# US 10,441,669 B2 · Multifunctional chelators, complexes, and compositions thereof, and methods of using same

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- Number: US 10,441,669 B2
- Document ID: US10441669B2
- Status: Granted
- Kind: B2
- Application number: 15/027,104
- Filed: 2014-10-06
- Published: 2016-08-18
- Granted: 2019-10-15
- Earliest claimed: 2013-10-04
- Assignees: Illinois Institute of Technology
- Applicants: Illinois Institute of Technology
- Inventors: Hyun-Soon Chong
- Web page: https://patentgrep.com/patent/US10441669B2

## CPC

- A61K 51/0482: {chelates from cyclic ligands, e.g. DOTA}
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07D 255/02: not condensed with other rings
- C07D 257/02: not condensed with other rings
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61K 51/0474: {complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group}
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Multifunctional chelators, metal complexes thereof, compositions thereof, and methods of making and use in diagnostic imaging and treatment of cellular disorders.

## Claims

### Claim 1

A compound of formula (I):
where k is 0 or 1; m is 0 or 1; and each of Y1-Y4 independently is one of a structure of formula (a-1), (a-2), or (a-3):
where p is 1 or 2; Z is hydrogen, formula (a-2), formula (a-3), Ar, a pyridylalkyl, a protecting group, an aryl containing group, an alkynyl containing group, an amine containing group, an azide containing group, or an amide containing group; Ar is or includes an aromatic ring or a heteroaromatic ring; and each R′ independently is OH, NH2, OR″, NR2″ wherein each R″ is one of alkyl, tert-butyl, allyl, benzyl, benzyloxy, or a protecting group; and
wherein each of R1-18 independently is or includes hydrogen, carboxyalkyl, alkylamido, alkyl, allyl, benzyl, benzyloxyalkyl, cycloalkyl, alkoxy, hydroxyalkyl, aryl, aryloxy, hydroxyaryl, heteroaryl, phenyl, vinyl, alkynyl, alkenyl, furannylalkyl, alkylthioalkyl, arylhydroxyalkyl, indanyl, inolylalkyl, naphthylalkyl, imidazolylalkyl, pyridiylalkyl, benzothiophenylalkyl, thiophenylalkyl, thioalkyl, thioaryl, thiobenzyl, hydroxy, an alkynyl containing group, substituted carbonyl, hydroxyalkyl, triazolylalkyl, aminoalkyl, benzothiophenylalkyl, carboxyl, carboxyalkyloxy, amine, a protected amine, carboxylic acid, holoalkylamido, aldehyde, ester, amido, tosyl, phthalimidyl, maleimidyl, trityl, tert-butyloxycarbonyl, carbobenzyloxy, o-nosyl, acetyl, fluoroacetyl, dimethoxybenzyl, p-methoxybenzyl, an amide containing group, a thioamide containing group, an amino acid-containing group, an ester containing group, a protecting group, an amine protecting group or:
where W is NH, oxygen, or sulfur, n is 1-5, and each of X1-X5 independently is or includes hydrogen, halo, cyano, alkyl, hydroxy, nitro, amino, alkylamino, thiocyano, isothiocyano, alkoxy, aryloxy, carboxyl, carboxyalkyl, carboxyalkyloxy, ester, amido, aldehydo, alkylamido, holoalkylamido, an ester containing group, an carbonyl containing group, an amide containing group, an amine containing group, a thioamide containing group, an alkynyl containing group, or an amino acid-containing group;
wherein more than one of Y1-Y4 is formula (a-1); and
wherein at least one of Y1-Y4 comprises:
where X1 is described above or comprises NH2, NHBoc, NCS or NPhth.

### Claim 2 (depends on 1)

The compound of claim 1, wherein at least one Z of Y1-Y4 is hydrogen.

### Claim 3 (depends on 1)

The compound of claim 1, wherein Ar is selected from:
where W is NH, oxygen, or sulfur, n is 0-5, and each of X1-X5 independently is or includes hydrogen, halo, cyano, alkyl, hydroxy, nitro, amino, alkylamino, thiocyano, isothiocyano, alkoxy, aryloxy, carboxyl, carboxyalkyl, carboxyalkyloxy, ester, amido, aldehydo, alkylamido, holoalkylamido, an ester containing group, an carbonyl containing group, an amide containing group, an amine containing group, a thioamide containing group, an alkynyl containing group, or an amino acid-containing group.

### Claim 4 (depends on 1)

The compound of claim 1, wherein one of R13-R18 comprises:
where n is 1-5.

### Claim 5 (depends on 1)

The compound of claim 1, wherein X5 comprises NO2.

### Claim 6 (depends on 1)

The compound of claim 1, wherein at least three of Y1-Y4 is formula (a-1).

### Claim 7 (depends on 1)

The compound of claim 1, wherein an other of Y1-Y4 is formula (a-3) with one of R17-18 comprising:
and n is 1-5.

### Claim 8 (depends on 1)

The compound of claim 1, wherein Z is selected from:
where W is NH, oxygen, or sulfur and n is 1-5.

### Claim 9 (depends on 8)

The compound of claim 8, wherein an other of Y1-Y4 is formula (a-3) with one of R17-18 comprising:
and n is 1-5.

### Claim 10

A compound of formula (I):
where k is 0 or 1; m is 0 or 1; and each of Y1-Y4 independently is one of a structure of formula (a-1), (a-2), or (a-3):
where p is 1 or 2; Z is hydrogen, formula (a-2), formula (a-3), Ar, a pyridylalkyl, a protecting group, an aryl containing group, an alkynyl containing group, an amine containing group, an azide containing group, or an amide containing group; Ar is or includes an aromatic ring or a heteroaromatic ring; and each R′ independently is OH, NH2, OR″, NR2″ wherein each R″ is one of alkyl, tert-butyl, allyl, benzyl, benzyloxy, or a protecting group;
wherein each of R1-18 independently is or includes hydrogen, carboxyalkyl, alkylamido, alkyl, allyl, benzyl, benzyloxyalkyl, cycloalkyl, alkoxy, hydroxyalkyl, aryl, aryloxy, hydroxyaryl, heteroaryl, phenyl, vinyl, alkynyl, alkenyl, furannylalkyl, alkylthioalkyl, arylhydroxyalkyl, indanyl, inolylalkyl, naphthylalkyl, imidazolylalkyl, pyridiylalkyl, benzothiophenylalkyl, thiophenylalkyl, thioalkyl, thioaryl, thiobenzyl, hydroxy, an alkynyl containing group, substituted carbonyl, hydroxyalkyl, triazolylalkyl, aminoalkyl, benzothiophenylalkyl, carboxyl, carboxyalkyloxy, amine, a protected amine, carboxylic acid, holoalkylamido, aldehyde, ester, amido, tosyl, phthalimidyl, maleimidyl, trityl, tert-butyloxycarbonyl, carbobenzyloxy, o-nosyl, acetyl, fluoroacetyl, dimethoxybenzyl, p-methoxybenzyl, an amide containing group, a thioamide containing group, an amino acid-containing group, an ester containing group, a protecting group, an amine protecting group or:
where W is NH, oxygen, or sulfur, n is 1-5, and each of X1-X5 independently is or includes hydrogen, halo, cyano, alkyl, hydroxy, nitro, amino, alkylamino, thiocyano, isothiocyano, alkoxy, aryloxy, carboxyl, carboxyalkyl, carboxyalkyloxy, ester, amido, aldehydo, alkylamido, holoalkylamido, an ester containing group, an carbonyl containing group, an amide containing group, an amine containing group, a thioamide containing group, an alkynyl containing group, or an amino acid-containing group;
wherein more than one of Y1-Y4 is formula (a-1); and
wherein at least one Z comprises:
where X1 is described above or comprises NH2, NHBoc, NCS or NPhth.

### Claim 11 (depends on 1)

The compound of claim 1, wherein k is 1.

### Claim 12 (depends on 1)

A complex comprising the compound of claim 1 and a metal ion, a radioactive isotope of the metal ion, or a radioactive isotope of carbon, nitrogen, iodine, fluorine, oxygen, or helium.

### Claim 13 (depends on 12)

The complex of claim 12, wherein the metal ion is selected from the group consisting of Ac, Al, Bi, Pb, Y, Mn, Cr, Fe, Co, Zn, Ni, Tc, Gd, In, Ga, Cu, Re, Sm, Pm, Ho, Zr, Am, Ce, U, a lanthanide, and an actinide.

### Claim 14 (depends on 1)

A conjugate comprising the compound of claim 1 and a targeting moiety, a fluorescence moiety, or a nanoparticle.

### Claim 15 (depends on 14)

The conjugate according to claim 14, wherein the targeting moiety comprises a biomolecule selected from a hormone, a bile acid, an amino acid, a peptide, a peptidomimetic, a protein, a deoxyribonucleic acid (DNA), a ribonucleic acid (RNA), a lipid, an albumin, a receptor molecule, a receptor binding molecule, a hapten, a monoclonal antibody, a polyclonal antibody, a peptide, an aptamer, a folic acid, an estrogen, or a transferrin.

### Claim 16 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 17 (depends on 1)

A method of generating a diagnostic image or measurement, the method comprising:
administering to an animal a composition comprising the compound of claim 1; and
imaging or measuring an amount of the composition in a tissue or organ of the animal using magnetic resonance imaging (MRI), fluorescence imaging (FI), x-ray contrast imaging, transmission electron microscopy imaging, a positron emission tomography (PET) imaging, or single photon emission computed spectroscopy (SPECT).

### Claim 18 (depends on 17)

The method of claim 17, wherein the composition includes complex comprising 90Y, 86Y, 111In, 213Bi, 212Bi, 212Pb, 225Ac, 177Lu, 68Ga, 166Ho, 153Sm, 149Pm, 64Cu, 89Zr, 18F or 67Cu.

### Claim 19 (depends on 1)

A method of preparing the compound of claim 1, comprising:
reacting a compound of formula (Ib-1):
wherein: m is 0 or 1; each of R1-12 and Y1-3 is as defined above, with a compound of formula (Ib-2) or (Ib-3):
where m is 0 or 1; p is 0 or 1; each of R21-22 independently is as defined for R1-20; and Q is a counter anion or a leaving group comprising halide, perchlorate, tetrafluoroborate, hexafluoroantimonate, me sylate, triflate, tosylate, carbonate, nitrate, phthalimide, or succinimide.

### Claim 20 (depends on 19)

The method of claim 19, further comprising providing a compound of formula (f-1):

### Claim 21 (depends on 20)

The method of claim 20, further comprising: converting (b-2) to (b-3) in the presence of halosequestering agent comprising AgClO4, AgOTf, Ag2CO3, AgOTs, AgNO3, AgSbF6, or AgBF4; and reacting (b-3) in situ with (1b-1) to obtain (f-1).

### Claim 22 (depends on 10)

The compound of claim 10, wherein one of R15-R16 comprises:
where n is 1-5.

### Claim 23 (depends on 10)

The compound of claim 10, wherein k is 1.

### Claim 24 (depends on 10)

A complex comprising the compound of claim 10 and a metal ion, a radioactive isotope of the metal ion, or a radioactive isotope of carbon, nitrogen, iodine, fluorine, oxygen, or helium.

### Claim 25 (depends on 10)

A conjugate comprising the compound of claim 10 and a targeting moiety, a fluorescence moiety, or a nanoparticle.