# US 5,707,603 A · Pyridine complexing agents and targeting immunoreagents useful in therapeutic and diagnostic compositions

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- Number: US 5,707,603 A
- Document ID: US5707603A
- Status: Granted
- Kind: A
- Application number: 08/375,276
- Filed: 1995-01-19
- Granted: 1998-01-13
- Earliest claimed: 1990-11-08
- Assignees: Nycomed Imaging AS
- Inventors: John L. Toner; David A. Hilborn; Bruce J. Murray; Timothy Z. Hossain; Robert A. Snow; Ashis K. Saha; Richard Philion; Clyde W. Shearman; Chandra Shah
- Web page: https://patentgrep.com/patent/US5707603A

## CPC

- C07D 213/53: Nitrogen atoms
- A61K 47/56: the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K 47/6887: {Antibody-chelate conjugates using chelates for therapeutic purposes (radioactive substances, e.g. for use in radio diagnosis or radiotherapy, A61K51/10; antibody-chelates for use in MRI A61K49/14)}
- A61K 51/1054: {the tumor cell being from lung}
- A61K 51/1063: {the tumor cell being from stomach or intestines}
- A61K 51/1093: {conjugates with carriers being antibodies}
- C07D 213/61: Halogen atoms or nitro radicals
- C07D 213/77: Hydrazine radicals
- C07D 471/04: Ortho-condensed systems
- 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

The invention provides targeting radioactive immunoreagents comprising a metal radionuclide ion, a complexing agent having structure A-I, as defined in the specification, and an immunoreactive group covalently bonded to the complexing agent. The present invention also provides novel complexing agents having the structure A-I, as defined in the specification. The targeting radioactive immunoreagents are particularly useful in therapeutic and diagnostic imaging compositions and methods.

## Claims

### Claim 1

A targeting radioactive immunoreagent comprising
a metal radionuclide ion,
a complexing agent, and
an immunoreactive group covalently bonded to said complexing agent,
said complexing agent having the structure ##STR39## wherein R is selected from hydrogen, alkyl, alkoxy, alkylthio, alkylamino, alkylformamido, aryl, aryloxy, heterocyclyl and a protein reactive group;
each R.sup.1 is independently selected from hydrogen, alkyl, alkoxy, alkylthio, alkylamino, alkylformamido, aryl, aryloxy, heterocyclyl and a protein reactive group, wherein each alkyl and alkylene moiety contains 1 to 20 carbon atoms, each aryl or arylene moiety contains 6-20 carbon atoms, and each heterocyclyl group contains at least 1, 5 or 6 membered ring and a heteroatom selected from the group consisting of N, S, P and O;
each R.sup.2 is independently selected from hydroxy, carboxy, hydroxyalkyl, carbonyliminodiacetic acid, methyleneiminodiacetic acid, methylenethioethyleneiminodiacetic acid, hydrazinylidenediacetic acid, and a salt of such acids, or the two R.sup.2 groups, taken together, represent the atoms necessary to complete a macrocyclic ring structure containing at least one heteroatom coordinating site and at least one alkylene group forming part of the ring structure;
each R.sup.3 is independently selected from hydrogen, alkyl, alkoxy, alkylthio, alkylamino, alkylformamido, aryl, aryloxy, heterocyclyl and a protein reactive group;
each R.sup.4 is independently selected from hydrogen and a protein reactive group;
n is 0, 1, 2, 3, or 4;
o is 0 or 1;
m is 0 or 1;
provided that at least one of n and m is 0 and at least one of R, R.sup.1, R.sup.3 and R.sup.4 is a protein reactive group.

### Claim 2 (depends on 1)

The immunoreagent of claim 1 wherein the complexing agent has the structure: ##STR40## wherein R, R.sup.1, R.sup.2 and R.sup.3 are as defined in claim 1 and n is 0, 1, 2, 3 or 4.

### Claim 3 (depends on 2)

The immunoreagent of claim 2 wherein n is 1, 2, 3, or 4 and R is ##STR41## wherein R.sup.5 is alkoxy or alkyl, p is 0, 1, 2, 3 or 4 and R.sup.6 is a protein reactive group.

### Claim 4 (depends on 3)

The immunoreagent of claim 3 wherein n is 1.

### Claim 5 (depends on 3)

The immunoreagent of claim 3 wherein R.sup.6 is selected from the group consisting of amino, alkylamino, arylamino, semicarbazido, thiocarbazido, thiosemicarbazido, isocyanato and isothiocyanato, vinyl sulfonylalkyloxy, vinyl sulfonylalkyl(polyoxyalkyl)oxy, amidatoalkyloxy, hydrazidoalkyloxy, azidocarbonylalkyloxy, aryloxycarbonyloxyalkyloxy, aryloxycarbonyl(polyoxyalkyl)oxy, 4,6-dichloro-2-triazinyloxy, dichlorotriazinyl(polyoxyalkyl)oxy, 4-alkoxy-6-chloro-2-triazinyloxy, 4-alkoxy-6-chloro-2-triazinyl(polyoxyalkyl)oxy, formylalkyl, aminoalkyl, thioalkyimidoaminoalkyloxy, thioalkylcarbonylaminoalkyloxy, maleimidoalkylcarbonylaminoalkyloxy, azido, 4,6-dichloro-2-triazinylamino, iodoalkylcarbonylamino, amidatoalkylamino, and amidatoarylalkylamino.

### Claim 6 (depends on 3)

The immunoreagent of claim 3 wherein R.sup.6 is selected from the group consisting of amino, isothiocyanato and thiosemicarbazido.

### Claim 7 (depends on 3)

The immunoreagent of claim 3 wherein said complexing agent is 4'-(3-amino-4-methoxy-phenyl)-6,6"-bis›N,N-di-(carboxymethyl)aminomethyl!- 2,2':6',2"-terpyridine tetrasodium salt or 4'-(3-amino-4-methoxyphenyl)-6,6"-bis(N',N'-dicarboxymethyl-N-methylhydraz ino)-2,2':6'2"-terpyridine tetrasodium salt.

### Claim 8 (depends on 1)

The immunoreagent of claim 1 wherein the complexing agent has the structure: ##STR42## wherein R.sup.2, R.sup.3 and R.sup.4 are as defined in claim 1.

### Claim 9 (depends on 8)

The immunoreagent of claim 8 wherein at least one R.sup.4 is selected from the group consisting of amino, isothiocyanato and thiosemicarbazido, vinyl sulfonylalkyloxy, vinyl sulfonylalkyl(polyoxyalkyl)oxy, amidatoalkyloxy, hydrazidoalkyloxy, azidocarbonylalkyloxy, aryloxycarbonyloxyalkyloxy, aryloxycarbonyl(polyoxyalkyl)oxy, 4,6-dichloro-2-triazinyloxy, dichlorotriazinyl(polyoxyalkyl)oxy, 4-alkoxy-6-chloro-2-triazinyloxy, 4-alkoxy-6-chloro-2-triazinyl(polyoxyalkyl)oxy, formylalkyl, aminoalkyl, thioalkyimidoaminoalkyloxy, thioalkylcarbonylaminoalkyloxy, maleimidoalkylcarbonylaminoalkyloxy, azido, 4,6-dichloro-2-triazinylamino, iodoalkylcarbonylamino, amidatoalkylamino, and amidatoarylalkylamino.

### Claim 10 (depends on 1)

The immunoreagent of claim 1 wherein said protein reactive group is selected from the group consisting of amino; alkylamino; arylamino; hydrazino; alkylhydrazino; arylhydrazino; carbazido; semicarbazido; thiocarbazido; thiosemicarbazido; sulfhydryl; sulfhydrylalkyl; sulfhydrylaryl; hydroxy; carboxy; carboxyalkyl and carboxyaryl; active halogen containing groups, 2-leaving group-substituted ethylsulfonyl and ethylcarbonyl; vinylsulfonyl; vinylcarbonyl; epoxy; isocyanato; isothiocyanato; aldehyde; aziridine; succinimidoxycarbonyl; activated acyl groups; mixed anhydrides; and groups that can be linked to protein or modified protein by use of a crosslinking agent.

### Claim 11 (depends on 1)

The immunoreagent of claim 1, wherein said protein reactive group is selected from the group consisting of amino, isocyanato, isothiocyanato, carbazido, semicarbazido, thiocarbazido and thiosemicarbazido, vinyl sulfonylalkyloxy, vinyl sulfonylalkyl(polyoxyalkyl)oxy, amidatoalkyloxy, hydrazidoalkyloxy, azidocarbonylalkyloxy, aryloxycarbonyloxyalkyloxy, aryloxycarbonyl(polyoxyalkyl)oxy, 4,6-dichloro-2-triazinyloxy, dichlorotriazinyl(polyoxyalkyl)oxy, 4-alkoxy-6-chloro-2-triazinyloxy, 4-alkoxy-6-chloro-2-triazinyl(polyoxyalkyl)oxy, formylalkyl, aminoalkyl, thioalkyimidoaminoalkyloxy, thioalkylcarbonylaminoalkyloxy, maleimidoalkylcarbonylaminoalkyloxy, azido, 4,6-dichloro-2-triazinylamino, iodoalkylcarbonylamino, amidatoalkylamino, and amidatoarylalkylamino.

### Claim 12 (depends on 1)

The immunoreagent of claim 1, wherein said immunoreactive group is selected from the group consisting of enzymes, amino acids, peptides, polypeptides, proteins, lipoproteins, glycoproteins, hormones, drugs, steroids, vitamins, polysaccharides, pharmaceuticals, haptens, lectins, toxins, nucleic acids, oligonucleotides, antibodies, antibody fragments, antigenic materials, avidin and biotin.

### Claim 13 (depends on 1)

The immunoreagent of claim 1, wherein said immunoreactive group is an antibody.

### Claim 14 (depends on 12)

The immunoreagent of claim 12, wherein said immunoreactive group is a protein.

### Claim 15 (depends on 1)

The immunoreagent of claim 1, wherein said radionuclide ion is selected from the group consisting of Sc, Fe, Pb, Ga, Y, Bi, Lu, Mn, Cu, Cr, Zn, Ge, Mo, Tc, Ru, In, Sn, Sm, Sb, W, Re, Po, Ta and Tl ions.

### Claim 16 (depends on 15)

The immunoreagent claim 15 wherein said radionuclide ion is selected from the group consisting of .sup.111 In.sup.+++, .sup.212 Pb.sup.++, .sup.68 Ga.sup.++, .sup.90 Y.sup.+++ and .sup.212 Bi.sup.+++ ions.

### Claim 17 (depends on 1)

The immunoreagent of claim 1, wherein R is a 4-alkoxy-3-aminophenyl or 4-alkoxy-3-isothiocyanatophenyl group.

### Claim 18 (depends on 1)

The immunoreagent of claim 1 wherein each R.sup.2 is methyleneiminodiacetic acid or a salt thereof.

### Claim 19 (depends on 1)

The immunoreagent of claim 1 wherein each R.sup.3 is H.

### Claim 20 (depends on 1)

The immunoreagent of claim 1 wherein R.sup.4 is amino or isothiocyanato.

### Claim 21 (depends on 15)

The immunoreagent of claim 15 wherein said metal radionuclide ion is .sup.90 Y.sup.+++.

### Claim 22 (depends on 13)

The immunoreagent of claim 13 wherein said antibody is selected from the group consisting of B72.3, 9.2.27, D612, UJ13A, NRLU-10, 7E11C.sub.5, CC49, TNT, PR1A3, ING-1, B174 and B43 antibodies.

### Claim 23 (depends on 22)

The immunoreagent of claim 22 wherein said antibody is selected from B72.3 and ING-1 antibodies.

### Claim 24 (depends on 22)

The immunoreagent of claim 22 wherein said metal radionuclide ion is .sup.90 Y.sup.+++.

### Claim 25 (depends on 1)

The immunoreagent of claim 1 selected from the group consisting of B72.3-TMT-.sup.90 Y, ING-1-TMT-.sup.90 Y, ING-1-THT-.sup.111 In, B72.3-TMT-.sup.111 In, B72.3-THT-.sup.90 Y, and B72.3-THT-.sup.111 In.

### Claim 26 (depends on 1)

A diagnostic imaging composition comprising the radioactive immunoreagent of claim 1.

### Claim 27 (depends on 1)

A therapeutic composition comprising the radioactive immunoreagent of claim 1 and a pharmaceutically acceptable carrier therefor.