# US 6,280,959 B1 · Metal complexes

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- Number: US 6,280,959 B1
- Document ID: US6280959B1
- Status: Granted
- Kind: B1
- Application number: 09/530,307
- Filed: 2000-04-27
- Published: 2001-08-16
- Granted: 2001-08-28
- Earliest claimed: 1997-10-31
- Assignees: SmithKline Beecham Corporation
- Inventors: John G. Gleason; Juan I. Luengo
- Web page: https://patentgrep.com/patent/US6280959B1

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 31/315: Zinc compounds
- A61K 31/555: containing heavy metals, e.g. hemin, hematin, melarsoprol
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07F 3/003: {without C-Metal linkages}
- G01N 33/566: using specific carrier or receptor proteins as ligand binding reagents {where possible specific carrier or receptor proteins are classified with their target compounds}
- G01N 2333/705: Assays involving receptors, cell surface antigens or cell surface determinants
- 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
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The invention describes zinc chelated dimeric cell-surface receptor ligands, pharmaceutical compositions containing these compounds, methods of using these compounds as agonist of dimeric cell-surface receptors. Novel processes used in preparing the compounds are also described. Further, the invention describes novel receptor binding moieties of the zinc chelated cell-surface receptor ligands.

## Claims

### Claim 1

A method for agonizing dimeric cell-surface receptors in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a zinc chelated dimeric cell-surface receptor ligand.

### Claim 2

A method for agonizing dimeric cell-surface receptors in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of an organic molecule having a molecular weight from about 100 to about 850, containing of from 1 to 4 zinc binding motifs and provided that each zinc binding motif forms at least two coordinate bonds to a zinc ion.

### Claim 3

A method for identifying agonists of dimeric cell-surface receptors which comprises contacting the receptor with dimeric cell-surface receptor ligand candidates in the presence of a zinc ion source, and selecting ligand candidates which bind to the receptor.

### Claim 4

A process for the preparation of a zinc chelated dimeric cell-surface receptor ligand which comprises reacting one or more receptor binding moieties and a zinc ion source followed by optional isolation of the zinc chelated dimeric cell-surface receptor ligand.

### Claim 5 (depends on 4)

A zinc chelated cell-surface receptor ligand prepared by the process of claim 4.

### Claim 6

A zinc chelated cell-surface receptor ligand.

### Claim 7 (depends on 5)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 5.

### Claim 8 (depends on 6)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 6.

### Claim 9 (depends on 5)

A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of claim 5 which process comprises bringing the compound into association with the pharmaceutically acceptable carrier or diluent.

### Claim 10 (depends on 6)

A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of claim 6 which process comprises bringing the compound into association with the pharmaceutically acceptable carrier or diluent.

### Claim 11

An isolated dimeric cell-surface receptor binding moiety of a zinc chelated cell-surface receptor ligand.

### Claim 12

A dimeric cell-surface receptor binding moiety.

### Claim 13 (depends on 1)

The method of claim 1 wherein the cell-surface receptor is the EPO receptor.

### Claim 14 (depends on 2)

The method of claim 2 wherein the cell-surface receptor is the EPO receptor.

### Claim 15 (depends on 11)

A method for agonizing the EPO receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 11.

### Claim 16 (depends on 12)

A method for agonizing the EPO receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 12.

### Claim 17 (depends on 11)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 11.

### Claim 18 (depends on 12)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 12.

### Claim 19 (depends on 11)

A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of claim 11 which process comprises bringing the compound into association with the pharmaceutically acceptable carrier or diluent.

### Claim 20 (depends on 12)

A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of a compound of claim 12 which process comprises bringing the compound into association with the pharmaceutically acceptable carrier or diluent.

### Claim 21 (depends on 11)

A method for agonizing dimeric cell-surface receptors in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 11.

### Claim 22 (depends on 12)

A method for agonizing dimeric cell-surface receptors in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 12.

### Claim 23 (depends on 11)

A compound of claim 11 for use as an active therapeutic substance.

### Claim 24 (depends on 12)

A compound of claim 12 for use as an active therapeutic substance.

### Claim 25 (depends on 1)

The method of claim 1 wherein the dimeric cell-surface receptor is the M-CSF receptor.

### Claim 26 (depends on 2)

The method of claim 2 wherein the dimeric cell-surface receptor is the M-CSF receptor.

### Claim 27 (depends on 11)

A method for agonizing the M-CSF receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 11.

### Claim 28 (depends on 12)

A method for agonizing the M-CSF receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 12.

### Claim 29 (depends on 1)

The method of claim 1 wherein the dimeric cell-surface receptor is the GRH receptor.

### Claim 30 (depends on 2)

The method of claim 2 wherein the dimeric cell-surface receptor is the GRH receptor.

### Claim 31 (depends on 11)

A method for agonizing the GRH receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 11.

### Claim 32 (depends on 12)

A method for agonizing the GRH receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 12.

### Claim 33 (depends on 1)

The method of claim 1 wherein the dimeric cell-surface receptor is the TPO receptor.

### Claim 34 (depends on 2)

The method of claim 2 wherein the dimeric cell-surface receptor is the TPO receptor.

### Claim 35 (depends on 11)

A method for agonizing the TPO receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 11.

### Claim 36 (depends on 12)

A method for agonizing the TPO receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 12.

### Claim 37 (depends on 1)

The method of claim 1 wherein the dimeric cell-surface receptor is the leptin receptor.

### Claim 38 (depends on 2)

The method of claim 2 wherein the dimeric cell-surface receptor is the leptin receptor.

### Claim 39 (depends on 11)

A method for agonizing the leptin receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 11.

### Claim 40 (depends on 12)

A method for agonizing the leptin receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 12.

### Claim 41 (depends on 1)

The method of claim 1 wherein the dimeric cell-surface receptor is the IFN receptor.

### Claim 42 (depends on 2)

The method of claim 2 wherein the dimeric cell-surface receptor is the IFN receptor.

### Claim 43 (depends on 11)

A method for agonizing the IFN receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 11.

### Claim 44 (depends on 12)

A method for agonizing the IFN receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 12.

### Claim 45 (depends on 1)

The method of claim 1 wherein the dimeric cell-surface receptor is the insulin receptor.

### Claim 46 (depends on 2)

The method of claim 2 wherein the dimeric cell-surface receptor is the insulin receptor.

### Claim 47 (depends on 11)

A method for agonizing the insulin receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 11.

### Claim 48 (depends on 12)

A method for agonizing the insulin receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 12.

### Claim 49 (depends on 1)

The method of claim 1 wherein the dimeric cell-surface receptor is selected from the TRK receptors.

### Claim 50 (depends on 2)

The method of claim 2 wherein the dimeric cell-surface receptor is selected from the TRK receptors.

### Claim 51 (depends on 11)

A method for agonizing a selected TRK receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 11.

### Claim 52 (depends on 12)

A method for agonizing a selected TRK receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 12.

### Claim 53 (depends on 1)

The method of claim 1 wherein said metal chelated dimeric cell-surface receptor ligand comprises a symmetrical multimer of a receptor binding moiety.