# US 2016/0354497 A1 · Cage amine ligands for metallo-radiopharmaceuticals

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- Number: US 2016/0354497 A1
- Document ID: US20160354497A1
- Status: Published application
- Kind: A1
- Application number: 15/240,836
- Filed: 2016-08-18
- Published: 2016-12-08
- Earliest claimed: 2011-12-06
- Assignees: The University of Melbourne
- Applicants: The University of Melbourne
- Inventors: Paul Donnelly; Brett Paterson
- Web page: https://patentgrep.com/patent/US20160354497A1

## CPC

- A61K 51/0482: {chelates from cyclic ligands, e.g. DOTA}
- A61K 51/088: {conjugates with carriers being peptides, polyamino acids or proteins (antibodies A61K51/10)}
- A61P 35/00: Antineoplastic agents
- C07B 59/002: {Heterocyclic compounds}
- C07D 487/08: Bridged systems
- C07F 1/08: Copper compounds
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- 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
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

The present invention relates to compounds that are useful as metal ligands and which can be bound to a biological entity such as a molecular recognition moiety and methods of making these compounds. Once the compounds that are bound to a biological entity are coordinated with a suitable metallic radionuclide, the coordinated compounds are useful as radiopharmaceuticals in the areas of radiotherapy and diagnostic imaging. The invention therefore also relates to methods of diagnosis and therapy utilising the radiolabelled compounds of the invention.

## Claims

### Claim 1

A compound of the formula (III):
wherein Lig is a nitrogen containing macrocyclic metal ligand;
L is a bond or a linking moiety;
L1 is a spacer group;
R is a moiety capable of binding to a biological entity or a protected form thereof or a synthon thereof.

### Claim 2 (depends on 1)

A compound according to claim 1 wherein Lig is a nitrogen containing cage metal ligand of the formula:
V is selected from the group consisting of N and CR1;
each Rx and Ry are independently selected from the group consisting of H, CH3, CO2H, NO2, CH2OH, H2PO4, HSO3, CN, CONH2 and CHO;
each p is independently an integer selected from the group consisting of 2, 3, and 4;
R1 is selected from the group consisting of H, OH, halogen, NO2, NH2, optionally substituted C1-C12alkyl, optionally substituted C6-C18aryl, cyano, CO2R2, NHR3, N(R3)2,
R2 is selected from the group consisting of H, halogen, an oxygen protecting group, optionally substituted C1-C12alkyl, optionally substituted C2-C12alkenyl, optionally substituted C2-C12alkynyl and optionally substituted C2-C12 heteroalkyl;
each R3 is independently selected from the group consisting of H, a nitrogen protecting group, optionally substituted C1-C12alkyl, —(C═O)-substituted C1-C12alkyl, optionally substituted C2-C12alkenyl, optionally substituted C2-C12alkynyl and optionally substituted C2-C12 heteroalkyl.

### Claim 3 (depends on 1, 24)

A compound according to claim 1 wherein Lig is selected from the group consisting of:
wherein R1 is as defined in claim 24.

### Claim 4 (depends on 1)

A compound according to claim 1 wherein L is a linking moiety having from 1 to 20 atoms in the normal chain.

### Claim 5 (depends on 1)

A compound according to claim 1 wherein L is a group of the formula
—(CH2)a—,
wherein optionally one or more of the CH2 groups may be independently replaced by a heteroatomic group selected from S, O, P and NR4 where R4 is selected from the group consisting of H, optionally substituted C1-C12alkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C6-C18aryl, and optionally substituted C1-C18heteroaryl;
a is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.

### Claim 6 (depends on 5)

A compound according to claim 5 wherein a is an integer selected from the group consisting of 1, 2, 3, 4, and 5.

### Claim 7 (depends on 1)

A compound according to claim 1 wherein L is selected from the group consisting of —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2CH2CH2CH2— and —CH2OCH2—.

### Claim 8 (depends on 1)

A compound according to claim 1 wherein L is —CH2CH2CH2—

### Claim 9 (depends on 1)

A compound according to claim 1 wherein L1 is a linking moiety having from 1 to atoms in the normal chain.

### Claim 10 (depends on 1)

A compound according to claim 1 wherein L1 is a group of the formula
—(CH2)a—,
wherein optionally one or more of the CH2 groups may be independently replaced by a heteroatomic group selected from S, O, P and NR4 where R4 is selected from the group consisting of H, optionally substituted C1-C12alkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C6-C18aryl, and optionally substituted C1-C18heteroaryl;
a is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.

### Claim 11 (depends on 10)

A compound according to claim 10 wherein a is an integer selected from the group consisting of 1, 2, 3, 4, and 5.

### Claim 12 (depends on 1)

A compound according to claim 1 wherein C is selected from the group consisting of —CH2—, —CH2CH2—, —CH2CH2CH2—, and —CH2CH2CH2CH2.

### Claim 13 (depends on 1)

A compound according to claim 1 wherein L1 is —CH2CH2CH2—

### Claim 14 (depends on 1)

A compound according to claim 1 wherein R is a moiety capable of taking part in a click chemistry reaction with a complementary moiety on a biological entity.

### Claim 15 (depends on 14)

A compound according to claim 14 wherein R is selected from the group consisting of —NCS, CO2H, NH2, an azide, an alkyne, an isonitrile, a tetrazine, or a protected form thereof or a synthon thereof.

### Claim 16 (depends on 1)

A compound according to claim 1 selected from the group consisting of:
or a metal complex or salt thereof.

### Claim 17 (depends on 1)

A compound according to claim 1, wherein the nitrogen containing macrocyclic metal ligand is coordinated with a metal ion.

### Claim 18 (depends on 17)

A compound according to claim 17 wherein the metal in the metal ion is selected from the group consisting of Cu, Tc, Gd, Ga, In, Co, Re, Fe, Au, Mg, Ca, Ag, Rh, Pt, Bi, Cr, W, Ni, V, Ir, Pt, Zn, Cd, Mn, Ru, Pd, Hg, and Ti.

### Claim 19 (depends on 17)

A compound according to claim 17 wherein the metal in the metal ion is a radionuclide selected from the group consisting of Cu, Tc, Gd, Ga, In, Co, Re, Fe, Au, Ag, Rh, Pt, Bi, Cr, W, Ni, V, Ir, Pt, Zn, Cd, Mn, Ru, Pd, Hg, and Ti.

### Claim 20 (depends on 17)

A compound according to claim 17, wherein the metal in the metal ion is a radionuclide selected from the group consisting of 60Cu, 62Cu, 64Cu and 67Cu.