3-Heterocyclic benzylamide derivatives as potassium channel openers
The present invention provides novel 3-heterocyclic benzylamides and related derivatives having the general Formula I wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A and Het are as defined in the specification, or a nontoxic pharmaceutically acceptable salt, solvate or hydrate thereof which are openers or activators of KCNQ potassium channels. The present invention also provides pharmaceutical compositions comprising said novel 3-heterocyclic benzylamides and to the method of treatment of disorders sensitive to KCNQ potassium channel opening activity such as migraine or a migraine attack, bipolar disorders, epilepsy, acute and chronic pain and anxiety.
1. A compound of Formula I or a pharmaceutically acceptable salt thereof
wherein
R 1 is selected from the group consisting of straight or branched chain C 1-6 alkyl optionally substituted with amino, C 1-4 alkylamino or di(C 1-4 alkyl) amino, pyridinyl, pyrrodidinyl, piperidinyl, 2-thienyl, furanyl, imidazolyl, indenyl, benzofuran, C 3-6 cycloalkyl and phenyl optionally substituted with substituent independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, and trifluoromethoxy;
A is —CH═CH—, 1,1-cyclopropyl, or —(CH 2 ) n —;
R 2 is C 1-4 alkyl, CF 3 or hydroxymethyl;
R 3 , R 4 , R 5 and R 6 each are independently hydrogen or fluoro;
n is an integer of 0 to 4, inclusive;
Het is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, thiazolyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl and triazolyl optionally substituted with substituents independently selected from the group consisting of C 1-4 alkyl, halogen, amino and dimethylaminomethyl;
provided that when Het is pyridinyl, pyrimidinyl or pyrazinyl, then A is not —CH═CH—.
2. The compound of claim 1 having the Formula Ic or a pharmaceutically acceptable salt thereof
wherein
R 1 is selected from the group consisting of straight or branched chain C 1-6 alkyl optionally substituted with amino, C 1-4 alkylamino or di(C 1-4 alkyl) amino, pyridinyl, pyrrodidinyl, piperidinyl, 2-thienyl, furanyl, imidazolyl, indenyl, benzofuran, C 3-6 cycloalkyl and phenyl optionally substituted with substituent independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, and trifluoromethoxy;
A is —CH═CH—, 1,1-cyclopropyl, or —(CH 2 ) n —;
R 2 is methyl or hydroxymethyl;
R 3 , R 4 , R 5 and R 6 each are independently hydrogen or fluoro;
n is an integer of 0 to 4, inclusive;
Het is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, thiazolyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl and triazolyl optionally substituted with substituents independently selected from the group consisting of C 1-4 alkyl, halogen, amino and dimethylaminomethyl;
provided that when Het is pyridinyl, pyrimidinyl or pyrazinyl, then A is not —CH═CH—.
3. The compound of claim 1 selected from the group consisting of:
(S)-3-(2-fluoro-phenyl)-N-[1-(3-[1,2,4]triazol-1-yl-phenyl)-ethyl]-acrylamide;
(S)-3-(2-fluoro-phenyl)-N-[1-(3-thiazol-2-yl-phenyl)-ethyl]-acrylamide;
(S)-3-(2-fluoro-phenyl)-N-[1-(3-pyrazol-1-yl-phenyl)-ethyl]-acrylamide;
(S)-3-(2-fluoro-phenyl)-N-[1-(3-imidazol-1-yl-phenyl)-ethyl]-acrylamide;
(S)-4-phenyl-N-[1-(3-pyridin-3-yl-phenyl)-ethyl]-butyramide;
(S)-N-[1-(3-pyridin-3-yl-phenyl)-ethyl]-benzamide;
(S)-1H-imidazole-4-carboxylic acid [1-(3-pyridin-3-yl-phenyl)-ethyl]-amide;
(S)-N-[1-(3-imidazol-1-yl-phenyl)-ethyl]-3-phenyl-acrylamide;
(S)-N-[1-(3-oxazol-5-yl-phenyl)-ethyl]-3-phenyl-acrylamide;
(S)-3-phenyl-N-[1-(3-thiazol-2-yl-phenyl)-ethyl]-acrylamide;
(S)-3-phenyl-N-[1-(3-pyrazol-1-yl-phenyl)-ethyl]-acrylamide; and
(S)-benzofuran-2-carboxylic acid {1-[3-(6-fluoro-pyridin-3-yl)-phenyl]-ethyl}-amide; or a pharmaceutically acceptable salt thereof.
4. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 in association with a pharmaceutically acceptable carrier, adjuvant or diluent.
5. A method forte treatment of disorders responsive to opening of the KCNQ potassium channels in a mammal in need thereof, wherein said disorders are acute and chronic pain, migraine, neuropathic pain, bipolar disorders, convulsions, mania, epilepsy, anxiety and depression, which comprises administering to said mammal a therapeutically effective amount of the compound of claim 1 .
6. The method of claim 5 wherein said disorder is migraine.
7. The method of claim 5 wherein said disorder is neuropathic pain.