# US 8,772,446 B2 · Bifunctional chelating agents

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- Number: US 8,772,446 B2
- Document ID: US8772446B2
- Status: Granted
- Kind: B2
- Application number: 13/030,766
- Filed: 2011-02-18
- Published: 2011-12-22
- Granted: 2014-07-08
- Earliest claimed: 2010-02-19
- Assignees: Nordion (Canada) Inc.
- Applicants: Mike Adam; Eszter Boros; Cara L. Ferreira; Chris Orvig; Eric William Price
- Inventors: Mike Adam; Eszter Boros; Cara L. Ferreira; Chris Orvig; Eric William Price
- Web page: https://patentgrep.com/patent/US8772446B2

## CPC

- C07D 213/79: Acids; Esters
- A61K 51/0478: {complexes from non-cyclic ligands, e.g. EDTA, MAG3}
- A61K 51/0497: {conjugates with a carrier being an organic compounds}
- A61K 51/082: {the peptide being a RGD-containing peptide}
- A61K 51/088: {conjugates with carriers being peptides, polyamino acids or proteins (antibodies A61K51/10)}
- 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

A bifunctional chelating agent of the formula (I): wherein the variables R1, R1′, Q1, Q2 and M are as defined in the description of the present application. Also described is a complex of the above chelating agent to an ion of a stable or radioactive metal; a conjugate of the complex covalently attached to a biological carrier; and a pharmaceutical composition containing the conjugate.

## Claims

### Claim 1

A bifunctional chelating agent of the formula (I):
wherein:
-M- is
Q1, Q2 and Q4 are independently H or R;
Q5 is H, R or R1″;
Q6 is H or R1″;
Q7 is H or R;
A1 and A2 form together with the atoms to which they are attached a C6-C10-aryl, C6—C1-10-heteroaryl, C3-C5-cycloalkyl, C7-C10-cycloalkyl or C3-C10-heterocyclyl group;
R is —C(O)-L,
—(CHR2)pCOR3 or —(CHR2)pPO2R4R5;
Q3 is H, —(CHR2)wCOR3 or —(CHR2)wPO2R4R5;
R1, R1′ and R1″ are independently
each R2 is independently hydrogen; C1-C4 alkyl or (C1-C2alkyl)phenyl; each R3, R4 and R5 are independently OH, an —O-protecting group or a leaving group;
R6 is H; OH; an alkyl-LG or alkoxy-LG, wherein LG is a leaving group; a boronate ester or a leaving group;
X and Y are each independently hydrogen or may be taken with an adjacent X and Y to form an additional carbon—carbon bond;
Z1 and Z2 are independently CH or N;
m is an integer from 0 to 10 inclusive;
n is 0 or 1;
p is 1 or 2;
r is 0 or 1;
w is 0 or 1;
z is 1 or 2;
L is a linker/spacer group covalently bonded to, and replacing one hydrogen atom of the carbon atom to which it is joined, said linker/spacer group being represented by the formula (II):
wherein:
s is an integer of 0 or 1;
t is an integer of 0 to 20 inclusive;
R7, R8 and R9 are independently H; an electrophilic, nucleophilic or electron-rich moiety that allows for covalent attachment to a carrier comprising a biotargeting group, a lipophilic moiety or a biosensor; a protected form or a precursor of the electrophilic, nucleophilic or electron-rich moiety; or a synthetic linker having an electrophilic, nucleophilic or electron-rich moiety that allows for covalent attachment to the carrier comprising a biotargeting group, a lipophilic moiety or a biosensor, or a protected form or a precursor of the electrophilic, nucleophilic or electron-rich moiety of the synthetic linker, and
Cyc represents a cyclic aliphatic moiety, aromatic moiety, aliphatic heterocyclic moiety, or aromatic heterocyclic moiety, each of said moieties optionally substituted with one or more groups, which do not interfere with binding to a carrier comprising a biotargeting group, a lipophilic moiety or a biosensor;
or a pharmaceutically acceptable salt thereof,
provided that the chelating agent is not 6,6′,6″,6′″-((ethane-1,2-diylbis(azanetriyl))tetrakis(methylene))tetrapicolinic acid, 6,6′-((ethane-1,2-diylbis((phosphonomethyl)azanediyl))bis(methylene))dipicolinic acid, 6,6′-((ethane-1,2-diylbis((carboxymethyl)azanediyl))bis(methylene))dipicolinic acid or 6,6′-((ethane-1,2-diylbis((pyridin-2-ylmethyl)azanediyl))bis(methylene))dipicolinic acid, and
provided that the bifunctional chelating agent comprises at least one covalently attached moiety that allows for covalent attachment to the carrier comprising a biotargeting group, a lipophilic moiety or a biosensor.

### Claim 2 (depends on 1)

The bifunctional chelating agent according to claim 1, wherein the bifunctional chelating agent is of formula (Ia):
wherein Q1, Q2, Q4 and z are as defined in claim 1.

### Claim 3 (depends on 1)

The bifunctional chelating agent according to claim 1, wherein Q1 and Q2
are each H and Q4 is
wherein L, X, Y, Q3, m, n and r are as defined in claim 1.

### Claim 4 (depends on 1, 3)

The bifunctional chelating agent according to claim 3, wherein Q1 and Q2are each H and Q4 is
wherein L, X, Y, m, n and r are as defined in claim 1.

### Claim 5 (depends on 1, 4)

The bifunctional chelating agent according to claim 4, wherein Q1 and Q2 are each H and Q4 is
wherein R8 is as defined in claim 1.

### Claim 6 (depends on 1)

The bifunctional chelating agent according to claim 1, wherein at least one of Q1and Q2is
and Q4 is H,
wherein L, X, Y, Q3, m, n and r are as defined in claim 1.

### Claim 7 (depends on 1, 6)

The bifunctional chelating agent according to claim 6, wherein at least one of Q1 and Q2 is
and Q4 is H,
wherein L, X, Y, m, n and r are as defined in claim 1.

### Claim 8 (depends on 1, 7)

The bifunctional chelating agent according to claim 7, wherein at least one of Q1 and Q2 is
and Q4 is H,
wherein R8 is as defined in claim 1.

### Claim 9 (depends on 1)

The bifunctional chelating agent according to claim 1, wherein at least one of Q1 and Q2 is —(CHR2)pCOR3 and Q4 is H, wherein R3 and p are as defined in claim 1.

### Claim 10 (depends on 1)

The bifunctional chelating agent according to claim 1, wherein at least one of Q1 and Q2 is —(CHR2)pCOR3 and Q4 is H, wherein R3 is a leaving group and p is as defined in claim 1.

### Claim 11 (depends on 1)

The bifunctional chelating agent according to claim 1, wherein at least one of Q1 and Q2 is —CH2COR3 and Q4 is H, wherein R3 is as defined in claim 1.

### Claim 12 (depends on 1)

The bifunctional chelating agent according to claim 1, wherein at least one of Q1 and Q2 is —CH2COR3 and Q4 is H, wherein R3 is a leaving group.

### Claim 13 (depends on 1)

The bifunctional chelating agent according to claim 1, wherein at least one of Q1 and Q2 is —CH2C≡CH and Q4 is H.

### Claim 14 (depends on 1)

The bifunctional chelating agent according to claim 1, wherein Q1 and Q2 are —(CHR2)pCOR3 and Q4 is R, wherein R2, R3, and R are as defined in claim 1.

### Claim 15 (depends on 1)

The bifunctional chelating agent according to claim 1, wherein R6 is NO2, NH2, isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido or carboxyl.

### Claim 16 (depends on 1)

A complex comprising the bifunctional chelating agent defined in claim 1 or a pharmaceutically acceptable salt thereof, and an ion of a stable or radioactive form of a metal selected from a group consisting of Ga, In, TI, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Sc, Y, Ti, Zr, Cr, Mn, Tc, Re, Fe, Ru, Co, Rh, Ir, Ni, Pd, Pt, Cu, Zn, Cd, Hg, Al, Ge, Sn, Pb, Sb, Bi, Te, Po, Mg, Ca, Sr, Ba, Ra, Ac, Th and U.

### Claim 17 (depends on 16)

The complex according to claim 16, wherein the ion is an ion of a radioactive metal selected from a group consisting of 66Ga, 67Ga, 68, 111In, 201Tl, 142Pr, 149Pm, 153Sm, 153Gd, 159Gd, 166Ho, 175Yb, 177Lu, 47Sc, 90Y, 89Zr, 51Cr, 99mTc, 188Re, 186Re, 57Co, 101mRh, 62Cu, 64Cu, 67Cu, 117mSn, 203Pb, 212Pb, 212Bi, 213Bi, 223Ra, and 225Ac.