The present invention relates to new compounds of formula I, wherein P, Q, X 1 , X 2 , X 3 , X 4 , X 5 , R, R 1 , R 2 , R 3 , R 4 , R 5 , G, M 1 , M 2 , M 3 , m and n, are defined as in formula I, a process for their preparation and new intermediates prepared therein, pharmaceutical formulations containing said compounds and to the use of said compounds in therapy.
1. A compound having the formula I
wherein:
P is a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S, wherein said ring may be fused with a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S;
R 1 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C 1-6 alkylhalo, OC 1-6 alkylhalo, C 1-6 alkyl, OC 1-6 alkyl, C 2-6 alkenyl, OC 2-6 alkenyl, C 2-6 alkynyl, OC 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, OC 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, OC 0-6 alkylaryl, (CO)R 8 , O(CO)R 8 , O(CO)OR 8 , C 1-6 alkylOR 8 , OC 2-6 alkylOR 8 , C 1-6 alkyl(CO)R 8 , OC 1-6 alkyl(CO)R 8 , C 0-6 alkylCO 2 R 8 , OC 1-6 alkylCO 2 R 8 , C 0-6 alkylcyano, OC 2-6 alkylcyano, C 0-6 alkylNR 8 R 9 , OC 2-6 alkylNR 8 R 9 , C 1-6 alkyl(CO)NR 8 R 9 , OC 1-6 alkyl(CO)NR 8 R 9 , C 0-6 alkylNR 8 (CO)R 9 , OC 2-6 alkylNR 8 (CO)R 9 , C 0-6 alkylNR 8 (CO)NR 8 R 9 , C 0-6 alkylSR 8 , OC 2-6 alkylSR 8 , C 0-6 alkyl(SO)R 8 , OC 2-6 alkyl(SO)R 8 , C 0-6 alkylSO 2 R 8 , OC 2-6 alkylSO 2 R 8 , C 0-6 alkyl(SO 2 )NR 8 R 9 , OC 2-6 alkyl(SO 2 )NR 8 R 9 , C 0-6 alkylNR 8 (SO 2 )R 9 , OC 2-6 alkylNR 8 (SO 2 )R 9 , C 0-6 alkylNR 8 (SO 2 )NR 8 R 9 , OC 2-6 alkylNR 8 (SO 2 )NR 8 R 9 , (CO)NR 8 R 9 , O(CO)NR 8 R 9 , NR 8 OR 9 , C 0-6 alkylNR 8 (CO)OR 9 , OC 0-6 alkylNR 8 (CO)OR 9 , SO 3 R 8 and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S, wherein said ring may be substituted by one or more A;
M 1 is selected from the group consisting of a bond, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 0-4 alkyl(CO)C 0-4 alkyl, C 0-3 alkylOC 0-3 alkyl, C 0-3 alkyl(CO)NR 8 , C 0-3 alkyl(CO)NR 8 C 1-3 alkyl, C 0-4 alkylNR 8 R 9 , C 0-3 alkylSC 0-3 alkyl, C 0-3 alkyl(SO)C 0-3 alkyl and C 0-3 alkyl(SO 2 )C 0-3 alkyl;
R 2 is selected from the group consisting of hydrogen, hydroxy, oxo, ═NR 8 , ═NOR 8 , C 1-4 alkylhalo, halo, C 1-4 alkyl, O(CO)C 1-4 alkyl, C 1-4 alkyl(SO)C 0-4 alkyl, C 1-4 alkyl(SO 2 )C 0-4 alkyl, (SO)C 0-4 alkyl, (SO 2 )C 0-4 alkyl, OC 1-4 alkyl, C 0-4 alkylcyano, C 1-4 alkylOR 8 and C 0-4 alkylNR 8 R 9 ;
X 1 and X 2 are N;
X 3 is O;
M 2 is a bond;
R 3 is selected from the group consisting of hydrogen, hydroxy, oxo, ═NR 8 , ═NOR 8 , C 1-4 alkylhalo, halo, C 1-4 alkyl, O(CO)C 1-4 alkyl, C 1-4 alkyl(SO)C 0-4 alkyl, C 1-4 alkyl(SO 2 )C 0-4 alkyl, (SO)C 0-4 alkyl, (SO 2 )C 0-4 alkyl, OC 1-4 alkyl, C 0-4 alkylcyano, C 1-4 alkylOR 8 and C 0-4 alkylNR 8 R 9 ;
Q is a 4, 5, or 6-membered ring containing one or more atoms independently selected from C, N, O or S, wherein said ring may be fused with a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S;
X 4 is N;
R 4 is selected from the group consisting of hydrogen, hydroxy, oxo, ═NR 8 , ═NOR 8 , C 1-4 alkylhalo, halo, C 1-4 alkyl, OC 0-6 alkylaryl, O(CO)C 1-4 alkyl, C 1-4 alkyl(SO)C 0-4 alkyl, C 1-4 alkyl(SO 2 )C 0-4 alkyl, (SO)C 0-4 alkyl, (SO 2 )C 0-4 alkyl, OC 1-4 alkyl, C 1-4 alkylOR 8 , C 0-4 alkylcyano and C 0-4 alkylNR 8 R 9 ;
M 3 is C 1-4 alkyl;
R 5 is selected from the group consisting of hydrogen, hydroxy, oxo, ═NR 8 , ═NOR 8 , C 1-4 alkylhalo, halo, C 1-4 alkyl, O(CO)C 1-4 alkyl, C 1-4 alkyl(SO)C 0-4 alkyl, C 1-4 alkyl(SO 2 )C 0-4 alkyl, (SO)C 0-4 alkyl, (SO 2 )C 0-4 alkyl, OC 1-4 alkyl, C 0-4 alkylcyano, C 1-4 alkylOR 8 and C 0-4 alkylNR 8 R 9 ;
G is a 5 or 6 membered ring containing one or more atoms selected from C, N, O or S, wherein said ring may be fused with a 5 or 6-membered ring containing one or more atoms independently selected from C, N, O or S, and wherein either of said rings may be substituted by one or more A;
R 6 is selected from the group consisting of hydrogen and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S, wherein said ring may be fused with a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S, and wherein any of the rings may be substituted by one or more A;
R 8 and R 9 are independently selected from hydrogen, C 1-6 alkyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S;
wherein any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, C 0-6 alkylheteroary and 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S as defined under R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , and R 9 may be substituted by one or more A;
A is selected from the group consisting of hydrogen, hydroxy, oxo, halo, nitro, C 1-6 alkyl, C 0-6 alkylC 3-6 cycloalkyl, C 1-6 alkylhalo, OC 1-6 alkylhalo, C 2-6 alkenyl, OC 1-6 alkyl, C 0-3 alkylaryl, C 1-6 alkylOR 8 , OC 2-6 alkylOR 8 , C 1-6 alkylSR 8 , OC 2-6 alkylSR 8 , (CO)R 8 , O(CO)R 8 , OC 2-6 alkylcyano, C 0-6 alkylcyano, C 0-6 alkylCO 2 R 8 , OC 1-6 alkylCO 2 R 8 , O(CO)OR 8 , OC 1-6 alkyl(CO)R 8 , C 1-6 alkyl(CO)R 8 , NR 8 OR 9 , C 0-6 alkylNR 8 R 9 , OC 2-6 alkylNR 8 R 9 , C 0-6 alkyl(CO)NR 8 R 9 , OC 1-6 alkyl(CO)NR 8 R 9 , OC 2-6 alkylNR 8 (CO)R 9 , C 0-6 alkylNR 8 (CO)R 9 , C 0-6 alkylNR 8 (CO)NR 8 R 9 , O(CO)NR 8 R 9 , NR 8 (CO)OR 9 , C 0-6 alkyl(SO 2 )NR 8 R 9 , OC 2-6 alkyl(SO 2 )NR 8 R 9 , C 0-6 alkylNR 8 (SO 2 )R 9 , OC 2-6 alkylNR 8 (SO 2 )R 9 , SO 3 R 8 , C 1-6 alkylNR 8 (SO 2 )NR 8 R 9 , OC 2-6 alkyl(SO 2 )R 8 , C 0-6 alkyl(SO 2 )R 8 , C 0-6 alkyl(SO)R 8 and OC 2-6 alkyl(SO)R 8 ;
m is selected from 0, 1, 2, 3 or 4; and
n is selected from 0, 1, 2 or 3;
or salt thereof,
with the proviso that the compound is not 1,2,4-oxadiazole 3-(2,3-dimethoxyphenyl)-5-[1-(phenylmethyl)-2-pyrrolidinyl]- or
Piperidine, 2-[3-(2,3-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-(phenylmethyl)-.
2. A pharmaceutical formulation comprising as an active ingredient a therapeutically effective amount of a compound according to claim 1 in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.
3. The pharmaceutical formulation according to claim 2 , for use in the prevention and/or treatment of mGluR5 receptor-mediated disorders.
4. A compound according to claim 1 , for use in therapy.
5. The compound according to claim 4 , for use in prevention and/or treatment of mGluR5 receptor-mediated disorders.
6. A method of treatment of mGluR5 receptor-mediated disorders selected from the group consisting of stroke, head trauma, anoxic injuries, ischemic injuries, hypoglycemia, epilepsy, neurodegenerative disorders, Alzheimer's disease and pain, comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound according to claim 1 .
7. The method according to claim 6 , wherein said mammal is a human.
8. The method according to claim 6 , wherein said mGluR5 receptor-mediated disorders are psychiatric disorders.
9. The method according to claim 6 , wherein said mGluR5 receptor-mediated disorders are neurological disorders.
10. The method according to claim 6 , wherein said mGluR5 receptor-mediated disorders are chronic and acute pain disorders.
11. A compound according to claim 1 selected from the group consisting of: 3-[5-(1-Pyridin-2-ylmethyl-piperidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile, 3-[3-(1-Pyridin-2-ylmethyl-piperidin-2-yl)-[1,2,4]oxadiazol-5-yl]-benzonitrile, 3-[5-(1-Thiazol-2-ylmethyl-piperidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile, 3-{5-[1-(1-Methyl-1H-imidazol-2-ylmethyl)-piperidin-2yl]-[1,2,4]oxadiazol-3-yl}-benzonitrile, 3-{5-[1-(6-Methyl-pyridin-2-ylmethyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzonitrile, 3-[3-(1-Thiazol-2-ylmethyl-piperidin-2-yl)-[1,2,4]oxadiazol-5-yl]-benzonitrile, 3-[5-(1-Thiazol-2-ylmethyl-pyrrolidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile, 3-{5-[1-(5-Chloro-pyridin-2-ylmethyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzonitrile, 2-[2-(5-m-Tolyl-[1,2,4]oxadiazol-3-yl)-piperidin-1-ylmethyl]-pyridine, 3-{5-[1-(5-Fluoro-pyridin-2-ylmethyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzonitrile, 3-[5S-(3-Pyridin-2-ylmethyl-thiazolidin-4-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile, 3-{5-[1-(3-Methyl-pyridin-2-ylmethyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzonitrile, 3-{5-[1-(4-Methyl-pyridin-2-ylmethyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzonitrile, 3-{5-[1-(5-Methyl-pyridin-2-ylmethyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzonitrile, 3-{5-[1-(1-Methyl-1H-benzoimidazol-2-ylmethyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzonitrile, 3-[5-(6-Methyl-1-pyridin-2-ylmethyl-piperidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile, 3-[5-(4,4-Difluoro-1-pyridin-2-ylmethyl-piperidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile, 3-[5-(4,4-Difluoro-1-thiazol-2-ylmethyl-piperidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile, 3-[5-(1-Quinolin-2-ylmethyl-piperidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile, 3-{5-[1-(1H-Benzimidazole-2-ylmethyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzonitrile, 3-{5-[1-(2-Methyl-thiazol-4-ylmethyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzonitrile, 3-{5-[1-(1-Benzyl-1H-imidazol-2-ylmethyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzonitrile, 3-[5-(4-Pyridine-2-ylmethyl-morpholin-3-yl)-[1,2,4]oxadiazol-3-yl)-benzonitrile, 3-{5-[1-(6-Bromo-pyridin-2-ylmethyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzonitrile, 3-{5-[1-(4-Methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzonitrile, 3-{5-[-(6- Chloro-pyridin-2-ylmethyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzonitrile, 3-[5-(1-Pyrazin-2-ylmethyl-piperidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile, 3-[5-(1-Pyrimidin-4-ylmethyl-piperidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile, 5 3-{5-[1-(5-Methyl-[1,2,4]oxadiazol-3-ylmethyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzonitrile, 3-{5-[1-(4-Chloro-pyridin-2-ylmethyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzonitrile, 2-{2-[3-(3-Cyano-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-ylmethyl}-thiazole-4-carbonitrile, 3-[5-(1-Benzothiazol-2-ylmethyl-piperidin-2-yl)-[1,2,4]oxadiazol-3-yl]benzonitrile, 6-{2-[3-(3-Cyano-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-ylmethyl}-nicotinonitrile 3-{5-[1-(5-Methyl-isoxazol-3-ylmethyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzonitrile, 3-Methoxy-5-[3-(1-pyridin-2-ylmethyl-piperidin-2-yl)-[1,2,4]oxadiazol-5-yl]-benzonitrile, 2-{2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-piperidin-1-ylmethyl}-pyridine, 3-[5-(1-Pyridin-2-ylmethyl-pyrrolidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile, 2-{2-[3-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-ylmethyl}-pyridine, (RS)-2-[2-(3-Thiophen-2-yl-[1,2,4]oxadiazol-5-yl)-piperidin-1-ylmethyl]-pyridine, 2-[2-(3-Phenyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-ylmethyl]-pyridine, 2-[2-(3-m-Tolyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-ylmethyl]-pyridine, (RS)-2-[2-(3-m-Tolyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-ylmethyl]-pyridine, (RS)-2-{2-[3-(3-Fluoro-5-imidazol-1-yl-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-methyl}-pyridine and 2-{2-[3-(3-Ethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-ylmethyl}-pyridine, and a salt thereof.
12. A compound according to claim 1 selected from the group consisting of: (R)- and (S)-3-[5-(1-Pyridin-2-ylmethyl-piperidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile; (S)-3-[5-(1-Thiazol-2-ylmethyl-piperidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile; 3-[5S-(3-Thiazol-2-ylmethyl-thiazolidin-4-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile; (S)-3-[5-(1-Thiazol-2-ylmethyl-pyrrolidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile; (S)-3-[5-(1-Pyridin-2-ylmethyl-pyrrolidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile; (S)-3-[5-(1-Pyridin-2-ylmethyl-2,5-dihydro-1H-pyrrol-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile; Trans-3-[5-(5-methyl-1-pyridin-2-ylmethyl-piperidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile; Cis-3-[5-(5-methyl-1-pyridin-2-ylmethyl-piperidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile; Cis-3-[5-(5-methyl-1-thiazol-2-ylmethyl-piperidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile; Cis-2-{2-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-methyl-piperidin-1-ylmethyl}-pyridine; Cis-3-[5-(3-Methyl-1-pyridin-2-ylmethyl-piperidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile; Trans-3-[5-(3-Methyl-1-pyridin-2-ylmethyl-piperidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile; Cis-3-[5-(3-Methyl-1-thiazol-2-ylmethyl-piperidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile; 3-[5-(4-Thiazol-2-ylmethyl-morpholin-3-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile; 3-{5-[4-(4-Methyl-pyridin-2-ylmethyl)-morpholin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzonitrile; 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-pyridin-2-ylmethyl-morpholine;
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-thiazol-2-ylmethyl-morpholine; 2-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-ylmethyl}-pyridine; and 2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-thiazol-2-ylmethyl-piperidine; and a salt thereof.