US 2018/0022698 A1 · 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.

Claims24

Dependent claims

1-30. (canceled)

A compound represented by structural formula (II):

or a pharmaceutically acceptable salt thereof, wherein:
Rp1 and Rp2 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;
Ri1 is H or a C1-C6 alkyl group;
Ri2 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;
Ri3 is H or an unsubstituted lower alkyl group;
and
Re is C3-C8-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 Ri1 is methyl, Ri2 is unsubstituted phenyl, and Re is benzyl, isopropyl, isobutyl, t-butyl, methoxyethyl, or 4,4-difluoro-3-methyl-3-buten-1-yl, and Rp1 is H, then Rp2 is not H;
when Ri1 is methyl, Ri2 is 2-methoxyphenyl, Re is t-butyl, and Rp1 is H, then Rp2 is not H, 3-amino, 3-azido, 4-bromo, or 4-nitro;
and
when Ri1 is methyl, Ri2 is 2-methoxyphenyl, Re is benzyl, and Rp1 is H, then Rp2 is not H.

8 more elements

A compound represented by structural formula (II):

or a pharmaceutically acceptable salt thereof, wherein:
Rp1 and Rp2 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;
Ri1 is H or a C1-C6 alkyl group;
Ri2 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;
Ri3 is H or an unsubstituted lower alkyl group;
and
Re 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 Ri2 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].

5 more elements

A compound represented by structural formula (II):

or a pharmaceutically acceptable salt thereof, wherein:
Rp1 and Rp2 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;
Ri1 is H;
Ri2 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;
Ri3 is H or an unsubstituted lower alkyl group;
and
Re 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 Ri2 is 4-(methylsulfonyl)phenyl, Re is methyl, and Rp1 is H, then Rp2 is not 4-fluoro;
and
when Ri2 is unsubstituted phenyl, Re is methyl, and Rp1 is H, then Rp2 is not 4-methoxy.

8 more elements

Dependencies are inferred from the claim text.

Novel methods, compounds, and compositions for anesthesia

Life of this patent

Novel methods, compounds, and compositions for anesthesia

Life of this patent

Abstract

Claims24