5-Fluoro-, Chloro-and Cyano-Pyridin-2-Yl-Tetrazoles as Ligands of the Metabotropic Glutamate Receptor-5
The present invention relates to new compounds of formula I, wherein Z, Q, X1, X2, R1 and R2, are as defined as in formula I, or salts, solvates or solvated salts thereof, processes for their preparation, pharmaceutical formulations containing said compounds and to the use of said compounds in therapy.
1 . Compounds of formula I
wherein:
X 1 is N and X 2 is C or X 1 is C and X 2 is N;
Z is fluoro, chloro or cyano;
R 1 and R 2 are independently selected from the group consisting of hydrogen, hydroxy, halo, C 1-6 alkylhalo, OC 1-6 alkylhalo, C 1-6 alkyl, OC 0-6 allyl, C 1-6 alkylOR 4 , OC 2-6 alkylOR 4 , C 0-6 alkylcyano, C 0-6 alkylNR 4 R 5 and OC 2-6 alkylNR 4 R 5 ;
R 4 and R 5 are independently selected from the group consisting of hydrogen, hydroxy and C 1-3 alkyl;
or salts, solvates or solvated salts thereof.
2 . The compounds of claim 1 wherein X 1 is C and X 2 is N.
3 . The compounds according to any one of the preceeding claims wherein Z is fluoro or cyano.
4 . The compounds according to any one of the preceeding claims wherein R 1 and R 2 are selected from the group consisting of hydrogen, hydroxy, halo, —C 1-3 alkylhalo, —OC 1-3 alkylhalo, —C 1-3 alkyl, —OC 0-3 alkyl, —C 1-3 alkylOR 4 , —OC 2-4 alkylOR 4 , —C 0-3 alkylcyano and C 0-3 alkylNR 4 R 5 ; and R 4 and R 5 are independently selected from hydrogen, methyl and ethyl.
5 . The compounds according to any one of the preceeding claims wherein R 1 is fluoro, chloro, bromo, iodo, methoxymethyl, methoxy, difluoromethoxy, trifluoromethoxy, 2-methoxy-ethoxy, ethylamino or amine.
6 . The compounds according to any one of the preceeding claims wherein R 2 is fluoro or cyano.
7 . Compounds selected from the group consisting of;
3-fluoro-5-[5-(5-fluoropyridin-2-yl)-2H-tetrazol-2-yl]benzonitrile,
6-[2-(3-cyano-5-fluorophenyl)-2H-tetrazol-S-yl]nicotinonitrile,
3-[5-(5-chloropyridin-2-yl)-2H-tetrazol-2-yl]-5-fluorobenzonitrile,
3-[5-(5-fluoro-pyridin-2-yl)-tetrazol-2-yl]-5-methoxymethyl-benzonitrile,
3-fluoro-5-[2-(5-fluoropyridin-2-yl)-2H-tetrazol-5-yl]benzonitrile,
6-[5-(3-cyano-5-fluorophenyl)-2H-tetrazol-2-yl]nicotinonitrile,
3-[2-(5-chloropyridin-2-yl)-2H-tetrazol-5-yl]-5-fluorobenzonitrile,
3-[5-(5-fluoropyridin-2-yl)-2H-tetrazol-2-yl]-5-(methoxymethyl)benzonitrile,
5-fluoro-2-[2-(3-fluoro-5-methoxyphenyl)-2H-tetrazol-5-yl]pyridine,
3-[5-(5-fluoro-pyridin-2-yl)-2H-tetrazol-2-yl]-5-methoxybenzonitrile,
3-[5-(5-fluoropyridin-2-yl)-2H-tetrazol-2-yl]-S-(trifluoromethoxy)benzonitrile,
3-(difluoromethoxy)-5-[5-(5-fluoropyridin-2-yl]-2H-tetrazol-2-yllbenzonitrile,
3-[5-(5-fluoropyridin-2-yl)-2H-tetrazol-2-yl] -5-(2-methoxyethoxy)benzonitrile,
3-(ethylamino)-5-[5-(5-fluoropyridin-2-yl)-2H-tetrazol-2-yl]benzonitrile,
3-amino-5-[5-(5-fluoropyridin-2-yl)-2H-tetrazol-2-yl]benzonitrile,
3-[5-(5-fluoropyridin-2-yl)-2H-tetrazol-2-yl]-5-iodobenzonitrile, and
or salts, solvates or solvated salts thereof.
8 . A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compound according to any one of claims 1 to 7 , in association with one or more pharmaceutically acceptable diluent, excipients and/or inert carrier.
9 . The pharmaceutical composition according to claim 8 , for use in the treatment of mGluR5 receptor mediated disorders.
10 . The compound according to any one of claims 1 to 7 , for use in therapy.
11 . The compound according to any one of claims 1 to 7 , for use in treatment of mGluR5 receptor mediated disorders.
12 . Use of the compound according to any one of claims 1 to 7 , in the manufacture of a medicament for the treatment of mGluR5 receptor mediated disorders.
13 . A method of treatment of mGluR5 receptor mediated disorders, comprising administering to a mammal, including man, in need of such treatment, a therapeutically effective amount of the compound according to any one of claims 1 to 7 .
14 . The method according to claim 13 , for use in treatment of neurological disorders.
15 . The method according to claim 13 , for use in treatment of psychiatric disorders.
16 . The method according to claim 13 , for use in treatment of chronic and acute pain disorders.
17 . The method according to claim 13 , for use in treatment of gastrointestinal disorders.
18 . A method for inhibiting activation of mGluR5 receptors, comprising treating a cell containing said receptor with an effective amount of the compound according to claim 1 .
19 . A process for making a pyridyl compound having a cyano substituent and a fluoro substituent comprising the steps of
1) treating the corresponding cyano amino pyridine with hydrogen fluoride in the presence of a suitable nitrate source and
2) allowing the mixture to decompose to the desired product.
20 . The process of claim 19 for making a pyridyl compound having a cyano substituent and a fluoro substituent comprising the steps of
1) treating the corresponding cyano amino pyridine with hydrogen fluoride in the presence of pyridine and sodium nitrite and
2) heating the mixture to induce in situ decomposition to the desired product.
21 . The process of claim 20 wherein, in step 1 the 70% hydrogen fluoride-pyridine is used.
22 . The process of claim 19 - 21 wherein the pyridyl compound is 5-fluoro-pyridine-2-carbonitrile.
23 . The process of claim 22 wherein the corresponding cyano amino pyridine is 5-amino-pyridine-2-carbonitrile.
24 . The process of claim 21 - 22 wherein the cyano amino pyridine of step 1 is combined with the hydrogen fluoride and cooled prior to adding the sodium nitrite and the reaction mixture was allowed to stir for 15 minutes to 1 hour at the cooled temperature followed by warming to room temperature, and in step 2 the reaction mixture was heated for approximately 1 hour.
25 . The process of claim 24 wherein in step 2 the reaction is heated to 80° C.