Title of Invention

PHENYLETHENYL OR PHENYLETHINYL DERIVATIVES AS GLUTAMATE RECEPTOR ANTAGONISTS

Abstract Phenylethenyl or Phenylethinyl Derivatives As Glutamate Receptor Antagonists The present invention relates to the uggjof compounds of formula (I) wherein R\R2, R3, R4 and I^are as defined in the description, A signifies-CH=CH, or -C=C; and B signifies (Bl); (B2); (B3); (B4); (B5) or (B6); wherein R6 and R26, X and Y have the significances given in the description , as well as pharmaceutical^ acceptable salts thereof, for the manufacture of medicaments for the treatment or prevention of mGluR5 receptor mediated disorders.
Full Text





imidazole as well as the synthesis of the corresponding phenylethenyl derivatives is
described in Chem. Pharm. Bull 1987,35(2), 823-828. The compounds have been prepared
by palladium catalyzed reaction of corresponding halogen-l,3-azoles with phenylacetylene
or styrene. l-Methyl-2-(4-methoxyphenylethynyl)-lH-imidazole can be synthesized as
nonlinear optical chromophore according to Chem Mater. 1994, 6(7), 1023-1032. The
preparation of 2-alkyl-5-phenylethynyl-lH-imidazole-4-carboxaldehydes as intermediates
for the manufacture of substituted imidazoles for use as angiotensin II blockers has been
described in WO 91/00277. l-Methyl-5-(2-phenylethenyl)-lH-imidazole has also been
prepared as intermediate for the synthesis of heterocyclic food mutagens according to
Environ. Health Perspect. 1986, 67,41-45. . „
It has now surprisingly been found that the compounds of general formula I are metabotropic glutamate receptor antagonists. Compounds of formula I are distinguished by valuable therapeutic properties. They can be used in the treatment or prevention of mGluR5 receptor mediated disorders.
In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor.
Glutamate is the major excitatory neurotransmitter in the brain and plays a unique role in a variety of central nervous system (CNS) functions. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group, namely the ionotropic receptors, forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein coupled receptors.
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 mGIuR8 belong to group III.
Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, epilepsy, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, as well as chronic and acute pain.
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 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-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 and pain. Selective mGluR5 antagonists are especially useful for the treatment of anxiety and pain.
Objects of the present invention are the use of compounds of formula I and their pharmaceutical^ acceptable salts for the manufacture of medicaments for the treatment or prevention of mGluR5 receptor mediated disorders, novel compounds of formula I-A or formula 1-B per se, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula I-A or formula 1-B for the treatment or prevention of mGluR5 receptor mediated disorders, such as Alzheimer's disease, senile dementia, Parkinson's disease, Huntington's chorea, cognitive disorders and memory deficits, cerebral ischemia, amyotrophic lateral sclerosis (ALS) and multiple sclerosis, restricted brain functions 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, psychiatric diseases such as psychosis, epilepsy, schizophrenia and anxiety, depression as well as chronic and acute pain.








Preferred lower alkanoyl groups are formyl, ethanoyl or propanoyl Preferred aryl groups are phenyl or naphthyl.
Heteroaryl groups are selected from furyl, pyrrolyl, thienyl, lH-imidazolyl, 2H-midazolyl, 4H-imidazolyl, lH-pyrazolyl, 3H-pyrazolyl, 4H-pyrazolyl, 1,2-oxazolyl, 1,3-Dxazolyl, lH-[l,2,4]triazolyl, 4H-[l,2,4]triazolyl, lH-[l,2,3]triazolyl, 2H-[l,2,3]triazolyl, lH-[l,2,3]triazolyl, [1,2,4] oxadiazolyl, [ 1,3,4]oxadiazolyl, [ 1,2,3]oxadiazolyl, 1H-:etrazolyl, 2H-tetrazolyl, [ 1,2,3,4] oxatriazolyl, [ 1,2,3,5] oxatriazolyl, 1,3-thiazolyl, 1,2-:hiazolyl, lH-pentazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, quinolinyl and their dihydro derivatives. The heteroaryl group is optionally substituted by lower alkyl. Preferred heteroaryl groups are pyrrolyl and [1,2,4] oxadiazolyl.
The term "pharmaceutical^ acceptable salt" refers to any salt derived from an inorganic or organic acid or base which possesses the desired pharmacological activity of the parent compound.
Especially preferred are compounds of formula I for the above mentioned use, in which A signifies -C=C- and B signifies Bl.
The following are examples of such compounds:
3,5-dimethyl-2-phenylethynyl-3H-imidazole-4-carboxylic acid ethyl ester, 5-methyl-2-phenylethynyl-3H-imidazole-4-carboxylic acid ethyl ester, 2-(3-methoxy-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester, 1 -methyl-2-phenylethynyl- lH-imidazole, 2-(5-nitro-2-phenylethynyl-imidazol-l-yl)-ethanol, 2-phenylethynyl-lH-imidazole,
2-(2,6-dichloro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester, 5-methyl-l-phenyl-2-phenylethynyl-lH-imidazole-4-carboxylic acid ethyl ester, 3,5-dimethyl-2-w-tolylethynyl-3H-imidazole-4-carboxylic acid ethyl ester, 2-(3-acetylamino-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester, 2-[3-(2,5-dimethyl-pyrrol-l-yl)-phenylethynyl]-3,5-dimethyl-3H-imidazole-4-carboxylic
acid ethyl ester,
5-(3,5-dimethyl'2-phenylethynyl-3H-imidazol-4-yl)-3-methyl-[l,2,4]oxadiazole, 3-cyclopropyl-5-(3,5-dimethyl-2-phenylethynyl-3H-imidazol-4-yl)-[ 1,2,4] oxadiazole, 2-(4-chloro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester, 2-(4-fluoro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester, 2-biphenyl-4-ylethynyl-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester, 2-(2-fluoro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester, 2-(2-fluoro-phenylethynyl)-l-methyl-lH-imidazole,

2-(4-amino-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester, 2-(2-chloro-phenylethynyl)«l-methyl-lH-imidazoleor (4,5-dichloro-2-phenylethynyl-imidazol-l-yl)-acetic acid ethyl ester.
Further preferred are compounds of formula I for the above mentioned use, in which A signifies -OC- and B signifies B2.
An example for such a compound is l-methyl-5-phenylethynyl-lH-imidazole.
Also preferred for the above mentioned use are compounds of formula I, in which A signifies -OC- and B signifies B3.
An example for such a compound is N-[2-(5-methoxy-2-phenylethynyl-lH-indol-3-yl)-ethyl]-acetamide.
Preferred compounds of formula I for the above mentioned use are also those, in which A signifies -C=C- and B signifies B4.
The following are examples of such compounds: 3-phenylethynyl-4H-5-thia-2,6,9b-triaza-cyclopenta[a]naphthalene or 3-phenylethynyl-4H-5-oxa-2,9b-diaza-cyclopenta[a]naphthalene.
Further preferred are compounds of formula I for the above mentioned use, in which A signifies -C=C- and B signifies B5.
Examples of such compounds are:
l-chloro-3-(2-methyl-5-nitro-4-phenylethynyl-imidazol-l-yl)-propan-2-ol) 3-methyl-5-phenylethynyl-3H-imidazole-4-carbaldehyde, 4-phenylethynyl-lH-imidazole, l-methyl-4-phenylethynyl-lH-imidazoleor l,2-dimethyl-5-nitro-4-phenylethynyl-lH-imidazole.
Also preferred are compounds of formula I for the above mentioned use, in which A signifies -C=C- and B signifies B6.
An example for such a compound is l,3-dimethyl-5-phenylethynyl-lH-pyrazole.
Further preferred are compounds of formula I for the above mentioned use, in which A signifies-C=C-.
Especially preferred are those compounds of formula I for the above mentioned use, in which A signifies -C=C- and B signifies Bl.

The following are examples of such compounds: 4,5-diisopropyl-l-methyl-2-styryMH-imidazole, 2-[2-(4-fluoro-phenyl)-vinyl]-4,5-diisopropyl-l-methyl-lH-imidazole, 2-[2-(4-cMoro-phenyl)-vinyl]-4,5-diisopropyl-l-methyl-lH-imidazole,
2-[2-(4-butoxy-phenyl)-vinyl]-4,5-diisopropyl-l-methyl-lH-imidazole,
4,5-diisopropyl-2-[2-(4-methoxy-2,3,6-tri^
4,5-diisopropyl-2-[2-(4-methoxy-phenyl)-vinyl]-l-methyMH-imidazole,
2-[2-(4-cUoro-3-fluoro-phenyl)-vinyl]-4,5-diisopropyl-l-methyl-lH-imidazole,
2-[2-(4-ethoxy-phenyl)-vinyl]-4)5-diisopropyl-l-methyl«lH-imidazole,
4,5-diisopropyl-l-methyl"2-[2-(23>4-trimethoxy-phenyl)-vinyl]-lH-imidazole,
2-[2-(2,4-dichloro-phenyl)-vinyl]-4,5-diisopropyl-l-methyl-lH-imidazoleor
4)5-diisopropyl-l-methyl»2-(2-p-tolyl-vinyl)-lH-imidazole.
Also preferred are compounds of formula I for the above mentioned use, in which A signifies -C=C- and B signifies B2.
Examples of such compounds are the following: 4-bromo-l-methyl-5-styryl-lH-imidazoleor l-methyl-5-styryl-lH-imidazole.
Further preferred objects of the present invention are compounds of formula I-A, in which B signifies Bl with the exception of l-methyl-2-phenylethynyl-lH-imidazole and 1-methyl-2-(4-methoxy-phenylethynyl)-lH-imidazole.
The following are examples of such compounds: 2-(5-nitro-2-phenylethynyl-imidazol-l-yl)-ethanol, 2-phenylethynyl- lH-imidazole, 2-(2-fluoro-phenylethynyl)-l-methyl-lH-imidazole, 2-(2-chloro-phenylethynyl)-l-methyl-lH-imidazoleor (4,5-dichloro-2-phenylethynyl-imidazol-l-yl)-acetic acid ethyl ester.
More preferred are compounds of formula I-A, in which B signifies Bl and R signifies (CH2)n-C(0)OR' or heteroaryl which is unsubstituted or substituted by lower alkyl or cycloalkyl. Especially preferred are those, in which R7 signifies (CH2)n-C(0)OR\ wherein N is 0 and R is lower alkyl.
Examples of such compounds are the following: 3,5-dimethyl-2-phenylethynyl-3H-imidazole-4-carboxylic acid ethyl ester, 5-methyl-2-phenylethynyl-3H-imidazole-4-carboxylic acid ethyl ester, 2-(3-methoxy-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester, 2-(2,6-dichloro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester,

5-metiayl-l«phenyl-2-phenylethynyl-lH-imidazole-4-carboxylic acid ethyl ester, 3,5-dimethyl-2-m-tolylethynyl-3H-imidazole-4-carboxylic acid ethyl ester, 2-(3-acetylamino-phenylethynyl)-3,5«dimethyl-3H-imidazole-4-carboxylic acid ethyl ester, 2-[3-(2,5-dimethyl-pyrrol-l-yl)-phenylethynyl]-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester,
5-(3,5-dimethyl-2-phenylethynyl-3H-imidazol-4-yl)-3-methyl-[l,254]oxadiazole, 3-cyclopropyl-5-(3,5-dimethyl-2-phenylethynyl-3H'imidazol-4-yl)-[l,2,4]oxadiazole) 2-(4-chloro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester, 2-(4-fluoro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester, 2-biphenyl-4-ylethynyl-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester, 2-(2-fluoro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester, or 2-(4-amino-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester.


and in which B signifies Bl and R7 signifies lower alkyl or -(CH2)n-C(0)OR\ Especially preferred are those in which R7 signifies lower alkyl.
Examples of such compounds are the following: 435-diisopropyl-l-methyl-2-styryl-lH-imidazole, 2-[2-(4-fluoro-phenyl)-vinyl]-4,5-diisopropyl-l-methyl-lH-imidazole) 2-[2-(4-chloro-phenyl)-vinyl]-4,5-diisopropyl-l-methyl-lH-imidazole, 2-[2-(4-butoxy-phenyl)-vinyl]-4,5-diisopropyl-l-methyl-lH-imidazole, 435-diisopropyl-2-[2-(4-methoxy-2)3,6-trime&^
4J5-diisopropyl-2-[2-(4-methoxy-phenyl)-vinyl]-l-methyl-lH-imidazole, 2-[2-(4-chloro-3-fluoro-phenyl)-vinyl]-4,5-diisopropyl-l-methyl-lH-imidazole) 2-[2-(4-ethoxy-phenyl)-vinyl]-435-diisopropyl-l-methyl-lH-imidazole, 4,5-diisopropyl-l-methyl-2-[2-(2,3,4-trimethoxy-phenyl)-vinyl]-lH-imidazole) 2-[2-(2)4-dichloro-phenyl)-vinyl]-4>5-diisopropyl-l-methyl-lH-imidazoleor 4,5-diisopropyl-l-methyl-2-(2-p-tolyl-vinyl)-lH-imidazole.



This reaction is catalyzed by palladium(II) salts.
In accordance with the invention, compounds of formula I, wherein A signifies -C=C-, are prepared by reacting an acetylene derivative of formula II, for example ethynylbenzene, with a suitable compound of formula III, for example 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ester. According to the method as described in Chem. Pharm. Ball 1987,35(2), 823-828 this palladium catalyzed C-C-coupling reaction requires the presence of bis(triphenylphosphine)-palladium(II)-chloride, cuprous iodide and triethylamine and is carried out in a polar solvent like dimethylformamide or acetonitrile at a temperature of 90 °C to 100 °C within 1.5 to 3 hours. The reaction can also be carried out in the presence equimolar amounts of bis(triphenylphosphine)-palladium(II)-chloride and triphenylphosphine and an excess of triethylamine at a temperature of 55 °C within 16 hours.
The phenylethynyl derivatives of formula II are commercially available or can be • easily prepared by methods well known in the art.
The compounds of formula III are also commercially available or can be prepared by appropiate methods depending on the heterocyclic system B.
2-Halogeno-lH-imidazoles of formula III (B = Bl) are prepared according to methods as described in US Patent No. (USP) 4,711,962, USP 3,341,548 and Synth. Commun. 1989,19,2551-2566.













preparations can be administered orally, e.g. in the form of tablets, coated tablets, drag£es, 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 pharmaceutical^ acceptable salts thereof can be processed with pharmaceutical^ 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 the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula I, but as a rule are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
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 IA or IB or pharmaceutical^ 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 IA or IB or pharmaceutical^ 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.

Finally, as mentioned earlier, the use of compounds of formula I and of pharmaceutical^ acceptable salts thereof for the production of medicaments, especially for the for the treatment or prevention of mGiuR5 receptor mediated disorders of the aforementioned kind, is also an object of the invention.
The following examples are provided for illustration of the invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof.
Example 1 3,5-Dimethyl-2-phenylethynyl-3H-imidazole-4-carboxylic acid ethyl ester
a) 2-Bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester
The title compound was prepared according to the method as described in USP 4,711,962.
b) 3,5-Dimethyl-2-phenvlethynyl-3H-imidazole-4-carboxylic acid ethyl ester
In analogy to the method as described in Chem. Pharm. Bull 1987, 35(2)y 823-828,17.5 mg (0.025 mmol) bis-(triphenylphosphine)-palladium-II-chloride, 2.9 mg (0.015 mmol) cuprous iodide, 60.5mg (0.6 mmol) triethylamine, 32.4 mg (0.3 mmol) ethynylbenzene and 61.8 mg (0.25mmol) 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester are dissolved in 1ml DMF and shaken for 3 h at 90 °C. The title compound (19.3 mg, 29%, MS: m/e = 269.3, [M+H+]) was isolated from the reaction mixture by HPLC chromatography (YMC CombiPrep C18 column 50x20mm, solvent gradient 10-95% CH3CN in 0.1% TFA(aq) over 6.0min, X = 230nm, flow rate 40ml/min).
lH-NMR (400MHz, CDC13, 25 °C): 5 (ppm) = 1.39 (3H; t, J = 7.22Hz), 2.51 (3H, s), 3.99 (3H, s), 4.35 (2H, q, J = 7.22Hz), 7.34 - 7.40 (3H, m), 7.56 - 7.59 (2H, m).
13C-NMR (100MHz, CDCI3,25 °C): 5 (ppm) = 14.26,15.78, 34.31,60.44, 77.83, 94.86, 119.77,121.14, 128.46,129.48,131.82,134.55,147.76,160.58.
Example 2 5-Methyl-2"phenvlethynyl-3H-imidazole-4-carboxylic acid ethyl ester a) 2-Bromo-5-methyl-3H-imidazole-4-carboxvlic acid ethyl ester The compound was prepared according to the method described in USP 4,711,962.

b) 5-Methyl-2-phenylethynyl-3H-imidazole-4-carboxYlic acid ethyl ester
The title compound, MS: m/e = 255.2 (M+H+) was prepared in accordance with the general method of example lb from 2-bromo-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester.
Example 3
2-(3-Methoxv-phenylethvnyl)-3,5-dimethvl-3H-imidazole-4-carboxylic acid ethyl ester
The title compound, MS: m/e = 299.3 (M+H+) was prepared in accordance with the general method of example lb from 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and l-ethynyl-3-methoxy-benzene.
Example 4
l-Methyl-2-phenylethvnvl-lH-imidazole
The title compound, MS: m/e = 183.0 (M+H+) was prepared in accordance with the general method of example lb from 2-iodo-l-methyl-lH-imidazole.
Example 5 2-(5-Nitro-2-phenylethynyl-imidazol-l-yl)-ethanol
a) 2-(2-Iodo-5-nitro-imidazol-l-ylVethanol
2-(2-Iodo-5-nitro-imidazol-l-yl)-ethanol was obtained in accordance with the method as described in USP 3,341,548.
b) 2-f5"Nitro-2-phenvlethynyl-imidazol-l-ylVethanol
The title compound, MS: m/e = 258.0. (M+H+) was prepared in accordance with the general method of example lb from 2-(2-iodo-5-nitro-imidazol-l-yl)-ethanol.

Example 6 2-Phenylethynvl-lH-imidazole
a) 2-Iodoimidazole
2-Iodoimidazole was prepared in accordance with the method as described in Synth Commun. 1989,19,2551-2566.
b) 2-Phenylethynyl-lH-imidazole
The title compound, MS: m/e = 169.4 (M+H+) was prepared in accordance with the general method of example lb from 2-iodoimidazole.
Example 7
2-(2,6-Dichloro-phenylethynyl)-3,5-dimethvl-3H-imidazole-4-carboxylic acid ethyl ester
The title compound, MS: m/e = 197.4 (M+H+) was prepared in accordance with the general method of example lb from l,3-dichloro-2-ethynyl-benzene and 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester.
Example 8
5-Methyl-l-phenyl-2-phenylethynyl-lH-imidazole-4-carboxvlic acid ethyl ester
a) 5-Methyl-2-oxo-l-phenyl"2,3-dihydro-lH-imidazole-4-carboxylic acid ethvl ester
The title compound was obtained by the method as described in USP 3,303,199.
b) 5-Methyl-l-phenvl-2-phenvlethynvl-lH-imidazole-4-carboxylic acid ethvl ester
A mixture of 492 mg (2 mmol) 5-methyl-2-oxo-l-phenyl-2,3-dihydro-lH-imidazole-4-carboxylic acid ethyl ester, 846 mg (3 mmol) trifluoromethanesulfonic anhydride, 303 mg (3 mmol) triethylamine and 10 ml dichloromethane was stirred for lh at room temperature. The volatile components were evaporated under reduced pressure and the obtained residue was filtered over silica gel (ethyl acetate / hexane = 1:4 as eluent). After evaporation of the solvent under reduced pressure, a yellow oil (463 mg) was obtained. 378 mg of this oil, 122 mg (1.2 mmol) Phenylacetylene, 70 mg (0.1 mmol) bis-(triphenylphosphine)-palladium-II-chloride, 303mg (3 mmol) triethylamine, and 10 mg (0.05 mmol) of cuprous iodide were dissolved in 5 ml DMF and stirred for 1.5 h at 100 °C. The reaction mixture was cooled to room temperature, diluted with 30 ml ether, washed

vith water and brine and dried over MgSCV Evaporation of the solvent gave an oil from Arhich the title compound (277 mg, 51 %) was isolated by column chromatography (silica ;el, Ethyl acetate / Hexane = 2:3 as eluant).
H-NMR (400 MHz, CDC13, 25 °C): 5 (ppm) = 1.44 (3H, t, J = 7Hz), 2.47 (3H, s), 4.42 ;2H, q, J = 7Hz), 7.20 - 7.42 (5H, m), 7.34 - 7.38 (2H, m), 7.53 - 7.60 (3H, m).
L3C-NMR (100 MHz, CDC13,25°C): 8 (ppm) = 11.53,14.94, 60.90, 79.34,92.92,121.91, 127.79,128.73,129.47,129.86,130.00,130.15, 131.90,132.08,135,42,137.91,163.75.
Example 9
3,5-Dimethyl-2-m-tolylethynyl-3H-imidazole-4-carboxvlic acid ethyl ester
The title compound, MS: m/e = 283.6 (M-f H+), was prepared in accordance with the general method of example lb from l-ethynyl-3-methyl-benzene and 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester.
Example 10
2-(3-Acetylamino-phenylethynvl)-3,5-dimethvl-3H-imidazole-4-carboxylic acid ethyl ester
The title compound, MS: m/e = 326.8 (M+H+), was prepared in accordance with the general method of example lb from N-(3-ethynyl-phenyl)-acetamide and 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester.
Example 11
(2-r3-f2.5-Dimethvl-pviTol-l-vl>)-phenvlethvnvll-3.5-dimethvl-3H-imidazole-4-carboxvlic acid ethyl ester
The title compound, MS: m/e = 362.8 (M+H4"), was prepared in accordance with the general method of example lb from 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and l-(3-ethynyl-phenyl)-2,5-dimethyl-lH-pyrrole.

Example 12 5-f3,5-DimethvI-2-phenylethyny^^
a) 5-(3,5-Dimethvl-3H-imidazol-4-vlV3-methvl-rL2,41oxadiazole
A solution of 3,5-dimethyl-3H-imidazole-4-carboxylic acid (1.0 g, 7.14 mmol) and 1,1'-:arbonyldiimidazole (1.74 g, 10.7 mmol) in DMF (35 ml) was stirred at RT for 3 h. N-lydroxy-acetamidine (0.68 g, 9.18 mmol) was added, the reaction mixture was stirred at 16 h at 80 °C, evaporated and dissolved in acetic acid (30 ml). The solution was stirred at 100 °C for 2 h, evaporated, poured into sat. NaHCOs solution (50 ml) and extracted with dichloromethane (7 x 30 ml). The combined organic layers were washed with brine (70 ml), dried (MgS04) and evaporated to give the tide compound (0.78 g, 61%) as a white solid, m.p. 95 °C and MS: m/e = 178.2 (M+).
b) 5-(2-Bromo-3,5-dimethyl-3H-imidazol-4-yl)-3-methvI-[L2,4loxadiazole
To a stirred solution of 5-(3,5-dimethyl-3H-imidazol-4-yl)-3-methyl-[l>2,4]oxadiazol (0.7 g, 3.93 mmol) in chloroform (7 ml) was added dropwise at RT a solution of bromine (0.94 g, 0.30 ml, 5.89 mmol) in chloroform (7 ml). The reaction mixture was stirred at RT for 26 h, evaporated, poured into sat. NaHCC>3 solution (40 ml) and extracted with dichloromethane (2 x 30 ml). The combined organic layers were washed with brine (40 ml), dried (MgS04) and evaporated to give the crude product as yellow oil (0.84 g). Purification by column chromatography on silica gel (ethyl acetate/MeOH 98 : 2) gave the title compound (0.52 g, 51%) as a white solid, m.p. 89 °C and MS: m/e = 256, 258 (M+).
c)5"(3,5-Dimethyl-2-phenylethynyl-3H-imidazol-4"Vl)-3-methvl-rL2.41oxadiazole
To a stirred solution of 5-(2-bromo-3,5-dimethyl-3H-imidazol-4-yl)-3-methyl-[l,2,4]oxadiazole (0.52 g, 2.02 mmol) in THF (10 ml) was added at RT bis(triphenyl-phosphin)palladium(II)chloride (71 mg, 0.1 mmol), phenylacetylene (0.31 g, 3.03 mmol), triphenylphosphine (27 mg, 0.1 mmol) and triethylamine (0.61 g, 6.07 mmol). Through the reaction mixture was bubbled argon for 10 min and stirring was continued at 55 °C for 16h. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with brine (40 ml), dried (MgS04) and evaporated to give the crude product as yellow oil (0.81 g). Purification by column chromatography on silica gel (ethyl acetate/toluene 5:1) gave the title compound (0.31 g, 55%) as a light yellow solid, m.p. 137 °C and MS: m/e = 278.1 (M+).

Example 13 3-Cyclopropvl-5-f3,5-dimethvl-2-phenylethynyl-3H-imidazol-4-yD-f 1,2,41 oxadiazole
a) 3-Cvclopropyl-5-(3,5-dimethyl-3H-imidazol-4-yD-fl,2,4loxadiazoIe
The title compound, off-white solid, m.p. 88 °C and MS: m/e = 204.3 (M+), was prepared from 3>5-dimethyl-3H-imidazole-4-carboxylic acid and N-hydroxy-cyclopropane-carboxamidine in accordance with the general procedure of example 12a.
b) 5-f2-Bromo-3,5"dimethyl-3H-imidazol-4-yD-3-cyclopropyl-[L2,4loxadiazole
The title compound, white solid, m.p. 81 °C and MS: m/e = 282, 284 (M+)> was prepared bybrominationof3-cyclopropyl-5-(3,5-dimethyl-3H-imidazol-4-yl)-[l,2,4]oxadiazolein accordance with the general method of example 12b.
c) 3-Cyclopropyl-5-(3,5-dimethyl-2-phenylethynyl-3H-imidazol-4-yD-[L2,4loxadiazole
The title compound, white solid, m.p. 120 °C and MS: m/e = 305.2 (M+H+), was prepared from 5-(2-bromo-3,5-dimethyl-3H-imidazol-4-yl)-3-cyclopropyl-[l,2,4]oxadiazoleand phenylacetylene in accordance with the general procedure of example 12c.
Example 14
2-(4-Chloro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester
The title compound, MS: m/e = 303.0 (M+H+) was prepared in accordance with the general method of example lb from 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and l-chloro-4-ethynylbenzene.
Example 15
2-(4-Fluoro-phenylethvnyl)-3,5-dimethvl-3H-imidazole-4-carboxvlic acid ethyl ester
The title compound, MS: m/e = 286.8 (M+H+) was prepared in accordance with the general method of example lb from 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and l-ethynyl-4-fluorobenzene.

Example 16
2-Biphenvl-4-ylethynyl-3,5-dimethyl-3H-imidazole-4--carboxylic acid ethyl ester The title compound, MS: m/e = 345.4 (M+H+) was prepared in accordance with the general method of example lb from 2-bromo-3,5-dimethyl-3H-imidazoIe-4-carboxylic acid ethyl ester and 4-ethynylbiphenyl.
Example 17
2-(2-Fluoro-phenylethynyl)-3,5-dimethyl-3H"imidazole-4-carboxvlic acid ethyl ester
The title compound, MS: m/e = 287.4 (M+H+) was prepared in accordance with the general method of example lb from 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and l-ethynyl-2-fluorobenzene.
Example 18
2-(2-Fluoro-phenylethynyl)-l-methyl-lH-imidazole
The title compound, MS: m/e = 201.2 (M+H+) was prepared in accordance with the general method of example lb from 2-iodo-l-methyl-lH-imidazole and l-ethynyI-2-fluorobenzene.
Example 19
2-(4-Amino-phenylethynyl)-3,5-dimethvl-3H-imidazole-4-carboxylic acid ethvl ester
The title compound, MS: m/e = 284.4 (M+H+) was prepared in accordance with the general method of example lb from 2-bromo-3>5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and 4-ethynylaniline.
Example 20
2-(2-Chloro-phenvlethvnvD-l-methyl-lH-imidazole
The title compound, MS: m/e = 217.6 (M+H+) was obtained in accordance with the general method of example lb from 2-iodo-l-methyl-lH-imidazole and l-chloro-2-ethynylbenzene.

Example 21
(4,5-Dichloro-2-phenylethvnyl-imidazol-l-ylVacetic acid ethyl ester
The title compound, MS: m/e = 323.0 (M+H+) was prepared in accordance with the general method of example lb from ethyl (2-bromo-4,5-dichloroimidazole-l-yl) acetate and ethynylbenzene.
Example 22
l-Methyl-5-phenylethynyl-lH-imidazole
The title compound, MS: m/e = 183.4(M+H+) was prepared in accordance with the general method of example lb from 5-iodo-l-methyl-lH-imidazole.
Example 23
N-[2-(5-Methoxy-2-phenvlethvnyl-lH-indol-3-yD-ethyl1-acetamide
a) N-[2-(2-iodo-5-methoxy-lH-indol-3-yl)-ethyn-acetamide
The title compound is obtained fromN-[2-(5-methoxy-indol-3-yl)-ethyl]-acetamide according to the method as described in/. Labelled Compel Radiopharm. 1997,39y 677-684.
b) N-f2-(5-Methoxy-2-phenylethynyl-lH-indol-3-yl)-ethyl1-acetamide
The title compound, MS: m/e = 333.3 (M-f H+) was prepared in accordance with the general method of example lb fromN-[2-(2-iodo-5-methoxy-lH-indol-3-yl)-ethyl]-acetamide.
Example 24
3-Phenylethynyl-4H-5-thia-2,6,9b-triaza"Cyclopentafa1 naphthalene
a) 3-Iodo-4H-5-thia-2,6,9b-triaza-cvclopenta[a1naphthalene
In analogy to the method as described in EP 0 059 390 the title compound was obtained.
b) 3-Phenylethvnyl-4H-5-thia-2,6,9b-triaza-cyclopentara1 naphthalene
The title compound, MS: m/e = 290.3 (M+H+) was prepared in accordance with the general method of example lb from 3-iodo-4H-5-thia-2,6,9b-triaza-cyclop enta [ a] n aphthalene.

Example 25 3-Phenylethynyl-4H-5-oxa-2,9b-diaza-cyclopenta[a1naphthalene
a) 3-Iodo"4H-5-oxa-2,9b-diaza-cyclopentara1naphthalene
3-Iodo-4H-5-oxa-2,9b-diaza-cyclopenta[a] naphthalene was obtained in analogy to the method as described EP 0 059 390.
b) 3-Phenylethynyl-4H-5-oxa-219b-diaza-cyclopenta[a1naphthalene
The title compound, MS: m/e = 273.2 (M+H+), 545.1 (2M+H+), was prepared in accordance with the general method of example lb from 3-iodo-4H-5-oxa-2,9b-diaza-cyclopenta [a] naphthalene.
Example 26
l-Chloro-3-(2-methvI-5-nitrO"4"phenylethynyl-imidazol-l-yl)-propan-2-ol
a) l-Chloro-3-f4-iodo-2'methyl-5-nitrO"imidazol-l-yl)-propan-2-ol
l-Chloro-3-(4-iodo-2-methyl-5-nitro-imidazol-l-yl)-propan-2-olwas obtained by the method as described in /. Med. Chem. 1974,17(9), 1019-20.
b) l-Chloro-3-f2-methyl-5-nitrO"4-phenyIethynyl-imidazol-l-yl)-propan-2-ol
The title compound, MS: m/e = 319.7, 321.9 (M+H+) was prepared in accordance with the general method of example lb from l-chloro-3-(4-iodo-2-methyl-5-nitro-imidazol-l-yl)-propan-2-ol.
Example 27
3-Methyl-5-phenylethynyl-3H-imidazole-4-carbaIdehyde
a) 5-Bromo-3-methvl-3H-imidazole-4-carbaldehyde
5-Bromo-3-methyl-3H-imidazole-4-carbaldehyde was obtained in accordance with the method as described in Chem. Pharm. Bull 1994,42,1784-1790.
b) 3-Methyl-5-phenvlethynyl-3H-imidazole-4-carbaldehyde
The title compound, MS; m/e = 210.6 (M+H+) was prepared in accordance with the general method of example lb from 5-bromo-3-methyl-3H-imidazole-4-carbaldehyde.

Example 28 4-PhenyIethvnvl-lH-imidazole
The title compound, MS: m/e = 169.2 (M+H+) was prepared in accordance with the general method of example lb from 4-bromoimidazole and ethynylbenzene.
Example 29
l-Methyl-4-phenylethynyl-lH-imidazole
The title compound, MS: m/e = 183.2 (M+H+) was prepared in accordance with the general method of example lb from 4-iodo-l-methyl-lH-imidazole.
Example 30 l,2-Dimethyl-5-nitro-4"phenylethynyl-lH-imidazole
a) l,2-Dimethyl-4-iodo-5-nitroimidazole
l,2-Dimethyl-4-iodo-5-nitroimidazole was obtained according to the method as described in Aust. J. Chem. 1987, 40(8), 1399-413
b) l,2-Dimethyl-5-nitro-4"phenylethynyl-lH-imidazole
The title compound, MS: m/e = 242.4 (M-f H+) was prepared in accordance with the general method of example lb from l,2-dimethyl-4-iodo-5-nitroimidazole.
Example 31 l,3-Dimethyl-5-phenylethynyl-lH-pyrazole
a) 5-Iodo-l,3-dimethyl-lH-pyrazole
The title compound was obtained according to the method as described in BuILAcad.Sci.USSR Div.Chem.ScL(Engl.TransL) 1983; 626-628 and in I7y.Akad.Nauk SSSR Ser.Khim. 1983; 688-690.
b) l,3-Dimethyl-5-phenvlethvnyl-lH-pyrazole
The title compound, MS: m/e = 196.8 (M+H+) was prepared in accordance with the general method of example lb from 5-iodo-l,3-dimethyl-lH-pyrazole.

Example 32 4,5-Diisopropyl-l-methyl-2-stVTyl-lH-imidazole z) 4,5-Diisopropyl-l-methyl-lH-imidazole-2-carbaldehvde
4,5-Diisopropyl-l-methyl-lH-imidazole-2-carbaldehyde was obtained analogously to the method as described in Inorg. Chitn. Acta 1999,296(1), 208-221.
b) 4,5-Diisopropyl-l-methyl-2-styTyl-lH--imidazole
194 mg (0.5 mmol) benzyltriphenylphosphoniumchloride and 97 mg (0.5 mmol) 4,5-diisopropyl-l-methyl-lH-imidazole-2-carbaldehyde were added to 1.3 ml of a 0.5 M solution of MeONa in MeOH. The mixture was shaken at 60 °C for 3 days, then cooled to room temperature. After addition of 0.2ml formic acid, the title compound (59 mg, 44%, MS: m/e = 269.4 [M+H+]) was isolated from the reaction mixture by HPLC chromatography (YMC CombiPrep C18 column 50x20mm, solvent gradient 10-95% CH3CN in 0.1% TFA(aq) over 6.0 min, X = 230 nm, flow rate 40 ml/min).
Example 33
2-[2-(4-Fluoro-phenyl)"Vinvll-4,5-diisopropyl-l-methvl-lH-imidazole
The title compound, MS: m/e = 286.8 (M-f-H*), was prepared in accordance with the general method of example 32b from 4-fluorobenzyl triphenylphosphonium chloride.
Example 34
2-[2-(4-Chloro-phenyl)-vinyl1-4,5-diisopropyl-l-methyl-lH-imidazole
The title compound, MS: m/e = 302.9 (M+H+), was prepared in accordance with the general method of example 32b from 4-chlorobenzyl triphenylphosphonium chloride.
Example 35
2-f2"(4-Butoxy-phenvl)-vinyn-4,5-diisopropyl-l-methyl-lH-imidazole
The title compound, MS: m/e = 340.9 (M+H+), was prepared in accordance with the general method of example 32b from (4-butoxybenzyl)triphenylphosphonium bromide.

Example 36
4,5-Diisopropyl-242-(4-metho:xY-2,3,6-trim
a) 23,6-Trimethyl-4-methoxybenzyltriphenyl-phosphonium chloride
2,3,6-Trimethyl-4-methoxybenzyltriphenyl-phosphonium chloride was obtained in accordance with the method as described in LiebigsAnn. Chem. 1984, JO, 1740-5.
b) 43-Diisopropyl-2-f2-(4-methoxy-2J,6-trimethyl-phenvD-vinyl1-l-methyl-lH-
imidazole
The title compound, MS: m/e = 340.9 (M+H+), was prepared in accordance with the general method of example 32b from 2,3,6-trimethyl-4-methoxybenzyltriphenyl-phosphonium chloride.
Example 37
4,5-Diisopropyl-2-[2-(4-methoxy-phenylVvinyn-l-methvl-lH-imidazole
The title compound, MS: m/e = 298.9 (M+H+), was prepared in accordance with the general method of example 32b from (4-methoxybenzyl)triphenylphosphonium bromide.
Example 38 2-[2-(4-Chloro-3-fluoro-phenyl)-vinyll-4,5-diisopropyl-l-methyl-lH-imidazoIe
a) 4-Chloro-3-fluorobenzvl triphenylphosphonium bromide
4-Chloro-3-fluorobenzyl triphenylphosphonium bromide was obtained according to the method as described in EP 0 692 485.
b) 2-[2-(4-ChloroO-fIuoro-phenyI)-vinyl1-4,5-diisopropyl-l-methvl-lH--imidazole
The title compound, MS: m/e = 320.8 (M+H+), was prepared in accordance with the general method of example 32b from 4-chloro-3-fluorobenzyl triphenylphosphonium bromide.

Example 39
2-f2-(4-Ethoxy-phenylVvinvl1-4,5-diisopropyl-l-methyl-lH-imidazole
The title compound, MS: m/e = 312.9 (M+H+), was prepared in accordance with the general method of example 32b from (4-ethoxybenzyl)triphenylphosphonium bromide.
Example 40 4,5-Diisopropyl-l-methyI-2-[2-(2,3^4-trimethoxy-phenyl)-vinvl1-lH-imidazole
a) Triphenyl-(23,4-trimethoxy-benzyl)-phosphonium bromide
Triphenyl-(2,3>4-trimethoxy-benzyl)-phosphonium bromide was obtained according to the method as described in DE 43 07 049.
b) 4,5-Diisopropyl-l-methyl-2-r2-(2,3,4-trimethoxy-phenyl,)-vmyl1-lH-imidazole
The title compound, MS: m/e = 359.0 (M-f H+), was prepared in accordance with the general method of example 32b from triphenyl-(2,3,4-trimethoxy-benzyl)-phosphonium bromide.
Example 41
2-f2-(2,4-Dichloro-phenyl)-vinyll-4,5-diisopropyI-l-methyl-lH-imidazole
The title compound, MS: m/e = 336.8 (M+H+), was prepared in accordance with the general method of example 32b from 2,4-dichlorobenzyltriphenylphosphonium chloride.
Example 42
4>5-Diisopropyl-l-methyl-2-(2-p-tolyl-vinyl)-lH-imidazole
The title compound, MS: m/e = 282.9 (M+H+), was prepared in accordance with the general method of example 32b from 4-methylbenzyltriphenylphosphonium bromide.
Example 43 4-Bromo-l-methyl-5-stvTvl-lH-imidazole z) 5-Bromo-3-methyl-3H4midazole-4-carbaldehvde

5-Bromo-3-methyl-3H-imidazole-4-carbaldehyde was obtained by the method as described in Chem. Pharm. Bull 1994,42,1784-1790,
b) 4-Bromo-l-methyl-5-styryl-lH-imidazole
The title compound, MS: m/e = 263.0 (M+H+), was prepared in accordance with the general method of example 21b from 5-bromo-3-methyl-3H~imidazole-4-carbaldehyde.
Example 44
l-Methyl-5-styiyl-lH-imidazole
The title compound was obtained according to the method as described in Chem. Pharm. Bull 1987; 35, 823-828.

Example A Tablets of the following composition are produced in a conventional manner:
mg/Tablet
Active ingredient 100
Powdered, lactose 95
White corn starch 35
Polyvinylpyrrolidone 8
Na carboxymethylstarch 10
Magnesium stearate 2
Tablet weight 250
Example B
Tablets of the following composition are produced 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 C
Capsules of the following composition are produced:
me/Capsule
Active ingredient 50
Crystalline, lactose 60
Microcrystalline cellulose 34
Talc 5
Magnesium stearate 1
Capsule fill weight 150
The active ingredient having a suitable particle size, the crystalline lactose and the microcrystalline cellulose are homogeneously mixed with one another, sieved and thereafter talc and magnesium stearate are admixed. The final mixture is filled into hard gelatine capsules of suitable size.




















R6 signifies hydrogen, d-Q-alkyl, -(CH2)n~C(0)OR or halogen;
R7 signifies hydrogen, d-Q-alkyl, -(CH2)n-C(0)OR>, halogen, nitro or heteroaryl
which is unsubstituted or substituted by Ci-d-alky! or cycloalkyl;
R8 signifies hydrogen, CrC6-alkyl, -(CH2)n-OH, -(CH2)„-C(0)OR" or aryl;
R9 signifies Ci-Q-alkyl;
R10 signifies hydrogen, CpQ-alkyl or halogen;
Rli signifies hydrogen or Ci-Ce-alkyl;
R12 signifies-(CH2)n-N(R)-C(0)-(Ci-C6)-alkyl;
R13 signifies hydrogen or Ci-Ce-alkyl;
R14, R15, R16 and R17 signify, independently from each other, hydrogen, Ci-Q-alkyl,
-(CH2)n-halogen or Ci-Ce-alkoxy;
R18, R19 and R20 signify, independently from each other, hydrogen, Crd-alkyl,
-(CH2)n-halogen or Q-Cralkoxy;
R21 signifies hydrogen or Ci-Cg-alkyl;
R22 signifies hydrogen, Cj-Q-alkyl or Q-Ce-alkyl carrying one or more
substituents seleaed from hydroxy or halogen;
R signifies hydrogen, CrQ-alkyl, Cj-Q-alkanoyl or nitro;
R ,R and R signify, independently from each other, hydrogen or Ci-Cg-alkyl;
n i$0, 1,2,3,4,5 or 6;
X is -CH2-, -O- or -S-; and
Y is-CH=or-N=;
and their pharmaceutically acceptable salts;
with the exception of
l-methyl-2-phenylethynyl-lH-imidazole,
1-methyl-2-(4-methoxy-phenylethynyl)-1H-imidazole,
1 -methyl-5-phenylethynyl-lH-imidazole, and
1 -methyl-4 -phenylethynyl- lH-imidazole.

2. A compound according to claim 1, wherein B signifies Bl as defined in claim 24.
3- A compound according to claim 2, wherein R7 signifies -(CH^JTCCOJOR* or heteroaryl which is unsubstituted or substituted by Q-C6-alkyl or cycloalkyl.
4. A compound according to claim 3, which compound is selected from the group consisting of
3,5-dimethyl-2-phenylethynyl-3H-imidazole-4-carboxylic acid ethyl ester, 5-methyl-2-phenylethynyl-3H-imidazole-4-carboxylic acid ethyl ester, 2-(3-methoxy-phenylethynyl)»3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester, 2-(2,6-dichloro-phenylethynyl)-3,5»dimethyl-3H-imidazole-4-carboxylic acid ethyl ester, 5-methyl-l-phenyl-2-phenylethynyl-lH-imidazole-4-carboxylic acid ethyl ester, 3,5-dimethyl-2-m-tolylethynyl-3H-imidazole-4-carboxylic acid ethyl ester, 2-(3-acetylamino-phenylethynyl)-3>5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester, 2-[3-(2,5-dimethyl-pyrrol-l"yl)-phenylethynyl]-3,5-dimethyl-3H-imidazole-4-carboxylic
acid ethyl ester, 5-(3,5*dimethyl-2-phenylethynyl-3H-imidazol-4-yl)-3-methyi-(l,2>4]oxadiazole,
3-cyclopropyl-5-(3,5-dimetiiyl-2-phenylet^^
2-(4-chloro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester, 2-(4-fluoro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester, 2-biphenyl-4-ylethynyl-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester, 2-(2-fluoro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester, or 2-(4-amino-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester.
5. A compound according to claim 2, which compound is selected from the group consisting of
2-(5-nitro-2-phenylethynyl-imidazoM-yl)-ethanol, 2-phenylethynyl- lH-imidazole, 2-(2-fluoro-phenylethynyl)-l-methyl-lH-imidazole, 2-(2-chIoro-phenylethynyl)-l-methyl-lH-imidazoleor (4,5-dichloro-2-phenylethynyl-imidazol-l-yl)-acetic acid ethyl ester.

6. A compound according to claim 1, wherein B signifies B2 as defined in claim 24.
7. A compound according to claim 1, wherein B signifies B3 as defined in claim 24.
8. A compound according to claim jt which compound is
N-[2-(5-melhoxy-2-phenylethynyl-lH-indol-3-yl)-ethyl]-acetamide.
9. A compound according to claim 1, wherein B signifies B4 as defined in claim 24.
10. A compound according to claim 9, which compound is selected from the group
consisting of
3-phenylethynyl-4H-5-thia-2,6,9b-triaza-cyclopenta[a]naphthalene or 3-phenylethynyl-4H-5-oxa-2,9b-diaza-cyclopenta[a]naphthalene.
11. A compound according to claim 1, wherein B signifies B5 as defined in claim 24.
12. A compound according to claim 11, which compound is selected from the group
consisting of
l-chloro-3-(2-methyl-5-nitro-4-phenylethynyl-imidazol-l-yl)-propan-2-ol, 3-methyl-5-phenylethynyl-3H-imidazole-4-carbaldehyde, 4-phenylethynyl-lH-imidazole or l,2-dimethyl-5-nitro-4"phenylethynyl-lH-imidazole.


R, R' and R* signify, independently from each other, hydrogen or Ci-Q-alkyl;
R6 signifies hydrogen, Ci-C6-alkyl, -(CH2)n-C(0)OR or halogen;
R7 signifies hydrogen, Q-Q-alkyl, -(CH2)n-C(0)OR>, halogen, nitro or heteroaryl
which is unsubstituted or substituted by Ci-Q-alkyl or cycloalkyl;
R8 signifies hydrogen, CrQ-alkyl, -(CH2)n-OH, -(CH2)n-C(0)OR" or aryl; and
n isO, 1,2,3,4,5 or 6;
and their pharmaceutical^ acceptable salts;
with the exception of 2-[2-(phenyl)-vinyl] -1 -methyl-lH-imidazole, 2- [2- (phenyl)-vinyl] -1 -ethyl- lH-imidazole 2- [ 2- (4-methyl-phenyl) -vinyl] -1 -methyl-1 H-imidazole, 2-[2-(4-chloro-phenyl)-vinyl] -1-methyl-lH-imidazole, 2-[2-(2,4-dichloro-phenyl)-vinyl]-l-methyl-lH-imidazole, 2-[2-(4-N,N'-dimethylamino-phenyl)-vinyl]-l-methyl-lH-imidazole, 2-[2-(2>4-dichloro-phenyl)-vinyl]-lH-imidazole, 2-[2-(phenyl)-vinyl]-4,5-dimethyl-lH-imidazole, 2-[2-(3-methoxy-phenyl)-vinyl]-l-methyl-5-nitro-lH-imidazole, 2-[2-(phenyl)-vinyl]-lH-imidazole, and 2- [2-(3-methoxy-phenyl)-vinyl]-1 -(2-hydroxyethyl)-5-nitro- lH-imidazole.
15. A compound according to claim 37, wherein R7 signifies Ci-Cg-alkyl or
-(CH2)n-C(0)OR









Documents:

839-chenp-2003-abstract.pdf

839-chenp-2003-claims.pdf

839-chenp-2003-correspondence others.pdf

839-chenp-2003-correspondence po.pdf

839-chenp-2003-description complete.pdf

839-chenp-2003-form 1.pdf

839-chenp-2003-form 18.pdf

839-chenp-2003-form 26.pdf

839-chenp-2003-form 3.pdf

839-chenp-2003-form 5.pdf

839-chenp-2003-pct.pdf


Patent Number 208706
Indian Patent Application Number 839/CHENP/2003
PG Journal Number 35/2007
Publication Date 31-Aug-2007
Grant Date 07-Aug-2007
Date of Filing 30-May-2003
Name of Patentee M/S. F. HOFFMANN-LA ROCHE AG
Applicant Address 124 GRENZACHERDTRASSE , CH-4070 BASEL.
Inventors:
# Inventor's Name Inventor's Address
1 MUTEL VINCENT 15 place des marechaux, f-68100 mulhouse.
PCT International Classification Number C07D 233/90
PCT International Application Number PCT/EP01/13714
PCT International Filing date 2001-11-26
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 00126615.4 2000-12-04 EUROPEAN UNION