Propofol analogs, process for their preparation, and methods of use
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 .- 46 . (canceled)
47 . A compound of the formula
wherein
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 ;
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;
except when X is C═O and R 2 and R 3 are methyl, then R 1 is not phenyl.
48 . The compound of claim 47 , wherein X is C═O, R 1 is C 4 -C 20 aryl, R 2 is hydrogen, and R 3 is methyl.
49 . The compound of claim 47 , wherein X is C═O, R 1 is C 4 -C 20 aryl, and R 2 and R 3 are ethyl.
50 . The compound of claim 47 , wherein X is C═O, R 1 is C 4 -C 20 aryl, R 2 is hydrogen, and R 3 is ethyl.
51 . The compound of claim 47 , wherein X is C═O, R 1 is C 4 -C 20 aryl, R 2 is methyl, and R 3 is ethyl.
52 . The compound of claim 47 , wherein X is C═O, R 1 is C 4 -C 20 aryl, R 2 is hydrogen, and R 3 is propyl.
53 . The compound of claim 47 , wherein X is C═O, R 1 is C 4 -C 20 aryl, R 2 is methyl, and R 3 is propyl.
54 . The compound of claim 47 , wherein X is C═O, R 1 is C 4 -C 20 aryl, R 2 is ethyl, and R 3 is propyl.
55 . The compound of claim 47 , wherein X is C═O, R 1 is C 4 -C 20 aryl, and R 2 and R 3 are propyl.
56 . The compound of claim 47 , wherein X is C═O and Y═H, R 1 is C 4 -C 20 aryl, and R 2 and R 3 are methyl.
57 . The compound of claim 47 , 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.
58 . The compound of claim 47 , wherein X is C═O and Y═H, R 1 is C 4 -C 20 aryl, and R 2 and R 3 are ethyl.
59 . The compound of claim 47 , wherein X is C═O and Y═H, R 1 is aryl, R 2 is hydrogen, and R 3 is ethyl.
60 . The compound of claim 47 , wherein X is C═O and Y═H, R 1 is C 4 -C 20 aryl, R 2 is methyl, and R 3 is ethyl.
61 . The compound of claim 47 , wherein X is C═O and Y═H, R 1 is C 4 -C 20 aryl, R 2 is hydrogen, and R 3 is propyl.
62 . The compound of claim 47 , wherein X is C═O and Y═H, R 1 is C 4 -C 20 aryl, R 2 is methyl, and R 3 is propyl.
63 . The compound of claim 47 , wherein X is C═O and Y═H, R 1 is C 4 -C 20 aryl, R 2 is ethyl, and R 3 is propyl.
64 . The compound of claim 47 , wherein X is C═O and Y═H, R 1 is C 4 -C 20 aryl, and R 2 and R 3 are propyl.
65 . The compound of any of claims 48 - 55 , wherein R 1 is phenyl.
66 . The compound of any of claims 48 - 55 , wherein R 1 is phenyl and Y is H.
67 . The compound of any of claims 48 - 55 , 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.
68 . The compound of any of claims 48 - 55 , wherein Y is H and 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.
69 . The compound of claim 47 , wherein Y is H.
70 . The compound of claim 47 , wherein Y is H and X is C═O.
71 . The compound of claim 47 , wherein Y is phosphate.
72 . The compound of claim 47 , wherein X is C═O, R 1 is 4-chlorophenyl, and R 2 and R 3 are each methyl.
73 . The compound of claim 47 , wherein X is C═O and Y is H, R 1 is 4-chlorophenyl, and R 2 and R 3 are each methyl.
74 . The compound of claim 47 , wherein X is C═O, R 1 is 4-trifluoromethylphenyl, and R 2 and R 3 are each methyl.
75 . The compound of claim 47 , wherein X is C═O and Y is H, R 1 is 4-trifluoromethylphenyl, and R 2 and R 3 are each methyl.
76 . The compound of claim 47 , wherein X is C═O, R 1 is 4-iodophenyl, and R 2 and R 3 are each methyl.
77 . The compound of claim 47 , wherein X is C═O and Y is H, R 1 is 4-iodophenyl, and R 2 and R 3 are each methyl.
78 . A method for preparing the compound of claim 47 , which method comprises reacting an alkylphenol with acyl chloride in the presence of Lewis acid.
79 . A method for preparing the compound of claim 47 , wherein X is C═O and Y is H, which method comprises reacting an alkylphenol with acyl chloride in the presence of Lewis acid.
80 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 47 and a pharmaceutically acceptable carrier or diluent.
81 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 47 , wherein X is C═O and Y is H, and a pharmaceutically acceptable carrier or diluent.
82 . The pharmaceutical composition of claim 80 , wherein the pharmaceutical composition is for parenteral administration and comprises nanoparticles of an anesthetic inducing effective amount of the compound and a pharmaceutically acceptable anesthetic carrier.
83 . The pharmaceutical composition of claim 82 , wherein X is C═O and Y is H, wherein the pharmaceutical composition is for parenteral administration and comprises nanoparticles of an anesthetic inducing effective amount of the compound and a pharmaceutically acceptable anesthetic carrier.
84 . 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 47 .
85 . 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 47 , wherein X is C═O and Y is H.
86 . The method of claim 84 , wherein said administering is by a method selected from the group consisting of oral administration, nasal respiratory administration, bolus injection, intravenous administration, continuous infusion, rectal administration, vaginal administration, sublingual administration, and cutaneous administration.
87 . The method of claim 85 , wherein said administering is by a method selected from the group consisting of oral administration, nasal respiratory administration, bolus injection, intravenous administration, continuous infusion, rectal administration, vaginal administration, sublingual administration, and cutaneous administration.
88 . The method of claim 84 , wherein the method of administration is continuous infusion.
89 . The method of claim 85 , wherein the method of administration is continuous infusion.