the method as desC1-ibed in the
above Method A:
Compound name and number Compound of MS: m/e I

I ... .,-1 1 . —»
* prepared according to De Lang and Brandsma, Synthetic Communications 28:225-232 (1998)
Example 5: 2-Butyl-6- [2-methyl-4-(2-metiiyl-pyridin-4-yIeliiyiiyl)-imidazol- 1-yl]-pyridine (65)
5 The title compound, MS: m/e = 33 L3 (M+H*) was obtained as a by-product in the synthesis of 2~cyclopropyl~6- [2-metliyl-4-(2-metiiyl-p^T:idin-4--ylethynyl) -imidazol- 1-yi] -pyridine (57) due to n-butyllithium impurities in the cyclopropylzinc chloride solution.
Example 6: 2-ButyI-5-[2-metkyI-4-(2-m pyridine (66)
10 The title compound, MS: m/e = 331.1 (M+H+) was obtained as a by-product in the synthesis of2-qrclopropyl-5-[2-methyl-4-(2-metiiyl-pyTidin-4-ylethynyl)-imidazol-l-yl]-pyridine (59) due to n-butyllithium impurities in the cyclopropylzinc chloride solution.
Example?: 2-Methoxy-6-[2-metbyl-4-(2-methyl-pyridin-4-ylethynyl)-iim pyrazine (67)

Example 10: 2-(2-Methoxy-etho:^)-6-[2-methyl-4^ imidaEol-l-ylj-pyrazine (86)
The title compound, MS: m/e = 350.4 (M+H*) was prepared by treatment of 100 mg 0.32
mmol) 2-chloro-6-[2-methyl~4-(2-metkyl-pyridin^ 1-yl]-pyrazine
(27) with 3 equiv. of 2-methoxyethanol and 3 equiv. of sodium hydride in 5 ml of THF (lh> 50°C). The compound, after extraction with methylene chloride / water, was purified by chromatography. Yield: 45 mg (0.13 mmol, 40%).
2- (2-Methory-ethoxy)-6- [2-methyl-4-(2-methyl-p)Tidin-4-ylethynyl)-imidasol-l-yl] -pyridine (87) [MS: m/e = 349.3 (M+H+)] was prepared in analogy to the method as desC1-ibed above from 6-fluoro-2-[2-melhiyl"4-(2-melhyl-p)rridin-4-yleth)myl)-imidazol-l-yl]-pyridine(33).
Example 11: 4-[l-(4-Huoro-phenyl)-2,5-dime&yl~lH-im pyridine (88)
Diisopropylamine (0.260 mg, 2.6 mmol) was dissolved in 5 mL dry tetrahydrofurane, n-butyllithium (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) in 5 mL dry tetrahydro&rane was added at -78°C and stirring was continued for 45 min at this temperature. Methyl iodide (410 mg, 2.9 mmol) was added at -78°C and the reaction mixture was si owly warmed to RT. The reaction mixture was quenched by addition of 50 mL water and extracted three times with

iiethylether (100 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The C1-ude product was purified by column chromatography on silica gel (methylenchloride/methanol 9:1) and the desired compound was obtained as a white solid (325 mg, 62%), MS: m/e = 306.4 (M+H+).
3-(4-Fluoro-phenyl)-2-methyl-5-(2-methyl-pyridin-4-ylelhynyl)-3H"imidazole-4-carb-aldehyde (89) [MS: m/e = 320.4 (M+)] was prepared in analogy to the method as above from 4-[l-(4-Fluoro-phenyl)-2-methyl-lH-imidazol-4-ylethynyl]-2-methyl-pyridine (1) and N,N~dimethyl-formamide.
Preparation of the pharmaC6utical compositions:
Example I: Tablets
Tablets of the following composition are produC6d in a conventional manner:
mg/Tablet
Active ingredient 100
Powdered, lactose 95
White corn starch 35
P olynnylpyrrolidone 8
Na carboxymethylstarch 10
Magnesium stearate ' 2
Tablet weight 250
Example II: Tablets
Tablets of the following composition are produC6d in a conventional manner:
mg/Tablet
Active ingredient 200
Powdered, lactose 100
White corn starch 64
Polyvinylpyrrolidone 12
Na carboxymethylstarch 20
Magnesium stearate 4
Tablet weight 400
Example III: Capsules
Capsules of the following composition are produC6d:

mg/Capsule
Active ingredient 50
c-ystalline, lactose 60
Micro-oc-ystalline C6llulose 34
Talc 5
Magnesium stearate 1
Capsule fill weight 150
The active ingredient having a suitable particle size, the c-ystalline lactose and the mic-o c-ystalline C6llulose are homogeneously mixed with one another, sieved and i thereafter talc and magnesium stearate are admixed. The final mixture is filled into hard gelatine capsules of suitable size.

CLAIMS
1. A hydrocarbon fluids container comprising:
a pouch made of polymer lam inate having at least three layers comprising: an outer layer of a first; polyalkylene or a first oriented nylon; at least one inner layer of a second oriented nylon or aluminum with the proviso that when the outer layer is a first polyalkylene the at least one inner layer is an oriented nylion; and an inside layer of a second polyalkylene; and a rigid outer box having one or more feces; wherein the pouch is disposed wi:hin the rigid box.
2. The container according to claim 1 further comprising a valve or a quill affixed to the
pouch and extending outwardly therefrom and a valve opening in a face of the box..
3 r The container according to claim 2 wherein the valve opening is located on the top fe.ce of the box where the pouch is placed inside the box:
4. The container according to any one of claims 1-3 wherein the box is made of a cellulosic material
5. The container according to any one of claims 1-4 wherein the box is made of cardboard.
6. The container according to claim !5 wherein the cardboard is coated with a fire retardant and/or water-repellant
7. The container according to any of claims 1-7 wherein the first polyalkylene is selected from the group of cast polypropylene linear low density polyethylene, low density polyethylene, ultra low density po lyethylene, high density polyethylene, polyethylene, polyethylene terephthalate, oriented and cross larpinated high density polyethylene and ethylene vinyl alcohol-linear (or density polyethylene copolymer.
8. The container according to any of claims 1-S wherein the second polyalkylene is selected from the group of cast polypropylene linear low density polyethylene, low density polyethylene, ultra low density polyethylene, high density polyethylene, polyethylene, polyethylene terephlhalate, oriented and cross laminated high density polyethylene and ethylene vinyl aJ cohol-linear (or density polyethylene copolymer.
9. The container according to any of claims 1-9 wherein the oriented nylon is selected from the'group of uniaxially oriented nylon and biaxially oriented nylon.

10. The container accordingto any one of claims 1-10 where the total laminate thickness is
from 15 microns to 260 microns,, the first layer is between 5:and 225 microns thick; the
inner oriented nylon layer is between 50 and 250 microns thick, the third layer is
between 5 and 225 microns thick;, and the aluminum layer is between 0.0001 and
0.00070 inches thick
11. The container according to claim 1 wherein the container comprises an additional inner
layer of an ethylene vinyl alcohol polymer layer.
[" 12. A hydrocarbon fluids container comprising:
[ a pouch of oriented and crosfi laminated high density polyethylene; and
a rigid box having at least onu fece, wherein the pouch is disposed within the rigid
box.
13. The container according to claim 12 wherein the flexible bag is between 50 to 200
microns thick.
14. The container according to claim 12 or 13 further comprising a valve affixed to the
pouch and extending outwardly tkercfrom.
15. The container according to claim 14 further comprising a valve opening in a face of the
box.
16. The container according to any o ne of claims 14 wherein the valve opening is located
on the top face of lie box where the pouch is placed inside the box.

wherein R1 has the meaning as defined above.
12. A pharmaceutical composition, in particular for use as an anxiolytic comprising a compound according to any one of claims 1 to 9 and a therapeutically inert carrier,
13. The use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment and prevention of mGluR5 receptor mediated disorders, in particular anxiety.
14. A method for the treatment or prevention of a disease or condition in which metabo-tropic glutamate receptor subtype 5 activation plays a role or is implicated comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to claim 1.

Documents:

2186-chenp-2005-abstract.pdf

2186-chenp-2005-claims.pdf

2186-chenp-2005-correspondnece-others.pdf

2186-chenp-2005-description(complete).pdf

2186-chenp-2005-form 1.pdf

2186-chenp-2005-form 26.pdf

2186-chenp-2005-form 3.pdf

2186-chenp-2005-form 5.pdf

2186-chenp-2005-form18.pdf

2186-chenp-2005-pct.pdf

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Patent Number

230705

Indian Patent Application Number

2186/CHENP/2005

PG Journal Number

13/2009

Publication Date

27-Mar-2009

Grant Date

27-Feb-2009

Date of Filing

08-Sep-2005

Name of Patentee

F. HOFFMANN-LA ROCHE AG

Applicant Address

124 GRENZACHERSTRASSE, CH-4070 BASEL,

Inventors:

#	Inventor's Name	Inventor's Address
1	BUETTELMANN, BERND	AMSELWEG 10, 79650 SCHOPFHEIM,
2	KOLCZEWSKI, SABINE	SCHILLERSTRASSE 35, 7961 RHEINFELDEN,
3	PORTER, RICHARD, HUGH, PHILLIP	HERRENWEG 34, CH-4153 REINACH,
4	VIEORA, ERIC	LINDENSTTRASSE 9, CH-4402 FRANKENDORF,
5	CECCARELLI, SIMONA, MARIA	OFFENBURGESTRASSE 29, CH-4057 BASEL,
6	JAESCKE, GEROG	82 EULERSTRASSE, CH-4051 BASEL,

PCT International Classification Number

C07D 401/06

PCT International Application Number

PCT/EP04/02276

PCT International Filing date

2004-03-05

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	03004952.2	2003-03-10	EUROPEAN UNION