# US 2019/0169113 A1 · Ketamine Derivatives

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- Number: US 2019/0169113 A1
- Document ID: US20190169113A1
- Status: Published application
- Kind: A1
- Application number: 16/269,015
- Filed: 2019-02-06
- Published: 2019-06-06
- Earliest claimed: 2012-10-08
- Assignees: Auckland Uniservices Limited
- Applicants: Auckland Uniservices Limited
- Inventors: James Wallace Sleigh; William Alexander Denny; Jiney Jose; Swarnalatha Akuratiya Gamage; Martyn Gregory Harvey; Logan James Voss
- Web page: https://patentgrep.com/patent/US20190169113A1

## CPC

- C07C 229/14: to carbon atoms of carbon skeletons containing rings
- A61P 23/00: Anaesthetics
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/20: Hypnotics; Sedatives
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07C 225/20: having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
- C07C 229/46: having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

pa The present invention relates to ketamine derivatives of the formula (I), pharmaceutical compositions comprising them, and methods for treating pain comprising administering them, and their use in the manufacture of medicaments for treating pain. The present invention also relates to methods for anaesthetizing and methods for sedating a subject comprising administering ketamine derivatives of the formula (II).

## Claims

### Claim 1

A method for anaesthetizing or sedating a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof to the subject, wherein:
wherein
Y1 is −C2-6aliphaticC(O)OR1, —C2-6aliphaticOC(O)R1, —C1-6aliphaticC(O)OC1-6aliphaticC(O)OR1, or —C1-6aliphaticC(O)OC1-6aliphaticOR3, wherein each aliphatic is optionally substituted with one or more R2;
R1 is C1-6aliphatic, optionally substituted with one or more halo, CN, NO2, NH2, NHR11, NR11-R12, C1-6haloalkyl, C1-6haloalkoxy, C(O)NH2, C(O)NHR11, C(O)NR11R12, SO2R11, OR11, C(O)R11, and C1-6aliphatic;
R2 is C1-6aliphatic, optionally substituted with one or more halo, OR11, or CN;
R3 is hydrogen or R1;
R11 and R12 are each independently C1-6aliphatic; or R11 and R12 together with the nitrogen atom to which they are attached are a heteroaryl or heterocyclyl ring;
Y2 is hydrogen or R2;
X1 and X2 are each independently hydrogen, R2, halo, NO2, NH2, NHR11, NR11R12, C1-6haloalkyl, C1-6haloalkoxy, C(O)NH2, C(O)NHR11, C(O)NR11R12, SO2R11, OR11, C(O)R11, C1-6aliphaticY1, OY1, C(O)Y1, SO2Y1, or C(O)NHY1 at any of the available 2-5 positions;
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein:
Y1 is −C2-6alkylC(O)OR1, —C2-6alkylOC(O)R1, —C1-6alkylC(O)OC1-6alkylC(O)OR1, or —C1-6alkylC(O)OC1-6alkylOR3, wherein each alkyl is optionally substituted with one or more R2;
R1 is C1-6aliphatic, optionally substituted with one or more halo, CN, NO2, NH2, NHR11, NR11-R12, C1-6haloalkyl, C1-6haloalkoxy, C(O)NH2, C(O)NHR11, C(O)NR11R12, SO2R11, OR11, C(O)R11, and C1-6aliphatic;
R2 is C1-6aliphatic, optionally substituted with one or more halo, OR11, or CN;
R3 is hydrogen or R1;
R11 and R12 are each independently C1-6aliphatic; or R11 and R12 together with the nitrogen atom to which they are attached are a heteroaryl or heterocyclyl ring;
Y2 is hydrogen or R2;
X1 and X2 are each independently hydrogen, R2, halo, NO2, NH2, NHR11, NR11R12, C1-6haloalkyl, C1-6haloalkoxy, C(O)NH2, C(O)NHR11, C(O)NR11R12, SO2R11, OR11, C(O)R11, C1-6aliphaticY1, OY1, C(O)Y1, SO2Y1, or C(O)NHY1 at any of the available 2-5 positions;
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 3 (depends on 2)

The method of claim 2, wherein Y1 is —C2-6alkylC(O)OR1 or —C2-6alkylOC(O)R1, wherein each alkyl is optionally substituted.

### Claim 4 (depends on 2)

The method of claim 2, wherein Y1 is —C2-6alkylC(O)OR1, wherein the alkyl is optionally substituted.

### Claim 5 (depends on 2)

The method of claim 2, wherein R1 is C1-6alkyl, C2-6alkenyl, cycloalkyl, or cycloalkenyl, wherein each alkyl and cycloalkyl are optionally substituted with one or more halo, CN, NO2, NH2, NHR11, NR11R12, C1-6haloalkyl, C1-6haloalkoxy, C(O)NH2, C(O)NHR11, C(O)NR11R12, SO2R11, OR11, and C(O)R11; and each alkyl is optionally substituted with cycloalkyl or cycloalkenyl; and each cycloalkyl is optionally substituted with C1-6alkyl or C2-6alkenyl.

### Claim 6 (depends on 5)

The method of claim 5, wherein R1 is C1-6alkyl or cycloalkyl, wherein each alkyl and cycloalkyl is optionally substituted.

### Claim 7 (depends on 6)

The method of claim 6, wherein R1 is C1-6alkyl, wherein each alkyl is optionally substituted.

### Claim 8 (depends on 2)

The method of claim 2, wherein R2 is C1-6alkyl or cycloalkyl, optionally substituted with one or more halo, OR11, or CN.

### Claim 9 (depends on 8)

The method of claim 8, wherein R2 is C1-6alkyl, optionally substituted with one or more halo, OR11, or CN.

### Claim 10 (depends on 2)

The method of claim 2, wherein Y2 is hydrogen or C1-6alkyl, wherein the alkyl is optionally substituted.

### Claim 11 (depends on 2)

The method of claim 2, wherein X1 and X2 are each independently hydrogen, R2, halo, NO2, NH2, NHR11, NR11R12, C1-6haloalkyl, C1-6haloalkoxy, C(O)NH2, C(O)NHR11, C(O)NR11R12, SO2R11, OR11, or C(O)R11; or X2 is C1-6alkylY1, OY1, C(O)Y1, SO2Y1, or C(O)NHY1 at any of the available 2-5 positions.

### Claim 12 (depends on 11)

The method of claim 11, wherein X1 and X2 are each independently hydrogen, R2, halo, C1-6haloalkyl, C1-6haloalkoxy, SO2R11, or OR11 at any of the available 2-5 positions.

### Claim 13 (depends on 12)

The method of claim 12, wherein X1 is 2-chloro; and X2 is hydrogen, R2, halo, C1-6haloalkyl, C1-6haloalkoxy, SO2R11, or OR11 at any of positions 3-5.

### Claim 14 (depends on 2)

The method of claim 2, wherein Y1 is —(CRARB)m(CRCRD)nC(O)OR1, —(CRARB)m(CRCRD)nOC(O)R1, —(CRARB)m-1(CRCRD)nC(O)O(CRGRH)p(CRERF)oC(O)OR1, or —(CRARB)m-1(CRCRD)nC(O)O(CRGRH)p(CRERF)oOR3; m is an integer from 2 to 6; o is an integer from 1 to 6; n and p are each independently 0 or 1; the sum of m and n and the sum of o and p is 6 or less; and RA, RB, RC, RD, RE, RF, RG, and RH at each instance of m, n, o, and p are each independently hydrogen or R2.

### Claim 15 (depends on 14)

The method of claim 14, wherein Y1 is (CRARB)m(CRCRD)nC(O)OR1.

### Claim 16 (depends on 14)

The method of claim 14, wherein RA, RB, RE, and RF at each instance of m and o are each independently hydrogen; and RC, RD, RG, and RH at each instance of n and p are each independently hydrogen or R2.

### Claim 17 (depends on 2)

The method of claim 2, wherein the compound is
3-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino)propyl acetate,
ethyl 3-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino) propanoate,
iso-propyl 3-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino) propanoate,
n-propyl 3-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino) propanoate,
ethyl 4-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino) butanoate,
isopropyl 4-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino) butanoate,
n-propyl 4-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino) butanoate,
methyl 5-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino) pentanoate,
ethyl 5-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino) pentanoate,
isopropyl 5-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino) pentanoate,
n-propyl 5-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino) pentanoate,
ethyl 3-((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)amino) propanoate,
ethyl 4-((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)amino) butanoate, or
methyl 5-((1-(2-chlorophenyl)-2-oxocyclohexyl)(methyl)amino) pentanoate, or
a pharmaceutically acceptable salt or solvate thereof.

### Claim 18 (depends on 2)

The method of claim 2, wherein X1 is 2-halo and X2 is hydrogen.

### Claim 19 (depends on 2)

The method of claim 2, wherein Y2 is hydrogen or methyl.

### Claim 20 (depends on 2)

The method of claim 2, wherein R1 is C1-6alkyl.

### Claim 21 (depends on 2)

The method of claim 2, wherein X1is 2-chloro and X2 is hydrogen.

### Claim 22 (depends on 2)

The method of claim 2, wherein the compound is methyl 5-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino)pentanoate, or a pharmaceutically acceptable salt or solvate thereof.

### Claim 23 (depends on 2)

The method of claim 2, wherein the compound is isopropyl 3-((1-(2-chlorophenyl)-2-oxocyclohexyl)amino)propanoate, or a pharmaceutically acceptable salt or solvate thereof.

### Claim 24

A compound of formula (I):
wherein
Y1 is —C2-6aliphaticC(O)OR1, —C2-6aliphaticOC(O)R1, —C1-6aliphaticC(O)OC1-6aliphaticC(O)OR1, or —C1-6aliphaticC(O)OC1-6aliphaticOR3, wherein each aliphatic is optionally substituted with one or more R2;
R1 is C1-6aliphatic, optionally substituted with one or more halo, CN, NO2, NH2, NHR11,
NR11-R12, C1-6halalkyl, C1-6haloalkoxy, C(O)NH2, C(O)NHR11, C(O)NR11R12, SO2R11, OR11, C(O)R11, and C1-6aliphatic;
R2 is C1-6aliphatic, optionally substituted with one or more halo, OR11, or CN;
R3 is hydrogen or R1;
R11 and R12 are each independently C1-6aliphatic; or R11 and R12 together with the nitrogen atom to which they are attached are a heteroaryl or heterocyclyl ring;
Y2 is hydrogen or R2;
X1 and X2 are each independently hydrogen, R2, halo, NO2, NH2, NHR11, NR11R12, C1-6haloalkyl, C1-6haloalkoxy, C(O)NH2, C(O)NHR11, C(O)NR11, R12, SO2R11, OR11, C(O)R11, C1-6aliphaticY1, OY1, C(O)Y1, SO2Y1, or C(O)NHY1 at any of the available 2-5 positions;
or a pharmaceutically acceptable salt or solvate thereof.