Benzoxazole derivatives having inhibitory activity against interleukin-6, preparation method thereof, and pharmaceutical composition containing the same
The present invention relates to benzoxazole derivatives represented by the Formula 1, which has an inhibitory activity against interleukin-6 (IL-6), a method for preparation thereof, and a pharmaceutical composition containing the same. The compound represented by the Formula 1 according to the present invention has a superior inhibitory activity against interleukin-6, and therefore, can be practically applied for prevention and treatment of diseases caused by abnormal interleukin-6 activity.
1. A compound having the chemical structure of Formula 1:
or a pharmaceutically acceptable salt thereof, wherein
R is hydrogen, R 1 CH 2 CO or R 1 CO;
R 1 is phenyl which is unsubstituted or substituted with one to three identical or different substituents each independently selected from the group consisting of C 1-10 alkyl, halogen, nitro, C 1-4 haloalkyl, C 1-4 alkoxy, and
and
R 2 is C 1-4 haloalkyl.
2. The compound according to claim 1 characterized in that said R 1 is phenyl substituted with one of C 1-10 alkyl, C 1-4 haloalkyl, halogen, and
3. The compound according to claim 1 characterized in that said R 1 is phenyl substituted with two identical or different substitutents each independently selected from the group consisting of halogen, nitro, C 1-4 haloalkyl and C 1-4 alkoxy.
4. The compound according to claim 3 characterized in that said R 1 is phenyl substituted with a halogen and a nitro, phenyl substituted with a halogen and a C 1-4 haloalkyl, phenyl substituted with two halogens, or phenyl substituted with two C 1-4 alkoxy.
5. The compound according to claim 1 characterized in that said R 1 is phenyl substituted with three C 1-4 alkoxy.
6. The compound according to claim 1 characterized in that said R 1 is phenyl which is unsubstituted or substituted with one to three identical or different substituents, each independently selected from the group consisting of ethyl; t-butyl; heptyl; chloromethyl; trifluoromethyl; fluoro; chloro; nitro; methoxy; ethoxy; and
7. The compound according to claim 1 characterized in that said R 2 is trifluoromethyl.
8. The compound according to claim 1 characterized in that the compound is selected from the group consisting of:
N-(2-(4-ethylphenyl)benzo[d]oxazole-2,5-diamine,
N-(2-(4-ethylphenylamino)benzo[d]oxazol-5-yl)-2-phenylacetamide,
N-(2-(4-ethylphenylamino)benzo[d]oxazol-5-yl)benzamide,
4-chloro-N-(2-(4-ethylphenylamino)benzo[d]oxazol-5-yl)benzamide,
2-chloro-N-(2-(4-ethylphenylamino)benzo[d]oxazol-5-yl)-4-nitrobenzamide,
2-chloro-N-(2-(4-ethylphenylamino)benzo[d]oxazol-5-yl)-5-nitrobenzamide,
3,4-dichlorobenzamide-N-(2-(4-ethylphenylamino)benzo[d]oxazol-5-yl)benz amide,
3-(chloromethyl)-N-(2-(4-ethylphenylamino)benzo[d]oxazol-5-yl)benzamide,
4-ethyl-N-(2-(4-ethylphenylamino)benzo[d]oxazol-5-yl)benzamide,
N-(2-(4-ethylphenylamino)benzo[d]oxazol-5-yl)-3-fluoro-5-(trifluoromethyl)benz amide,
2-ethoxy-N-(2-(4-ethylphenylamino)benzo[d]oxazol-5-yl)benzamide,
4-t-butyl-N-(2-(4-ethylphenylamino)benzo[d]oxazole-5-yl)benzamide,
N-(2-(4-ethylphenylamino)benzo[d]oxazol-5-yl)-3,4-dimethoxybenzamide,
N-(2-(4-ethylphenylamino)benzo[d]oxazol-5-yl)-3,4,5-trimethoxybenzamide,
N-(2-(4-ethylphenylamino)benzo[d]oxazol-5-yl)-4-heptylbenzamide, and
N-(2-(4-ethylphenylamino)benzo[d]oxazol-5-yl)-2-(3-(trifluoromethyl)phenyl amino)benzamide.
9. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier or a pharmaceutically acceptable salt thereof.
10. The pharmaceutical composition according to claim 9 , wherein said compound is effective to treat an inflammation.
11. A method for preparing a compound having the chemical structure of Formula 1:
comprising the step of:
reacting a compound having the chemical structure of Formula 2:
with a compound having the chemical structure of Formula 3:
R—X Formula 3
in the presence of a base, wherein R is R 1 CH 2 CO or R 1 CO and R 1 is phenyl which is unsubstituted or substituted with one to three identical or different substituents each independently selected from the group consisting of C 1-10 alkyl, halogen, nitro, C 1-4 haloalkyl, C 1-4 alkoxy, and
and
R 2 is C1-4 haloalkyl.
12. The method according to claim 11 characterized in that said base is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine, N,N-dimethylaniline, 2,6-lutidine and pyridine.
13. The method according to claim 11 characterized in that the equivalent ratio of the compound of Formula 2 and the compound of Formula 3 is 1:0.9 to 1.5.