# US 2018/0022698 A1 · Novel methods, compounds, and compositions for anesthesia

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- Number: US 2018/0022698 A1
- Document ID: US20180022698A1
- Status: Published application
- Kind: A1
- Application number: 15/519,543
- Filed: 2015-10-16
- Published: 2018-01-25
- Earliest claimed: 2014-10-16
- Assignees: The Board of Trustees of the Leland Stanford Junior University; The United States Government as represented by the Department of Veterans Affairs
- Applicants: The Board of Trustees of the Leland Stanford Junior University; The United States Government AS Represented By the Department of Veterans Affairs
- Inventors: Edward John BERTACCINI; Margaret Frances DAVIES
- Web page: https://patentgrep.com/patent/US20180022698A1

## CPC

- C07D 207/34: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/402: 1-aryl substituted, e.g. piretanide
- A61P 23/00: Anaesthetics
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/22: Anxiolytics
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim at position 1

1-30. (canceled)

### Claim 31

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.

### Claim 32 (depends on 31)

The compound of claim 31, wherein Ri2 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.

### Claim 33 (depends on 32)

The compound of claim 32, wherein Ri2 is a phenyl group optionally substituted with one or more alkyl, alkoxy, or halo groups.

### Claim 34 (depends on 31)

The compound of claim 31, wherein Re is an optionally substituted C3-C8-alkyl or aralkyl group.

### Claim 35 (depends on 34)

The compound of claim 34, wherein Re is an optionally substituted C3-C8-alkyl group.

### Claim 36 (depends on 31)

The compound of claim 31, wherein Rp1 and Rp2 are independently H, alkyl, alkoxy, hydroxyl, thio, amino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, trihalomethyl, cyano, nitro, phosphoryl, sulfonyl, sulfonamido, or azido.

### Claim 37 (depends on 36)

The compound of claim 36, wherein Rp1 and Rp2 are independently H, alkyl, alkoxy, or halo.

### Claim 38

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].

### Claim 39 (depends on 38)

The compound of claim 38, wherein Ri2 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.

### Claim 40 (depends on 39)

The compound of claim 39, wherein Ri2 is a phenyl group substituted with one or more alkyl, alkoxy, or halo groups.

### Claim 41 (depends on 38)

The compound of claim 38, wherein Re is an optionally substituted lower alkyl or aralkyl group.

### Claim 42 (depends on 41)

The compound of claim 41, wherein Re is an optionally substituted lower alkyl group.

### Claim 43 (depends on 38)

The compound of claim 38, wherein Rp1 and Rp2 are independently H, alkyl, alkoxy, hydroxyl, thio, amino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, trihalomethyl, cyano, nitro, phosphoryl, sulfonyl, sulfonamido, or azido.

### Claim 44 (depends on 43)

The compound of claim 43, wherein Rp1 and Rp2 are independently H, alkyl, alkoxy, or halo.

### Claim at position 16

45-50. (canceled)

### Claim 51

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.

### Claim 52 (depends on 51)

The compound of claim 51, wherein Ri2 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.

### Claim 53 (depends on 52)

The compound of claim 52, wherein Ri2 is a phenyl group optionally substituted with one or more alkyl, alkoxy, or halo groups.

### Claim 54 (depends on 51)

The compound of claim 51, wherein Re is an optionally substituted lower alkyl or aralkyl group.

### Claim 55 (depends on 54)

The compound of claim 54, wherein Re is an optionally substituted lower alkyl group.

### Claim 56 (depends on 51)

The compound of claim 51, wherein Rp1 and Rp2 are independently H, alkyl, alkoxy, hydroxyl, thio, amino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, trihalomethyl, cyano, nitro, phosphoryl, sulfonyl, sulfonamido, or azido.

### Claim 57 (depends on 56)

The compound of claim 56, wherein Rp1 and Rp2 are independently H, alkyl, alkoxy, or halo.

### Claim at position 24

58-59. (canceled)