| Title of Invention | IMIDAZOLE DERIVATIVES |
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| Abstract | The present invention relates to imidazole derivatives of the general formula (I) wherein R1, R2,R3, R4, and Y are as defined herein, a process for the manufacture thereof, their use for treating or preventing metabotropic glutamate receptors mediated disorders, their use for the preparation of medicaments for treating such disorders and pharmaceutical compositions containing them. |
| Full Text | WO 2005/023795 PCT/EP2004/009558 Giutamate is the major excitatory neurotransmitter in the brain and plays a unique role in a variety of central nervous system (CNS) functions. The giutamate-dependent stimulus receptors are divided into two main groups. The first main group, namely the ionotropic receptors, forms ligand-controlled ion channels. The metabotropic giutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein coupled receptors. At present, eight different members of these mGluR are known and of these some even have sub-types. According to their sequence homology, signal transduction mechanisms and agonist selectivity, these eight receptors can be sub-divided into three sub-groups: mGluRl and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III. Ligands of metabotropic giutamate receptors belonging to the first group can be used'fofthe treatment or prevention-of acute and/or chronic neurological disorders such as psychosis, epilepsy, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, as well as chronic and acute pain. Other treatable indications in this 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 giutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depressions. Disorders mediated full or in part by mGluR5 are for example acute, traumatic and chronic degenerative processes of the nervous system, such as Alzheimer's disease, senile dementia, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric diseases such as schizophrenia and anxiety, depression, pain, drug dependency, smoking cessation und ethanol dependence (Expert Opin. Titer. Patents (2002), 12, (12)). Selective mGluR5 antagonists are especially useful for the treatment of anxiety and pain. WO 2005/023795 PCT/EP2004/009558 The invention relates to compounds of formula I and their pharmaceutically acceptable salts, to the above-mentioned compounds as pharmaceutically active substances and their production. The invention also relates to a process for preparing a compound according to general formula I following the general procedures as outlined above for compounds of formula I. Moreover the invention relates also to medicaments containing one or more compounds of the present invention and pharmaceutically acceptable excipients for the treatment and prevention of mGluRS receptor mediated disorders, such as acute and/or chronic neurological disorders, in particular anxiety and chronic or acute pain. The invention also relates to the use of a compound in accordance with the present invention as well as its pharmaceutically acceptable salt for the manufacture of medicaments for the treatment and prevention of mGluR5 receptor mediated disorders as outlined-above. The following definitions of general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination. The term "lower alkyl" used in the present description denotes straight-chain or branched saturated hydrocarbon residues with 1 to 6 carbon atoms, preferably with 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl and the like. The term "lower alkoxy" denotes an -0-Cr6 alkyl group, wherein alkyl is as defined above such as methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, pentyloxy, hexyloxy, including their isomers. The term"cycloalky" denotes a saturated carbocyclic group, containing 3 - 12 an preferably 3-6 carbon atoms. The term "halogen" denotes fluorine, chlorine, bromine and iodine. The term "aryl " denotes a monovalent cyclic aromatic hydrocarbon radical consisting of one or more fused rings in which at least one is aromatic in nature and which may comprise from 5 to 12 carbon atoms as ring members, for example phenyl, benzyl, naphthyl, biphenyl or indanyl. The term "heteroaryl" denotes a monovalent aromatic carbocyclic radical, containing at least one heteroatom and which may comprise from 3 to 11 carbon atoms WO 2005/023795 PCT/EP2004/009558 Solution 2 is heated to 40 °C and solution 1 is added dropwise. The reaction mixture is heated to about 60 °C and tetrabutylammonium fluoride solution if. :-..lded dropwise during 45 min. The reaction is than stirred at room temperature overnight. The solvent is evaporated, dried and purified by chromatography. A compound of formula II is obtained. Step 3 Sodium hydride is suspended in THF. A solution of a compound of formula II, for example 2-methyl-4-(2-methyl-lH-imidazol-4-ylethynyl)-pyridine in dry THF is added and the reaction mixture is stirred at room temperature for about 30 min. a corresponding compound of formula R2 Yhal, for example 2-(bromomethyl)pyridine hydrobromide, 2-chloromethyl-6-methyl-pyridine hydrochloride or (2-bromoethyl)benzene is added and stirring is continued overnight The reaction mixture is poured into water, extracted, dried and purified by flash chromatography and a mixture of two regioisomers of a compound of formula I is obtained. This mixture can be separated by crystallization. Pharmaceutically acceptable salts of compounds of formula I can be manufactured readily according to methods known per se and taking into consideration the nature of the compound to be converted into a salt. Inorganic or organic acids such as, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like are suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula I. Compounds which contain the alkali metals or alkaline earth metals, for example sodium, potassium, calcium, magnesium or the like, basic amines or basic amino acids are suitable for the formation of pharmaceutically acceptable salts of acidic compounds. The compounds of formula I and their pharmaceutically acceptable salts are, as already mentioned above, metabotropic glutamate receptor antagonists and can be used for the treatment or prevention of mGluR5 receptor mediated disorders, such as acute and/or chronic neurological disorders, cognitive disorders and memory deficits, as well as acute and chronic pain. Treatable neurological disorders are for instance epilepsy, schizophrenia, anxiety, acute, traumatic or chronic degenerative processes of the nervous system, such as Alzheimer's disease, senile dementia, Huntington's chorea, ALS, multiple sclerosis, dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate- WO 2005/023795 PCT/EP2004/009558 pharmaceutical 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. The compounds of formula I and pharmaceutically acceptable salts thereof can be processed with pharmaceutically-inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and tie like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula I, but as a rule are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like. In addition, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. As mentioned earlier, medicaments containing a compound of formula I or pharmaceutically acceptable salts thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such medicaments which comprises bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers. The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. 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 described. 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. |
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| Patent Number | 278151 | ||||||||||||||||||||||||||||||||||||||||||
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| Indian Patent Application Number | 751/CHENP/2006 | ||||||||||||||||||||||||||||||||||||||||||
| PG Journal Number | 52/2016 | ||||||||||||||||||||||||||||||||||||||||||
| Publication Date | 16-Dec-2016 | ||||||||||||||||||||||||||||||||||||||||||
| Grant Date | 15-Dec-2016 | ||||||||||||||||||||||||||||||||||||||||||
| Date of Filing | 02-Mar-2006 | ||||||||||||||||||||||||||||||||||||||||||
| Name of Patentee | F. HOFFMANN-LA ROCHE AG | ||||||||||||||||||||||||||||||||||||||||||
| Applicant Address | 124 GRENZACHERSTRASSE, CH-4070 BASEL, SWITZERLAND | ||||||||||||||||||||||||||||||||||||||||||
Inventors:
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| PCT International Classification Number | C07D401/00 | ||||||||||||||||||||||||||||||||||||||||||
| PCT International Application Number | PCT/DP04/09558 | ||||||||||||||||||||||||||||||||||||||||||
| PCT International Filing date | 2004-08-27 | ||||||||||||||||||||||||||||||||||||||||||
PCT Conventions:
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