# US 2024/0199588 A1 · Chiral TACN/NOTA compounds/derivatives with and without metals for application

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- Number: US 2024/0199588 A1
- Document ID: US20240199588A1
- Status: Published application
- Kind: A1
- Application number: 18/550,178
- Filed: 2022-03-21
- Published: 2024-06-20
- Earliest claimed: 2021-03-19
- Assignees: The Hong Kong Polytechnic University
- Applicants: The Hong Kong Polytechnic University
- Inventors: Ga-Lai LAW
- Web page: https://patentgrep.com/patent/US20240199588A1

## CPC

- C07D 403/14: containing three or more hetero rings
- A61K 49/0002: {General or multifunctional contrast agents, e.g. chelated agents}
- A61K 49/106: {the complex-forming compound being cyclic, e.g. DOTA}
- A61K 51/0482: {chelates from cyclic ligands, e.g. DOTA}
- C07D 255/02: not condensed with other rings
- C07D 401/14: containing three or more hetero rings
- 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)

## Abstract

Cyclic 1,4,7-triazacyclononane-1,4,7-triacetic acid chelators and metal complexes comprising the same useful as positron emission tomography imaging agents, magnetic resonance imaging contrast agents, and computed tomography imaging agents, and optical imaging agents, and methods of use and preparation thereof.

## Claims

### Claim 1

A chiral NOTA chelator of Formula 1:
or a pharmaceutically acceptable salt or zwitterion thereof, wherein
R1 is selected from the group consisting of hydrogen, alkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, araalkyl, and —(CR2)nY, wherein n is a whole number selected from 1-10; each R is independently hydrogen, alkyl, cycloalkyl, or aryl; or two R taken together with the carbon(s) to which they are attached form a 3-6 membered cycloalkyl; and Y is hydrogen, alkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cyano, halide, —N3, —R5, —OR3, —OP(OR3)3, —SR3, —NR32, —(C═O)OR3, —O(C═O)R3, —O(C═O)OR3, —(NR3)(C═O)R3, —(C═O)NR32, —O(C═O)NR32, —(NR3)(C═O)OR3, —(NR3)(C═O)NR32, or —(NR3)(C═NR3)NR32, wherein R3 for each instance is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl heterocyloalkyl, aryl, and heteroaryl; or two R3 taken together with the atom(s) they are attached form a 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or 5 membered heteroaryl; or R1 is a side chain of a naturally occurring amino acid or the side chain of a D-isomer of a naturally occurring amino acid; or R1 is a moiety having the structure:
wherein X is azide, alkyne, halide, tosylate, mesylate, or hydroxyl; and
R2 is —(C═O)OH, —(C═O)NHR5, or —(CH2)mZ, wherein m is a whole number selected from 2-8; R5 is a targeting agent; and Z is moiety of Formula 2:
or a pharmaceutically acceptable salt or zwitterion thereof; or R2 is a moiety of Formula 3:
or a pharmaceutically acceptable salt or zwitterion thereof, wherein R6 for each occurrence is independently hydrogen, alkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cyano, halide, —N3, —R5, —OR3, —OP(OR3)3, —SR3, —NR32, —(C═O)OR3, —O(C═O)R3, —O(C═O)OR3, —(NR3)(C═O)R3, —(C═O)NR32, —O(C═O)NR32, —(NR3)(C═O)OR3, —(NR3)(C═O)NR32, or —(NR3)(C═NR3)NR32, wherein R3 for each instance is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl heterocyloalkyl, aryl, and heteroaryl; or two R3 taken together with the atom(s) they are attached form a 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or 5 membered heteroaryl; or R6 is a moiety of Formula 4:
wherein p is a whole number selected from 1-6;
each A2 is independently —CO2R5, —NHR5, —OR5, N3, or alkyne; and R4 is hydrogen or alkyl, with the proviso that if one R2 is —(CH2)2Z and four R2 are each —(C═O)OH, then each R1 cannot be hydrogen; and if three R2 are each —(C═O)OH, then each R1 cannot be hydrogen.

### Claim 2 (depends on 1)

The chiral NOTA chelator of claim 1, wherein each R1 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, and —(CR2)nY, wherein Y is heteroaryl or aryl; and n is 1-4.

### Claim 3 (depends on 1, 2)

The chiral NOTA chelator of claim 1 or 2, wherein each R2 is —(C═O)OH; or each R2 is —(C═O)NHR5.

### Claim 4 (depends on 1)

The chiral NOTA chelator of claim 1, wherein the chiral NOTA chelator has Formula 5:
or a pharmaceutically acceptable salt or zwitterion thereof, wherein
A1 is OH or NHR5;
each R1 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, and —(CR2)nY, wherein Y is heteroaryl or aryl; and n is 1-4; and
R5 is a targeting agent.

### Claim 5 (depends on 4)

The chiral NOTA chelator of claim 4, wherein each R1 is C1-C6 alkyl; or each R1 is —(CR2)nY, wherein n is a whole number selected from 1-4; and Y is aryl or heteroaryl.

### Claim 6 (depends on 4)

The chiral NOTA chelator of claim 4, wherein each R1 is ethyl; or each R1 is 3-(λ3-methyl)-1H-indole.

### Claim 7 (depends on 1)

The chiral NOTA chelator of claim 1, wherein the chiral NOTA chelator has Formula 7 or Formula 8
or a pharmaceutically acceptable salt or zwitterion thereof, wherein
p is a whole number selected from 1-4;
each A2 is independently —CO2R5, —NHR5, —OR5, N3, or alkyne;
R1 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, and —(CR2)nY, wherein Y is heteroaryl or aryl; and n is 1-4;
R4 is hydrogen or alkyl;
R5 is hydrogen or a targeting agent; and
R6 for each occurrence is independently hydrogen, alkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cyano, halide, —N3, —R5, —OR3, —OP(OR3)3, —SR3, —NR32, —(C═O)OR3, —O(C═O)R3, —O(C═O)OR3, —(NR3)(C═O)R3, —(C═O)NR32, —O(C═O)NR32, —(NR3)(C═O)OR3, —(NR3)(C═O)NR32, or —(NR3)(C═NR3)NR32, wherein R3 for each instance is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl heterocyloalkyl, aryl, and heteroaryl; or two R3 taken together with the atom(s) they are attached form a 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or 5 membered heteroaryl.

### Claim 8 (depends on 7)

The chiral NOTA chelator of claim 7, wherein each R1 is C1-C6 alkyl; and R6 for each occurrence is independently hydrogen, alkyne, halide, —N3, —R5, —NH2, or —(C═O)OH.

### Claim 9 (depends on 7)

The chiral NOTA chelator of claim 7, wherein p is a whole number selected from 1-2; each A2 is independently —CO2R5; each R1 is C1-C6 alkyl; R4 is hydrogen; and R6 is hydrogen.

### Claim 10 (depends on 9)

The chiral NOTA chelator of claim 9, wherein R1 is ethyl; and R5 is hydrogen.

### Claim 11 (depends on 1)

The chiral NOTA chelator of claim 1, wherein the chiral NOTA chelator has Formula 6:
or a pharmaceutically acceptable salt or zwitterion thereof, wherein
m is a whole number selected from 2-8;
A1 is OH or NHR5;
R1 is selected from the group consisting of hydrogen, alkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, araalkyl, and —(CR2)nY, wherein n is a whole number selected from 1-10; each R is independently hydrogen, alkyl, cycloalkyl, or aryl; or two R2 taken together with the carbon(s) to which they are attached form a 3-6 membered cycloalkyl; and Y is hydrogen, alkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cyano, halide, —N3, —R5, —OR3, —OP(OR3)3, —SR3, —NR32, —(C═O)OR3, —O(C═O)R3, —O(C═O)OR3, —(NR3)(C═O)R3, —(C═O)NR32, —O(C═O)NR32, —(NR3)(C═O)OR3, —(NR3)(C═O)NR32, or —(NR3)(C═NR3)NR32, wherein R3 for each instance is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl heterocyloalkyl, aryl, and heteroaryl; or two R3 taken together with the atom(s) they are attached form a 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or 5 membered heteroaryl; or R1 is a side chain of a naturally occurring amino acid or the side chain of a D-isomer of a naturally occurring amino acid; or R1 is a moiety having the structure:
wherein X is azide, alkyne, halide, tosylate, mesylate, or hydroxyl; and
R5 is a targeting agent.

### Claim 12 (depends on 11)

The chiral NOTA chelator of claim 11, wherein each R1 is C1-C6 alkyl; and m is a whole number selected from 2-4.

### Claim 13 (depends on 11)

The chiral NOTA chelator of claim 11, wherein R1 is ethyl.

### Claim 14 (depends on 1)

The chiral NOTA chelator of claim 1, wherein the chiral NOTA chelator is selected from the group consisting of:
or a pharmaceutically acceptable salt or zwitterion thereof, wherein A1 is OH or NHR5;
A2 is OH or NHR5; and R6 is hydrogen or R5.

### Claim 15 (depends on 1)

A chiral NOTA complex comprising the chiral NOTA chelator of claim 1 and at least one metal.

### Claim 16 (depends on 14)

The chiral NOTA complex of claim 14, wherein the at least one metal is a Group 8-13 element of the periodic table, a lanthanide, or an actinide.

### Claim 17 (depends on 14)

The chiral NOTA complex of claim 14, wherein the at least one metal is Gd, Eu, Tb, Lu, Yb, Y, In, or Mn.

### Claim 18 (depends on 15)

A pharmaceutical composition comprising the chiral NOTA complex of claim 15 and at least one pharmaceutically acceptable excipient.

### Claim 19 (depends on 15)

The chiral NOTA complex of claim 15 for use in imaging a sample.

### Claim 20 (depends on 19)

The chiral NOTA complex for use of claim 19, wherein the imaging comprises positron emission tomography (PET), magnetic resonance imaging (MRI), computed tomography (CT) imaging, or optical imaging.

### Claim 21 (depends on 15)

The chiral NOTA complex of claim 15 for use in imaging a subject.

### Claim 22 (depends on 20)

The chiral NOTA complex for use of claim 20, wherein the imaging comprises positron PET, MRI, CT, or optical imaging.