Substituted piperazines as metabotropic glutamate receptor antagonists
The invention relates to compounds of formula I or pharmaceutically acceptable salts or solvates thereof: where Ar 1 , Ar 2 , Hy, L, R 1 , m and n are as defined in the description. The invention also includes pharmaceutical compositions and uses thereof, processes for making the compounds, as well as methods for the medical treatment of mGluR5-mediated disorders.
1 . A compound of formula I:
wherein:
Ar 1 and Ar 2 are independently selected, optionally substituted, aryl or heteroaryl groups, wherein the substituents are selected from the group consisting of F, Cl, Br, I, OH, nitro, C 1-6 -alkyl, C 1-6 -alkylhalo, OC 1-6 -alkyl, OC 1-6 -alkylhalo, C 2-6 -alkenyl, C 2-6 -alkynyl, CN, CO 2 R 2 , SR 2 , S(O)R 2 , SO 2 R 2 , aryl, heteroaryl, cycloalkyl and heterocycloalkyl, wherein any cyclic substituent may be further substituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, nitro, C 1-6 -alkyl, C 1-6 -alkylhalo, OC 1-6 -alkyl, OC 1-6 -alkylhalo, C 2-6 -alkenyl, C 2-6 -alkynyl, CN, CO 2 R 2 , SR 2 , S(O)R 2 and SO 2 R 2 ;
R 1 , in each instance, is independently selected from the group consisting of F, Cl, Br, I, OH, CN, nitro, C 1-6 -allyl, OC 1-6 -alkyl, C 1-6 -alkylhalo, OC 1-6 -alkylhalo, (CO)R 2 , O(CO)R 2 , O(CO)OR 2 , CO 2 R, CONR 2 R 3 , C 1-6 -alkyleneOR 2 , OC 2-6 -alkyleneOR 2 and C 1-6 -alkylenecyano;
R 2 and R 3 are independently selected from the group consisting of H, C 1-6 -alkyl, C 1-6 -alkylhalo, C 2-6 -alkenyl, C 2-6 -alkynyl and cycloalkyl;
Hy is a 5-membered heterocyclic ring containing two or three heteroatoms independently selected from the group consisting of N, O and S, wherein the ring is optionally substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, OH, nitro, C 1-6 -alkyl, C 1-6 -alkylhalo, OC 1-6 -alkyl, OC 1-6 -alkylhalo, CN, CO 2 R 2 , CONR 2 R 3 , SR 2 , S(O)R 2 and SO 2 R 2 ;
L is selected from the group consisting of —CR 4 R 5 —, —C(O)—, —C(NR 4 )— and —C(S)—;
R 4 and R 5 are independently selected from the group consisting of H, C 1-6 -alkyl, C 1-6 -alkylhalo, C 2-6 -alkenyl and C 2-6 -alkynyl;
m is an integer selected from the group consisting of 0, 1, 2, 3 and 4; and
n is an integer selected from the group consisting of 1 and 2;
or a pharmaceutically acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof
2 . A compound according to claim 1 , wherein Ar 1 is an optionally-substituted phenyl group.
3 . A compound according to claim 2 wherein Ar 2 is selected from the group consisting of an optionally-substituted pyridyl group and an optionally-substituted pyrazine group.
4 . A compound according to claim 3 wherein Ar 2 is an optionally-substituted 2-pyridyl group.
5 . A compound according to claim 4 wherein L is selected from the group consisting of CH 2 and CH(Me).
6 . A compound according to claim 5 wherein Hy is selected from the group consisting of isoxazole, 1,2,4-oxadiazole and 1,2,3-triazole.
7 . A compound selected from the group consisting of:
3-(4-{1-[5-(3-chlorophenyl)isoxazol-3-yl]ethyl}piperazin-1-yl)pyrazine-2-carbonitrile,
2-(4-{1-[5-(3-chlorophenyl)isoxazol-3-yl]ethyl}piperazin-1-yl)nicotinonitrile,
6-(4-{1-[5-(3-chlorophenyl)isoxazol-3-yl]ethyl}piperazin-1-yl)nicotinonitrile,
1-{1-[5-(3-chlorophenyl)isoxazol-3-yl]ethyl}-4-pyridin-2-ylpiperazine,
2-(4-{1-[5-(3-chlorophenyl)isoxazol-3-yl]ethyl}piperazin-1-yl)pyrazine,
3-(4-{1-[5-(3-cyanophenyl)isoxazol-3-yl]ethyl}piperazin-1-yl)pyrazine-2-carbonitrile,
3-(4-{1-[5-(5-chloro-2-fluorophenyl)isoxazol-3-yl]ethyl}piperazin-1-yl)pyrazine-2-carbonitrile,
6-(4-{1-[5-(5-chloro-2-fluorophenyl)isoxazol-3-yl]ethyl}piperazin-1-yl)nicotinonitrile,
3-(3-{1-[4-(3-nitropyridin-2-yl)piperazin-1-yl]ethyl}isoxazol-5-yl)benzonitrile,
1-{1-[5-3-chlorophenyl)isoxazol-3-yl]ethyl}-4-(3-nitropyridin-2-yl)piperazine,
3-(4-{1-[5-3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}piperazin-1-yl)pyrazine-2-carbonitrile,
6-(4-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}piperazin-1-yl)nicotinonitrile
2-(4-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}piperazin-1-yl)nicotinonitrile
6-(4-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethyl}piperazin-1-yl)nicotinonitrile
3-(4-{1-[1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}piperazin-1-yl)pyrazine-2-carbonitrile,
2-(4-{1-[1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}piperazin-1-yl)nicotinonitrile,
6-(4-{1-[1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}piperazin-1-yl)nicotinonitrile,
6-(4-{1-[1-(5-chloro-2-fluoro phenyl)-1H-1,2,3-triazol-4-yl]ethyl}piperazine-1-yl)nicotinonitrile,
5-(4-{1-[5-(3-chlorophenyl)isoxazol-3-yl]ethyl}piperazin-1-yl)pyrimidine-4-carbonitrile,
5-(4-{1-[5-3-chlorophenyl)isoxazol-3-yl]ethyl}piperazin-1-yl)pyrazine-2-carbonitrile,
2-(4-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethyl}piperazin-1-yl)nicotinonitrile,
3-(4-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethyl}piperazin-1-yl)pyrazine-2-carbonitrile,
6-(4-{[5-(5-chloro-2-fluorophenyl)isoxazol-3-yl]methyl}piperazin-1-yl)nicotinonitrile,
3-(4-{[5-(5-chloro-2-fluorophenyl)isoxazol-3-yl]methyl}piperazin-1-yl)pyrazine-2-carbonitrile,
1-{[5-(3-chlorophenyl)isoxazol-3-yl]carbonyl}-4-nitropyridin-2-yl)piperazine, and
1-{[2-(3-chlorophenyl)-1,3-oxazol-5-yl]carbonyl}-4-(3-nitropyridin-2-yl)piperazine.
8 . A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compound according to claim 1 , in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.
9 . The pharmaceutical composition according to claim 8 for use in the treatment of mGluR 5 mediated disorders.
10 . The compound according to claim 1 for use in therapy.
11 . The compound according to claim 1 for use in treatment of mGluR5 mediated disorders.
12 . Use of the compound according to claim 1 in the manufacture of a medicament for the treatment of mGluR5-mediated disorders.
13 . A method of treatment of mGluR5-mediated disorders, comprising administering to a mammal a therapeutically effective amount of the compound according to claim 1 .
14 . The method according to claim 13 , wherein the mammal is a human.
15 . The method according to claim 14 , wherein the disorders are neurological disorders.
16 . The method according to claim 14 , wherein the disorders are psychiatric disorders.
17 . The method according to claim 14 , wherein the disorders are chronic and acute pain disorders.
18 . The method according to claim 14 , wherein the disorders are gastrointestinal disorders.
19 . A method for inhibiting activation of mGlur5 receptors, comprising treating a cell containing said receptor with an effective amount of a compound according to claim 1.