US2007185217A1PendingUtilityA1

Propofol analogs, process for their preparation, and methods of use

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Assignee: ABRAXIS BIOSCIENCE INCPriority: Dec 23, 2003Filed: Dec 23, 2004Published: Aug 9, 2007
Est. expiryDec 23, 2023(expired)· nominal 20-yr term from priority
Inventors:Chunlin TaoCheng Zhi YuNeil P. DesaiVuong Trieu
A61P 25/00A61P 25/20C07C 311/29C07C 49/83C07C 49/84C07D 317/54C07C 317/24C07C 255/56C07C 39/373A61K 31/095C07D 317/56C07C 235/84C07C 39/367C07C 205/45C07C 325/02C07C 309/87A61P 23/00A61K 31/12C07C 251/48A61K 31/15C07D 317/58C07C 225/22C07C 69/78C07C 45/46A61K 31/05
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Claims

Abstract

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.

Claims

exact text as granted — not AI-modified
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.

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