Propofol analogs, process for their preparation, and methods of use
View Patent ↗The invention provides para substituted dialkylphenol derivatives of propofol. The invention further provides pharmaceutical compositions comprising such analogs, methods for preparing such analogs, and methods of using such analogs to induce general anesthesia, sedation, and/or hypnotic or sleep effects in a patient.
1. A compound of the formula
wherein
X is C═O and Y═H, R 1 is C 4 -C 20 aryl, R 2 is hydrogen, and R 3 is methyl, ethyl or propyl with the proviso that R 1 is not phenyl.
2. A compound of the formula
wherein
R 1 is selected from the group consisting of 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 4-bromophenyl, 3-bromophenyl, 2-bromophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-nitrophenyl, 3-nitrophenyl, 2-nitrophenyl, 4-cyanophenyl, 3-cyanophenyl, 2-methylphenyl, 4-methylphenyl, 3-chloromethylphenyl, 2-iodophenyl, 4-iodophenyl, 4-trifluoromethoxyphenyl, 3-propylphenyl, 2-ethylphenyl, 4-bromomethylphenyl, 4-dimethylaminophenyl, 4-biphenyl, 1-naphthalenyl, 2-naphthalenyl, 2-furanyl, 5-nitro-2-furanyl, 2-thiophenyl, 3,4-methylenedioxyphenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, 2,5-bis(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, 4-chloro-3-nitrophenyl, 5-bromo-2-methoxyphenyl, 4-methyl-3-nitrophenyl, 2-fluoro-3-trifluoromethylphenyl, 2-fluoro-5-trifluoromethylphenyl, 2-fluoro-6-trifluoromethylphenyl, 3-fluoro-4-trifluoromethylphenyl, 3-fluoro-5-trifluoromethylphenyl, 2,4-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,5-dichloro-4-methoxyphenyl, 2,3,4-trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trichlorophenyl, 2,4-dichloro-5-fluorophenyl, 3,4,5-trimethoxyphenyl, 2,4,5-trifluoro-3-methoxyphenyl, 2,3,4,5-tetrafluorophenyl, and pentafluorophenyl;
R 2 and R 3 are C 1 -C 6 alkyl;
X is C═O, C═S, C═C, CR 4 R 5 , C(OR 6 )R 7 or C═N—OR 8 ;
Y is hydrogen, COR 4 , COOR 4 , CONR 4 R 5 , COSR 4 or phosphate;
wherein R 4 , R 5 , R 6 , R 7 and R 8 are hydrogen or C 1 -C 6 alkyl.
3. The compound of claim 2 , wherein Y is H.
4. A compound of the formula
wherein Y is phosphate;
R 1 is hydrogen, C 1 -C 6 alkyl, or C 4 -C 20 aryl;
R 2 and R 3 are C 1 -C 6 alkyl;
X is C═O, C═S, C═C, CR 4 R 5 , C(OR 6 )R 7 or C═N—OR 8 ;
wherein R 4 , R 5 , R 6 , R 7 and R 8 are hydrogen or C 1 -C 6 alkyl;
except when X is C═O and R 2 and R 3 are methyl, then R 1 is not phenyl.
5. A compound of the formula
wherein X is C═O, R 1 is 4-chlorophenyl, and R 2 and R 3 are each methyl;
Y is hydrogen, COR 4 , COOR 4 , CONR 4 R 5 , COSR 4 or phosphate; and
R 4 , R 5 , R 6 , R 7 and R 8 are hydrogen or C 1 -C 6 alkyl.
6. A compound of the formula
wherein X is C═O and Y is H, R 1 is 4-chlorophenyl, and R 2 and R 3 are each methyl; and
R 4 , R 5 , R 6 , R 7 and R 8 are hydrogen or C 1 -C 6 alkyl.
7. A compound of the formula
wherein X is C═O, R 1 is 4-trifluoromethylphenyl, and R 2 and R 3 are each methyl;
Y is hydrogen, COR 4 , COOR 4 , CONR 4 R 5 , COSR 4 or phosphate; and
R 4 , R 5 , R 6 , R 7 and R 8 are hydrogen or C 1 -C 6 alkyl.
8. A compound of the formula
wherein X is C═O and Y is H, R 1 is 4-trifluoromethylphenyl, and R 2 and R 3 are each methyl; and
R 4 , R 5 , R 6 , R 7 and R 8 are hydrogen or C 1 -C 6 alkyl.
9. A compound of the formula
wherein X is C═O, R 1 is 4-iodophenyl, and R 2 and R 3 are each methyl;
Y is hydrogen, COR 4 , COOR 4 , CONR 4 R 5 , COSR 4 or phosphate; and
R 4 , R 5 , R 6 , R 7 and R 8 are hydrogen or C 1 -C 6 alkyl.
10. A compound of the formula
wherein X is C═O and Y is H, R 1 is 4-iodophenyl, and R 2 and R 3 are each methyl; and
R 4 , R 5 , R 6 , R 7 and R 8 are hydrogen or 1 - 6 alkyl.
11. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 2 and a pharmaceutically acceptable carrier.
12. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 3 and a pharmaceutically acceptable carrier.
13. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 4 and a pharmaceutically acceptable carrier.
14. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 5 and a pharmaceutically acceptable carrier.
15. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 6 and a pharmaceutically acceptable carrier.
16. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 7 and a pharmaceutically acceptable carrier.
17. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 8 and a pharmaceutically acceptable carrier.
18. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 9 and a pharmaceutically acceptable carrier.
19. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 10 and a pharmaceutically acceptable carrier.
20. A method of inducing sedation, hypnosis and/or sleep effect, or general anesthesia in a patient, which method comprises administering to the patient a therapeutically effective amount of the compound of claim 2 .
21. A method of inducing sedation, hypnosis and/or sleep effect, or general anesthesia in a patient, which method comprises administering to the patient a therapeutically effective amount of the compound of claim 3 .
22. A method of inducing sedation, hypnosis and/or sleep effect, or general anesthesia in a patient, which method comprises administering to the patient a therapeutically effective amount of the compound of claim 4 .
23. A method of inducing sedation, hypnosis and/or sleep effect, or general anesthesia in a patient, which method comprises administering to the patient a therapeutically effective amount of the compound of claim 5 .
24. A method of inducing sedation, hypnosis and/or sleep effect, or general anesthesia in a patient, which method comprises administering to the patient a therapeutically effective amount of the compound of claim 6 .
25. A method of inducing sedation, hypnosis and/or sleep effect, or general anesthesia in a patient, which method comprises administering to the patient a therapeutically effective amount of the compound of claim 7 .
26. A method of inducing sedation, hypnosis and/or sleep effect, or general anesthesia in a patient, which method comprises administering to the patient a therapeutically effective amount of the compound of claim 8 .
27. A method of inducing sedation, hypnosis and/or sleep effect, or general anesthesia in a patient, which method comprises administering to the patient a therapeutically effective amount of the compound of claim 9 .
28. A method of inducing sedation, hypnosis and/or sleep effect, or general anesthesia in a patient, which method comprises administering to the patient a therapeutically effective amount of the compound of claim 10 .