Substituted melatonin derivatives, process for their preparation, and methods of use
View Patent ↗The invention provides 2 aryl substituted derivatives of melatonin. The invention further provides pharmaceutical compositions comprising such derivatives, methods for preparing such derivatives, and methods of using such derivatives to induce general anesthesia, sedation, and/or hypnotic or sleep effects in a patient, and to treat conditions affected by melatonin activity in a patient.
1. A compound of the formula
wherein
R 1 is a halogen or nitro,
R 2 is C 4 -C 20 aryl,
R 3 is methoxy, ethoxy, amino or dimethylamino.
2. The compound of claim 1 , wherein R 3 is methoxy.
3. The compound of claim 1 , wherein R 3 is ethoxy.
4. The compound of claim 1 , wherein R 3 is amino.
5. The compound of claim 1 , wherein R 3 is dimethylamino.
6. The compound of claim 1 , wherein R 2 is selected from the group consisting of phenyl, 4-(fluorophenyl), 3-(fluorophenyl), 2-(fluorophenyl), 4-(chlorophenyl), 3-(chlorophenyl), 2-(chlorophenyl), 4-(methylphenyl), 3-(methylphenyl), 2-(methylphenyl), 4-(methoxyphenyl), 3-(methoxyphenyl), 2-(methoxyphenyl), 4-(ethoxyphenyl), 3-(ethoxyphenyl), 2-(ethoxyphenyl), 4-(vinylphenyl), 4-(acetylphenyl), 3-(acetylphenyl), 2-(acetylphenyl), 4-(trifluoromethylphenyl), 3-(trifluoromethylphenyl), 4-(trimethylsilylphenyl), 3-(trimethylsilylphenyl), 4-(methylthiophenyl), 4-(tert-butylphenyl), 4-(dimethylaminophenyl), 4-(ethylphenyl), 4-(benzoxyphenyl), 4-(biphenyl), 2-furanyl, 2-(thiophenyl), 2-(5-methylthiophenyl), 3-(thiophenyl), 2-(indolyl), 1-(naphthalenyl), 2-(naphthalenyl), 4-(dibenzofuranyl), 1-(thianthrenyl), 2,3-(dichlorophenyl), 2,5-(dichlorophenyl), 3,4-(dichlorophenyl), 3,5-(dichlorophenyl), 2,3-(difluorophenyl), 2,4-(difluorophenyl), 2,5-(difluorophenyl), 2,6-(difluorophenyl), 3,4-(difluorophenyl), 3,5-(difluorophenyl), 3,5-(dibromophenyl), 3,5-(bis(trifluoromethyl)phenyl), 2,3-(dimethylphenyl), 2,5-(dimethylphenyl), 2,6-(dimethylphenyl), 3,5-(dimethylphenyl), 2,4-(dimethoxyphenyl), 2,5-(dimethoxyphenyl), 3,4-(dimethoxyphenyl), 2,3,4-(trimethoxyphenyl), 2,4,6-(trifluorophenyl), and 2,3,4,5,6-(pentafluorophenyl).
7. The compound of claim 1 , wherein the compound is N-(2-(5-methoxy-2-methoxyphenyl-1H-indol-3-yl)ethyl)acetamide.
8. The compound of claim 1 , wherein the compound is N-(2-(5-methoxy-2-p-tolyl-1H-indol-3-yl)ethyl)acetamide.
9. The compound of claim 1 , wherein the compound is N-(2-(2-(4-tert-butylphenyl)-5-methoxy-1H-indol-3-yl)ethyl)acetamide.
10. The compound of claim 1 , wherein the compound is N-(2-(2-(3-trifluoromethylphenyl)-5-methoxy-1H-indol-3-yl)ethyl)acetamide.
11. The compound of claim 1 , wherein the compound is N-(2-(2-(4-trifluoromethylphenyl)-5-methoxy-1H-indol-3-yl)ethyl)acetamide.
12. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier or diluent.
13. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 6 and a pharmaceutically acceptable carrier or diluent.
14. A pharmaceutical composition comprising a therapeutically effective amount of nanoparticles of the compound of claim 1 and a pharmaceutically acceptable carrier.
15. A pharmaceutical composition comprising a therapeutically effective amount of nanoparticles of the compound of claim 6 and a pharmaceutically acceptable carrier.
16. A pharmaceutical composition comprising an anesthetic inducing effective amount of the compound of claim 1 and a pharmaceutically acceptable anesthetic carrier.
17. A pharmaceutical composition comprising an anesthetic inducing effective amount of the compound of claim 6 and a pharmaceutically acceptable anesthetic carrier.
18. The compound of claim 1 , wherein R 2 is a substituted C 4 -C 20 aryl.
19. The compound of claim 18 , wherein the substituted C 4 -C 20 aryl is substituted by one or more of halogen, C 1 -C 6 alkoxy, amino, alkylamino, thiol, alkythiol, hydroxyl, —CHO, —NO 2 , phenyl, vinyl, —CN, Si(CH 3 ) 3 , —OCH 2 O—, or combinations thereof.
20. The compound of claim 6 , wherein R 2 is a substituted C 4 -C 20 aryl.
21. The compound of claim 20 , wherein the substituted C 4 -C 20 aryl is substituted by one of more of halogen, C 1 -C 6 alkoxy, amino, alkylamino, thiol, alkythiol, hydroxyl, —CHO, —NO 2 , phenyl, vinyl, —CN, Si(CH 3 ) 3 , —OCH 2 O—, or combinations thereof.
22. The compound of claim 2 , wherein R 2 is selected from the group consisting of phenyl, 4-(fluorophenyl), 3-(fluorophenyl), 2-(fluorophenyl), 4-(chlorophenyl), 3-(chlorophenyl), 2-(chlorophenyl), 4-(methylphenyl), 3-(methylphenyl), 2-(methylphenyl), 4-(methoxyphenyl), 3-(methoxyphenyl), 2-(methoxyphenyl), 4-(ethoxyphenyl), 3-(ethoxyphenyl), 2-(ethoxyphenyl), 4-(vinylphenyl), 4-(acetylphenyl), 3-(acetylphenyl), 2-(acetylphenyl), 4-(trifluoromethylphenyl), 3-(trifluoromethylphenyl), 4-(trimethylsilylphenyl), 3-(trimethylsilylphenyl), 4-(methylthiophenyl), 4-(tert-butylphenyl), 4-(dimethylaminophenyl), 4-(ethylphenyl), 4-(benzoxyphenyl), 4-(biphenyl), 2-furanyl, 2-(thiophenyl), 2-(5-methylthiophenyl), 3-(thiophenyl), 2-(indolyl), 1-(naphthalenyl), 2-(naphthalenyl), 4-(dibenzofuranyl), 1-(thianthrenyl), 2,3-(dichlorophenyl), 2,5-(dichlorophenyl), 3,4-(dichlorophenyl), 3,5-(dichlorophenyl), 2,3-(difluorophenyl), 2,4-(difluorophenyl), 2,5-(difluorophenyl), 2,6-(difluorophenyl), 3,4-(difluorophenyl), 3,5-(difluorophenyl), 3,5-(dibromophenyl), 3,5-(bis(trifluoromethyl)phenyl), 2,3-(dimethylphenyl), 2,5-(dimethylphenyl), 2,6-(dimethylphenyl), 3,5-(dimethylphenyl), 2,4-(dimethoxyphenyl), 2,5-(dimethoxyphenyl), 3,4-(dimethoxyphenyl), 2,3,4-(trimethoxyphenyl), 2,4,6-(trifluorophenyl), and 2,3,4,5,6-(pentafluorophenyl).
23. The compound of claim 3 , wherein R 2 is selected from the group consisting of phenyl, 4-(fluorophenyl), 3-(fluorophenyl), 2-(fluorophenyl), 4-(chlorophenyl), 3-(chlorophenyl), 2-(chlorophenyl), 4-(methylphenyl), 3-(methylphenyl), 2-(methylphenyl), 4-(methoxyphenyl), 3-(methoxyphenyl), 2-(methoxyphenyl), 4-(ethoxyphenyl), 3-(ethoxyphenyl), 2-(ethoxyphenyl), 4-(vinylphenyl), 4-(acetylphenyl), 3-(acetylphenyl), 2-(acetylphenyl), 4-(trifluoromethylphenyl), 3-(trifluoromethylphenyl), 4-(trimethylsilylphenyl), 3-(trimethylsilylphenyl), 4-(methylthiophenyl), 4-(tert-butylphenyl), 4-(dimethylaminophenyl), 4-(ethylphenyl), 4-(benzoxyphenyl), 4-(biphenyl), 2-furanyl, 2-(thiophenyl), 2-(5-methylthiophenyl), 3-(thiophenyl), 2-(indolyl), 1-(naphthalenyl), 2-(naphthalenyl), 4-(dibenzofuranyl), 1-(thianthrenyl), 2,3-(dichlorophenyl), 2,5-(dichlorophenyl), 3,4-(dichlorophenyl), 3,5-(dichlorophenyl), 2,3-(difluorophenyl), 2,4-(difluorophenyl), 2,5-(difluorophenyl), 2,6-(difluorophenyl), 3,4-(difluorophenyl), 3,5-(difluorophenyl), 3,5-(dibromophenyl), 3,5-(bis(trifluoromethyl)phenyl), 2,3-(dimethylphenyl), 2,5-(dimethylphenyl), 2,6-(dimethylphenyl), 3,5-(dimethylphenyl), 2,4-(dimethoxyphenyl), 2,5-(dimethoxyphenyl), 3,4-(dimethoxyphenyl), 2,3,4-(trimethoxyphenyl), 2,4,6-(trifluorophenyl), and 2,3,4,5,6-(pentafluorophenyl).
24. The compound of claim 4 , wherein R 2 is selected from the group consisting of phenyl, 4-(fluorophenyl), 3-(fluorophenyl), 2-(fluorophenyl), 4-(chlorophenyl), 3-(chlorophenyl), 2-(chlorophenyl), 4-(methylphenyl), 3-(methylphenyl), 2-(methylphenyl), 4-(methoxyphenyl), 3-(methoxyphenyl), 2-(methoxyphenyl), 4-(ethoxyphenyl), 3-(ethoxyphenyl), 2-(ethoxyphenyl), 4-(vinylphenyl), 4-(acetylphenyl), 3-(acetylphenyl), 2-(acetylphenyl), 4-(trifluoromethylphenyl), 3-(trifluoromethylphenyl), 4-(trimethylsilylphenyl), 3-(trimethylsilylphenyl), 4-(methylthiophenyl), 4-(tert-butylphenyl), 4-(dimethylaminophenyl), 4-(ethylphenyl), 4-(benzoxyphenyl), 4-(biphenyl), 2-furanyl, 2-(thiophenyl), 2-(5-methylthiophenyl), 3-(thiophenyl), 2-(indolyl), 1-(naphthalenyl), 2-(naphthalenyl), 4-(dibenzofuranyl), 1-(thianthrenyl), 2,3-(dichlorophenyl), 2,5-(dichlorophenyl), 3,4-(dichlorophenyl), 3,5-(dichlorophenyl), 2,3-(difluorophenyl), 2,4-(difluorophenyl), 2,5-(difluorophenyl), 2,6-(difluorophenyl), 3,4-(difluorophenyl), 3,5-(difluorophenyl), 3,5-(dibromophenyl), 3,5-(bis(trifluoromethyl)phenyl), 2,3-(dimethylphenyl), 2,5-(dimethylphenyl), 2,6-(dimethylphenyl), 3,5-(dimethylphenyl), 2,4-(dimethoxyphenyl), 2,5-(dimethoxyphenyl), 3,4-(dimethoxyphenyl), 2,3,4-(trimethoxyphenyl), 2,4,6-(trifluorophenyl), and 2,3,4,5,6-(pentafluorophenyl).
25. The compound of claim 5 , wherein R 2 is selected from the group consisting of phenyl, 4-(fluorophenyl), 3-(fluorophenyl), 2-(fluorophenyl), 4-(chlorophenyl), 3-(chlorophenyl), 2-(chlorophenyl), 4-(methylphenyl), 3-(methylphenyl), 2-(methylphenyl), 4-(methoxyphenyl), 3-(methoxyphenyl), 2-(methoxyphenyl), 4-(ethoxyphenyl), 3-(ethoxyphenyl), 2-(ethoxyphenyl), 4-(vinylphenyl), 4-(acetylphenyl), 3-(acetylphenyl), 2-(acetylphenyl), 4-(trifluoromethylphenyl), 3-(trifluoromethylphenyl), 4-(trimethylsilylphenyl), 3-(trimethylsilylphenyl), 4-(methylthiophenyl), 4-(tert-butylphenyl), 4-(dimethylaminophenyl), 4-(ethylphenyl), 4-(benzoxyphenyl), 4-(biphenyl), 2-furanyl, 2-(thiophenyl), 2-(5-methylthiophenyl), 3-(thiophenyl), 2-(indolyl), 1-(naphthalenyl), 2-(naphthalenyl), 4-(dibenzofuranyl), 1-(thianthrenyl), 2,3-(dichlorophenyl), 2,5-(dichlorophenyl), 3,4-(dichlorophenyl), 3,5-(dichlorophenyl), 2,3-(difluorophenyl), 2,4-(difluorophenyl), 2,5-(difluorophenyl), 2,6-(difluorophenyl), 3,4-(difluorophenyl), 3,5-(difluorophenyl), 3,5-(dibromophenyl), 3,5-(bis(trifluoromethyl)phenyl), 2,3-(dimethylphenyl), 2,5-(dimethylphenyl), 2,6-(dimethylphenyl), 3,5-(dimethylphenyl), 2,4-(dimethoxyphenyl), 2,5-(dimethoxyphenyl), 3,4-(dimethoxyphenyl), 2,3,4-(trimethoxyphenyl), 2,4,6-(trifluorophenyl), and 2,3,4,5,6-(pentafluorophenyl).