# US 7,410,960 B2 · Metal complexes and therapeutic uses thereof

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- Number: US 7,410,960 B2
- Document ID: US7410960B2
- Status: Granted
- Kind: B2
- Application number: 10/468,935
- Filed: 2002-02-22
- Published: 2004-08-05
- Granted: 2008-08-12
- Earliest claimed: 2001-02-23
- Assignees: University of Western Sydney; The University of Sydney
- Inventors: Ronald Ralph Fenton; Janice Aldrich-Wright
- Web page: https://patentgrep.com/patent/US7410960B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- C07F 1/005: {without C-Metal linkages}
- C07F 15/0066: {without a metal-carbon linkage}
- C07F 15/0093: {without a metal-carbon linkage}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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

A compound of formula I or a salt thereof [ML1L2]2+ (I) where M is selected from the group consisting of platinum(II), palladium (II) and copper(II); L1 is an intercalator moiety; and L2 is a bidentate ligand, provided that when L2 is other than a bidentate ligand containing an aryl or phenyl group, L2 is a chiral bidentate ligand.

## Claims

### Claim 1

A compound of formula I or a salt thereof
[ML1L2]2+ I
where M is selected from the group consisting of platinum(II), palladium (II) and copper(II);
L1 is 1,10-phenanthroline or an alkyl-substituted derivative thereof; and L2 is a chiral diamine ligand.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein M is platinum(II).

### Claim 3 (depends on 1)

A compound according to claim 1, wherein L2 is a compound according to formula IIa or IIb:
R1R2N—CH R3—(CnH2n)—CHR4—NR5R6 IIa
wherein in formula IIa, the group —(CnH2n)— may be acyclic or cyclic, n is 0 to 4 inclusive, R1, R2, R3, R4, R5 and R6, which may be the same or different, are independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, or cycloalkyl; wherein the substituted alkyl, aryl, or cycloalkyl is substituted with at least one methyl group, or R1, R2, R5 and R6 are as defined above and R3 and R4 are joined to form, with the —(CnH2n)— group, a cycloalkane having 6 to 8 ring carbons, and wherein the compound of formula IIa has at least one chiral centre, and
wherein in formula IIb, A is an aromatic ring of 6 to 8 carbons, R1, R2, R4 and R5, which may be the same or different, are independently selected from hydrogen or a substituted or unsubstituted alkyl, aryl, or cycloalkyl, wherein the substituted alkyl, aryl, or cycloalkyl is substituted with at least one methyl group, and
wherein the compound of formula IIb includes at least one chiral centre.

### Claim 4 (depends on 1)

A compound according to claim 1, wherein the intercalator moiety forms a square-planar or pseudo-planar complex.

### Claim 5 (depends on 1)

A compound according to claim 1, wherein L1 is selected from 1,10-phenanthroline or 1,10-phenanthroline substituted with at least one alkyl group.

### Claim 6 (depends on 5)

A compound according to claim 5, wherein L1 is selected from the group consisting of 4-methyl-1,10-phenanthroline, 5,6-dimethyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 3,8-dimethyl-1,10-phenanthroline, 3,4,7,8-tetramethyl-1,10-phenanthroline and 4,7-diamino-1,10-phenanthroline.

### Claim 7 (depends on 1)

A compound according to claim 1 which is in the form of a salt.

### Claim 8 (depends on 7)

A compound according to claim 7, wherein the counter ion of the salt is selected from the group consisting of chloride, perchlorate, hexafluorophosphate, sulfate and nitrate.

### Claim 9 (depends on 8)

A compound according to claim 8, wherein the counter ion is chloride ion.

### Claim 10 (depends on 1)

A compound according to claim 1, which is in the form of a racemate.

### Claim 11 (depends on 1)

A compound according to claim 1, which is in the form of a diastereomer.

### Claim 12 (depends on 1)

A compound according to claim 1, which is in the form of a pure enantiomer.

### Claim 13 (depends on 1)

A compound according to claim 1 selected from the group consisting of (2S,3R-butanediamine)(1,10-phenanthroline)platinum(II) cation, (2S,3S-butanediamine)(1,10-phenanthroline)platinum(II) cation, (2R,3R-butanediamine)(1,10-phenanthroline)platinum(II) cation, (1S,2S-cyclohexanediamine)(1,10-phenanthroline)platinum(II) cation, (1R,2R-cyclohexanediamine)(1,10-phenanthroline)platinum(II) cation, (N,N′-dimethyl-1S,2S-cyclohexanediamine)(1,10-phenanthroline)platinum(II) cation and (N,N′-dimethyl-1R,2R-cyclohexanediamine)(1,10-phenanthroline)platinum(II) cation.

### Claim 14 (depends on 1)

A method of treatment of a cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound according to claim 1, wherein the cancer is testicular, ovarian, breast, bladder, head and neck, lung, colon, neoblastoma, or epidermoid cancer.

### Claim 15

A method of treatment of a cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound of formula I or a salt thereof
[ML1L2]2+ I
where M is selected from the group consisting of platinum(II), palladium (II) and copper(II);
L1 is 1,10-phenanthroline or an alkyl-substituted derivative thereof; and
L2 is a chiral diamine ligand,
wherein the cancer is testicular, ovarian, breast, bladder, head and neck, lung, colon, neoblastoma, or epidermoid cancer.

### Claim 16 (depends on 15)

A method according to claim 15, wherein the compound of formula I is used simultaneously, sequentially or separately with another anticancer therapy selected from surgery, radiotherapy and/or chemotherapy.

### Claim 17 (depends on 16)

A method according to claim 16, wherein the compound of formula I is administered with an anticancer compound, a cytotoxic agent and/or a secondary anticancer agent.

### Claim 18 (depends on 17)

A method according to claim 17, wherein the compound of formula I is administered with another anticancer compound or cytotoxic agent.

### Claim 19 (depends on 15)

A method according to claim 15, wherein M is platinum(II).

### Claim 20 (depends on 15)

A method according to claim 15, wherein L2 is a compound according to formula IIa or IIb:
R1R2N—CHR3—(CnH2n)—CH R4—N R5R6 IIa
wherein in formula IIa, the group —(CnH2n)— may be acyclic or cyclic, n is 0 to 4 inclusive, R1, R2, R3, R4, R5 and R6, which may be the same or different, are independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, or cycloalkyl; wherein the substituted alkyl, aryl, or cycloalkyl is substituted with at least one methyl group, or R1, R2, R5 and R6 are as defined above and R3 and R4 are joined to form, with the —(CnH2n)—group, a cycloalkane having 6 to 8 ring carbons, and wherein the compound of formula IIa has at least one chiral centre, and
wherein in formula IIb, A is an aromatic ring of 6 to 8 carbons, R1, R2, R4 and R5, which may be the same or different, are independently selected from hydrogen or a substituted or unsubstituted alkyl, aryl, or cycloalkyl, wherein the substituted alkyl, aryl, or cycloalkyl is substituted with at least one methyl group, and
wherein the compound of formula IIb includes at least one chiral centre.

### Claim 21 (depends on 15)

A method according to claim 15, wherein the intercalator moiety forms a square-planar or pseudo-planar complex.

### Claim 22 (depends on 15)

A method according to claim 15, wherein L1 is selected from 1,10-phenanthroline or 1,10-phenanthroline substituted with at least one alkyl group.

### Claim 23 (depends on 22)

A method according to claim 22, wherein L1 is selected from the group consisting of 4-methyl-1,10-phenanthroline, 5,6-dimethyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 3,8-dimethyl-1,10-phenanthroline, 3,4,7,8-tetramethyl-1,10-phenanthroline and 4,7-diamino-1,10-phenanthroline.

### Claim 24 (depends on 15)

A method according to claim 15, wherein the compound is in the form of a salt.

### Claim 25 (depends on 24)

A method according to claim 24, wherein the counter ion of the salt is selected from the group consisting of chloride, perchlorate, hexafluorophosphate, sulfate and nitrate.

### Claim 26 (depends on 25)

A method according to claim 25, wherein the counter ion is chloride ion.

### Claim 27 (depends on 15)

A method according to claim 15, which is in the form of a racemate.

### Claim 28 (depends on 15)

A method according to claim 15, which is in the form of a diastereomer.

### Claim 29 (depends on 15)

A method according to claim 15, which is in the form of a pure enantiomer.

### Claim 30 (depends on 15)

A method according to claim 15, wherein the compound is selected from the group consisting of (2S,3R-butanediamine)(1,10-phenanthroline)platinum(II) cation, (2S,3S-butanediamine)(1,10-phenanthroline)platinum(II) cation , (2R,3R-butanediamine)(1,10-phenanthroline)platinum(II) cation, (1S,2S-cyclohexanediamine)(1,10-phenanthroline)platinum(II) cation, (1R,2R-cyclohexanediamine)(1,10-phenanthroline)platinum(II) cation, (N,N′-dimethyl-1S,2S-cyclohexanediamine)(1,10-phenanthroline)platinum(II) cation and (N,N′-dimethyl-1R,2R-cyclohexanediamine)(1,10-phenanthroline)platinum(II) cation.

### Claim 31 (depends on 15)

A method according to claim 15, wherein M is palladium(II).

### Claim 32 (depends on 15)

A method according to claim 15, wherein M is copper(II).

### Claim 33

A pharmaceutical composition comprising a compound in accordance with formula I
[ML1L2]2+ I
where M is selected from the group consisting of platinum(II), palladium (II) and copper(II);
L1 is 1,10-phenanthroline or an alkyl-substituted derivative thereof; and
L2 is a chiral diamine ligand,
in an amount sufficient to have an antitumour effect in an animal or human together with at least one pharmaceutically acceptable excipient, diluent and/or carrier.

### Claim 34 (depends on 33)

A pharmaceutical composition according to claim 33 in a form suitable for oral, parenteral or rectal administration.

### Claim 35 (depends on 34)

A composition according to claim 34 in an injectable form.

### Claim 36 (depends on 34)

A composition according to claim 34 in a dosage form selected from the group consisting of tablets, capsules and powders.

### Claim 37 (depends on 33)

A composition according to claim 33, wherein the compound of formula I is (2S,3R-butanediamine)(1,10-phenanthroline)platinum(II) cation, (2S,3S-butanediamine)(1,10-phenanthroline)platinum(II) cation , (2R,3R-butanediamine)(1,10-phenanthroline)platinum(II) cation, (1S,2S-cyclohexanediamine)(1,10-phenanthroline)platinum(II) cation, (1R,2R-cyclohexanediamine)(1,10-phenanthroline)platinum(II) cation, (N,N′-dimethyl-1S,2S-cyclohexanediamine)(1,10-phenanthroline)platinum(II) cation and (N,N′-dimethyl-1R,2R-cyclohexanediamine)(1,10-phenanthroline)platinum(II) cation.

### Claim 38 (depends on 1)

A compound according to claim 1, wherein M is palladium(II).

### Claim 39 (depends on 1)

A compound according to claim 1, wherein M is copper(II).