Novel methods, compounds, and compositions for anesthesia

Abstract

Methods of treatment useful in the inducement or maintenance of anesthesia in a subject are provided. The methods comprise administering to a subject in need of anesthesia a compound disclosed herein. Also provided are novel compounds having anesthetic effects, pharmaceutical compositions comprising the compounds, and packaged pharmaceuticals. Computer modeling of the compounds demonstrates favorable interactions with the GABA receptor type A. In addition, the compounds display reversible anesthetic effects in an animal model, with dose-response curves similar to those of known general anesthetics. GABA receptor-mediated effects are also demonstrated in a hippocampal brain slice preparation.

1 - 30 . (canceled) 
     
     
         31 . A compound represented by structural formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R p1  and R p2  are independently H, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkylamino, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkanoyl, cycloalkamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylalky, heterocyclylalkoxy, heterocyclylalkanoyl, heterocyclylalkamino, hydroxyl, thio, amino, alkanoylamino, alkylcarboxy, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, carboxy, carbonate, carbamate, guanidinyl, urea, halo, trihalomethyl, cyano, nitro, phosphoryl, or azido, each of which may be optionally substituted where chemically feasible; 
         R i1  is H or a C 1 -C 6  alkyl group; 
         R i2  is a phenyl group optionally substituted with one or more alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkylamino, alkylthio, aryl, aryloxy, arylamino, aralkyl, aralkoxy, aralkanoyl, aralkamino, heteroaryl, heteroaryloxy, heteroarylamino, heteroaralkyl, heteroaralkoxy, heteroaralkanoyl, heteroaralkamino, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkanoyl, cycloalkamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylalky, heterocyclylalkoxy, heterocyclylalkanoyl, heterocyclylalkamino, hydroxyl, thio, amino, amido, alkanoylamino, aroylamino, aralkanoylamino, alkylcarboxy, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, carboxy, carbonate, carbamate, guanidinyl, urea, halo, trihalomethyl, cyano, nitro, phosphoryl, sulfonyl, sulfonamido, or azido groups, and wherein two adjacent substituent groups can combine to form a ring; 
         R i3  is H or an unsubstituted lower alkyl group; and 
         R e  is C 3 -C 8 -alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkenyl, heterocyclyl, or heterocyclylalky, and is optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkylamino, alkylthio, aryl, aryloxy, arylamino, aralkyl, aralkoxy, aralkanoyl, aralkamino, heteroaryl, heteroaryloxy, heteroarylamino, heteroaralkyl, heteroaralkoxy, heteroaralkanoyl, heteroaralkamino, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkanoyl, cycloalkamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylalky, heterocyclylalkoxy, heterocyclylalkanoyl, heterocyclylalkamino, hydroxyl, thio, amino, amido, alkanoylamino, aroylamino, aralkanoylamino, alkylcarboxy, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, carboxy, carbonate, carbamate, guanidinyl, urea, halo, trihalomethyl, cyano, nitro, phosphoryl, or azido; 
         provided that when R i1  is methyl, R i2  is unsubstituted phenyl, and R e  is benzyl, isopropyl, isobutyl, t-butyl, methoxyethyl, or 4,4-difluoro-3-methyl-3-buten-1-yl, and R p1  is H, then R p2  is not H; 
         when R i1  is methyl, R i2  is 2-methoxyphenyl, R e  is t-butyl, and R p1  is H, then R p2  is not H, 3-amino, 3-azido, 4-bromo, or 4-nitro; and 
         when R i1  is methyl, R i2  is 2-methoxyphenyl, R e  is benzyl, and R p1  is H, then R p2  is not H. 
       
     
     
         32 . The compound of  claim 31 , wherein R i2  is a phenyl group optionally substituted with one or more alkyl, alkoxy, hydroxyl, thio, amino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, trihalomethyl, cyano, nitro, phosphoryl, sulfonyl, sulfonamido, or azido groups. 
     
     
         33 . The compound of  claim 32 , wherein R i2  is a phenyl group optionally substituted with one or more alkyl, alkoxy, or halo groups. 
     
     
         34 . The compound of  claim 31 , wherein R e  is an optionally substituted C 3 -C 8 -alkyl or aralkyl group. 
     
     
         35 . The compound of  claim 34 , wherein R e  is an optionally substituted C 3 -C 8 -alkyl group. 
     
     
         36 . The compound of  claim 31 , wherein R p1  and R p2  are independently H, alkyl, alkoxy, hydroxyl, thio, amino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, trihalomethyl, cyano, nitro, phosphoryl, sulfonyl, sulfonamido, or azido. 
     
     
         37 . The compound of  claim 36 , wherein R p1  and R p2  are independently H, alkyl, alkoxy, or halo. 
     
     
         38 . A compound represented by structural formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R p1  and R p2  are independently H, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkylamino, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkanoyl, cycloalkamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylalky, heterocyclylalkoxy, heterocyclylalkanoyl, heterocyclylalkamino, hydroxyl, thio, amino, alkanoylamino, alkylcarboxy, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, carboxy, carbonate, carbamate, guanidinyl, urea, halo, trihalomethyl, cyano, nitro, phosphoryl, or azido, each of which may be optionally substituted where chemically feasible; 
         R i1  is H or a C 1 -C 6  alkyl group; 
         R i2  is a phenyl group substituted with one or more alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkylamino, alkylthio, aryl, aryloxy, arylamino, aralkyl, aralkoxy, aralkanoyl, aralkamino, heteroaryl, heteroaryloxy, heteroarylamino, heteroaralkyl, heteroaralkoxy, heteroaralkanoyl, heteroaralkamino, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkanoyl, cycloalkamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylalky, heterocyclylalkoxy, heterocyclylalkanoyl, heterocyclylalkamino, hydroxyl, thio, amino, amido, alkanoylamino, aroylamino, aralkanoylamino, alkylcarboxy, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, carboxy, carbonate, carbamate, guanidinyl, urea, halo, trihalomethyl, cyano, nitro, phosphoryl, sulfonyl, sulfonamido, or azido groups, and wherein two adjacent substituent groups can combine to form a ring; 
         R i3  is H or an unsubstituted lower alkyl group; and 
         R e  is alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkenyl, heterocyclyl, or heterocyclylalky, and is optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkylamino, alkylthio, aryl, aryloxy, arylamino, aralkyl, aralkoxy, aralkanoyl, aralkamino, heteroaryl, heteroaryloxy, heteroarylamino, heteroaralkyl, heteroaralkoxy, heteroaralkanoyl, heteroaralkamino, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkanoyl, cycloalkamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylalky, heterocyclylalkoxy, heterocyclylalkanoyl, heterocyclylalkamino, hydroxyl, thio, amino, amido, alkanoylamino, aroylamino, aralkanoylamino, alkylcarboxy, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, carboxy, carbonate, carbamate, guanidinyl, urea, halo, trihalomethyl, cyano, nitro, phosphoryl, or azido; 
         provided that R i2  is not 2-aminophenyl, 3-aminophenyl, 3-amino-4-hydroxyphenyl, 4-aminophenyl, 3-azidophenyl, 1,1′-biphenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-carboxyphenyl, 2-(chlorocarbonyl)phenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,4-dimethylphenyl, 4-fluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-(ethoxycarbonyl)phenyl, 4-(methoxycarbonyl)phenyl, 2-methylphenyl, 4-methylphenyl, 4-(methylsulfonyl)phenyl, 4-(methylthio)phenyl, 3-(4-morpholinylsulfonyl)phenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-(phenylamino)phenyl, 4-(1H-pyrrol-1-yl)phenyl, 4-(1-methyl-1H-pyrazol-4-yl)phenyl, 2-hydroxy-5-aminophenyl, or 4-[5-(4-chlorophenyl)-3-(ethoxycarbonyl)-2-methyl-1H-pyrrol-1-yl]phenyl]. 
       
     
     
         39 . The compound of  claim 38 , wherein R i2  is a phenyl group substituted with one or more alkyl, alkoxy, hydroxyl, thio, amino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, trihalomethyl, cyano, nitro, phosphoryl, sulfonyl, sulfonamido, or azido groups. 
     
     
         40 . The compound of  claim 39 , wherein R i2  is a phenyl group substituted with one or more alkyl, alkoxy, or halo groups. 
     
     
         41 . The compound of  claim 38 , wherein R e  is an optionally substituted lower alkyl or aralkyl group. 
     
     
         42 . The compound of  claim 41 , wherein R e  is an optionally substituted lower alkyl group. 
     
     
         43 . The compound of  claim 38 , wherein R p1  and R p2  are independently H, alkyl, alkoxy, hydroxyl, thio, amino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, trihalomethyl, cyano, nitro, phosphoryl, sulfonyl, sulfonamido, or azido. 
     
     
         44 . The compound of  claim 43 , wherein R p1  and R p2  are independently H, alkyl, alkoxy, or halo. 
     
     
         45 - 50 . (canceled) 
     
     
         51 . A compound represented by structural formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R p1  and R p2  are independently H, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkylamino, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkanoyl, cycloalkamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylalky, heterocyclylalkoxy, heterocyclylalkanoyl, heterocyclylalkamino, hydroxyl, thio, amino, alkanoylamino, alkylcarboxy, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, carboxy, carbonate, carbamate, guanidinyl, urea, halo, trihalomethyl, cyano, nitro, phosphoryl, or azido, each of which may be optionally substituted where chemically feasible; 
         R i1  is H; 
         R i2  is a phenyl group optionally substituted with one or more alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkylamino, alkylthio, aryl, aryloxy, arylamino, aralkyl, aralkoxy, aralkanoyl, aralkamino, heteroaryl, heteroaryloxy, heteroarylamino, heteroaralkyl, heteroaralkoxy, heteroaralkanoyl, heteroaralkamino, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkanoyl, cycloalkamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylalky, heterocyclylalkoxy, heterocyclylalkanoyl, heterocyclylalkamino, hydroxyl, thio, amino, amido, alkanoylamino, aroylamino, aralkanoylamino, alkylcarboxy, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, carboxy, carbonate, carbamate, guanidinyl, urea, halo, trihalomethyl, cyano, nitro, phosphoryl, sulfonyl, sulfonamido, or azido groups, and wherein two adjacent substituent groups can combine to form a ring; 
         R i3  is H or an unsubstituted lower alkyl group; and 
         R e  is alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkenyl, heterocyclyl, or heterocyclylalky, and is optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkylamino, alkylthio, aryl, aryloxy, arylamino, aralkyl, aralkoxy, aralkanoyl, aralkamino, heteroaryl, heteroaryloxy, heteroarylamino, heteroaralkyl, heteroaralkoxy, heteroaralkanoyl, heteroaralkamino, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkanoyl, cycloalkamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylalky, heterocyclylalkoxy, heterocyclylalkanoyl, heterocyclylalkamino, hydroxyl, thio, amino, amido, alkanoylamino, aroylamino, aralkanoylamino, alkylcarboxy, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, carboxy, carbonate, carbamate, guanidinyl, urea, halo, trihalomethyl, cyano, nitro, phosphoryl, or azido; 
         provided that 
         when R i2  is 4-(methylsulfonyl)phenyl, R e  is methyl, and R p1  is H, then R p2  is not 4-fluoro; and 
         when R i2  is unsubstituted phenyl, R e  is methyl, and R p1  is H, then R p2  is not 4-methoxy. 
       
     
     
         52 . The compound of  claim 51 , wherein R i2  is a phenyl group optionally substituted with one or more alkyl, alkoxy, hydroxyl, thio, amino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, trihalomethyl, cyano, nitro, phosphoryl, sulfonyl, sulfonamido, or azido groups. 
     
     
         53 . The compound of  claim 52 , wherein R i2  is a phenyl group optionally substituted with one or more alkyl, alkoxy, or halo groups. 
     
     
         54 . The compound of  claim 51 , wherein R e  is an optionally substituted lower alkyl or aralkyl group. 
     
     
         55 . The compound of  claim 54 , wherein R e  is an optionally substituted lower alkyl group. 
     
     
         56 . The compound of  claim 51 , wherein R p1  and R p2  are independently H, alkyl, alkoxy, hydroxyl, thio, amino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, trihalomethyl, cyano, nitro, phosphoryl, sulfonyl, sulfonamido, or azido. 
     
     
         57 . The compound of  claim 56 , wherein R p1  and R p2  are independently H, alkyl, alkoxy, or halo. 
     
     
         58 - 59 . (canceled)