Bridged aromatic substituted amine ligands with donor atoms

Details Bridged aromatic substituted amine ligands with donor atoms Bridged aromatic substituted amine ligands with donor atoms

2000-11-28

2003-03-04

Raymond, Richard L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Radioactive metal containing

C534S014000, C534S015000, C549S005000, C549S022000, C549S037000, C549S060000, C549S218000, C549S221000, C549S231000

Reexamination Certificate

active

06528627

ABSTRACT:

TECHNICAL FIELD
The present invention relates generally to chelation compounds, radionuclide metal chelate compounds (i.e., complexes) and radiolabeled targeting moieties (i.e., conjugates) formed therefrom, and methods of making and using these compounds, complexes and conjugates for diagnostic and therapeutic purposes. This invention is more particularly related to compounds in which at least two of the chelating atoms are nitrogen atoms which are directly attached to aromatic rings and there is a non-hydrogen substituent directly attached to at least one of these nitrogen chelating atoms.
BACKGROUND OF THE INVENTION
Radiolabeled chelation compounds have been studied and used as pharmaceuticals for diagnostic and therapeutic purposes for a number of years. The requirements for a useful radiolabeled chelating compound are well known to those skilled in the art of nuclear medicine and radiopharmaceutical research. Briefly, these requirements include: efficient final preparation of the radiopharmaceutical, such that preparation in the hospital or pharmacy is possible; efficient transport of the radiopharmaceutical to the target organ; efficient extraction of the radiopharmaceutical by the target organ, such that adequate target to background ratios are achieved to allow diagnostic and therapeutic distinctions; and adequate retention in the target organ to allow detection and therapy using conventionally available radiation monitoring equipment. Representative organs of interest are those containing malignant cells or activated platelets. Imaging agents and therapeutic agents have typically been unsuitable due to poor in vivo stability post-chelation, resulting in inadequate retention and accretion by the effected cells.
Thus, there is a need in the art for improved chelation compounds for imaging and therapy. The present invention fulfills this need and further provides other related advantages.
SUMMARY OF THE INVENTION
Briefly stated, the present invention in one aspect provides compounds having.the formula:
wherein:
n=0 or 1;
R
1
and R
2
are independently selected from hydrogen, ═O, with the proviso that both are not ═O, —(CH
2
)
m
—Z where m is 0-10 and Z represents a conjugation group or targeting moiety, and —(Ch
2
)
m
—W where m is 0-10 and W represents a hydrolyzable group, or R
1
and R
2
are taken together to form a cyclic anhydride or a benzene ring;
R
3
is hydrogen, lower alkyl, alkoxy, halogen, hydroxyl, nitro, —(CH
2
)
m
—Z or —(CH
2
)
m
—W;
R
4
and R
5
are attached at one or more of the ring positions and are independently selected from hydrogen, lower alkyl, alkoxy, halogen, hydroxyl, nitro, —(CH
2
)
m
—Z and —(CH
2
)
m
—W;
R
6
and R
7
are independently selected from hydrogen with the proviso that both are not hydrogen, lower alkyl, alkoxy, halogen, hydroxyl, nitro, —(CH
2
)
m
—Z, —(CH
2
)
m
—W and
 where Q represents a multivalent acid functionality group able to coordinate with metal ions, and p=0 to 1; R
12
and R
13
are independently selected from hydrogen, hydroxyl, carboxyl, phosphonic and hydrocarbon radicals having from 1-10 carbon atoms, and physiologically acceptable salts of the acid radicals;
X, X′, Y and Y′ are independently selected from carbon, nitrogen, oxygen and sulfur to independently form five or six member aromatic rings wherein the remaining ring atoms are carbon;
A and A′ are independently selected from sulfur, nitrogen and oxygen, where sulfur may bear a hydrogen or a sulfur protecting group, or where A and A′ are both sulfur, A and A′ may be joined together by a bond; where an oxygen or a nitrogen may bear a hydrogen; or where A or A′ is nitrogen, A may bear R
8
or R
10
or both and A′ may bear R
9
or R
11
or both, wherein R
8
, R
9
, R
10
and R
11
are independently selected from lower alkyl, alkoxy, halogen, hydroxyl, nitro, —(CH
2
)
m
—Z, —(CH
2
)
m
—W and
 or R
8
and R
10
may be joined to form a cyclic anhydride or R
9
and R
11
may be joined to form a cyclic anhydride; or when A and A′ are both nitrogen, R
10
and R
11
may be joined to form T, where T
 and n is 0 to 1, and R
1
′ and R
2
′ are independently selected from hydrogen, ═O, with the proviso that both are not ═O, —(CH
2
)
m
—Z and —(CH
2
)
m
—W or R
1
′ and R
2
′ are taken together to form a cyclic anhydride or a benzene ring; and R
3
′ is hydrogen, lower alkyl, alkoxy, halogen, hydroxyl, nitro, —(CH
2
)
m
—Z and —(CH
2
)
m
—W; and
said compound has at least.one Z, W and Q.
In another aspect, the invention provides chelates comprising radionuclide metals (including oxides or nitrides thereof) complexed by a compound described above. A preferred metal chelate compound is of the formula:
wherein:
M is a radionuclide metal or an oxide or a nitride thereof selected from technetium, copper, rhenium, sumarian, yttrium, indium, lead, bismuth, ruthenium, rhodium, gold and palladium;
n=0 or 1;
R
1
and R
2
are independently selected from hydrogen, ═O with the proviso that both are not ═O, —(CH
2
)
m
—Z where m is 0-10 and Z represents a conjugation group or targeting moiety, and —(CH
2
)
m
—W where m is 0-10 and W represents a hydrolyzable group, or R
1
and R
2
are taken together to form a cyclic anhydride or a benzene ring;
R
3
is hydrogen, lower alkyl, alkoxy, halogen, hydroxyl, nitro, —(CH
2
)
m
—Z or —(CH
2
)
m
—W;
R
4
and R
5
are attached at one or more of the ring positions and are independently-selected from hydrogen, lower alkyl, alkoxy, halogen, hydroxyl, nitro, —(CH
2
)
m
—Z and —(CH
2
)
m
—W;
R
6
and R
7
are independently selected from hydrogen with the proviso that both are not hydrogen, lower alkyl, alkoxy, halogen, hydroxyl, nitro, —(CH
2
)
m
—Z, —(CH
2
)
m
—W— and
 where Q represents a multivalent acid functionality group able to coordinate with metal ions, and p=0 to 1; R
12
and R
13
are independently selected from hydrogen, hydroxyl, carboxyl, phosphonic and hydrocarbon radicals having from 1-10 carbon atoms, and physiologically acceptable salts of the acid radicals;
X, X′, Y and Y′ are independently selected from carbon, nitrogen, oxygen and sulfur to independently form 5 or 6 member aromatic rings wherein the remaining ring atoms are carbon;
A and A′ are independently selected from sulfur, nitrogen and oxygen, where A or A′ is nitrogen, A may bear R
8
or R
10
or both and A′ may bear R
9
or R
11
or both, wherein R
8
, R
9
, R
10
and R
11
are independently selected from lower alkyl, alkoxy, halogen, hydroxyl, nitro, —(CH
2
)
m
—Z, —(CH
2
)
m
—W and
or R
8
and R
10
may be joined to form a cyclic anhydride or R
9
and R
11
may be joined to form a cyclic anhydride; or when A and A′ are both nitrogen, R
10
and R
11
may be joined to form T, where T is
 and n is 0 to 1, and R
1
′ and R
2
′ are independently selected from hydrogen, ═O, with the proviso that both are not ═O, —(CH
2
)
m
—Z or R
1
′ and R
2
′ are taken together to form a cyclic anhydride or a benzene ring; and R
3
′ is hydrogen, lower alkyl, alkoxy, halogen, hydroxyl, nitro, —(CH
2
)
m
—Z or —(CH
2
)
m
—W; and
said compound has at least one Z, W or Q.
Yet another aspect of the invention provides for the use of the chelation compounds described above in methods for diagnostic and therapeutic purposes. A diagnostic method is described for detecting the presence or absence of a target site within a mammalian host. This method comprises providing to cells a diagnostically effective dose of a compound of the present invention which contains a metal radionuclide, such as
99m
Tc and/or
111
In, and detecting the biodistribution of the radionuclide. A therapeutic method is described for delivering a radionuclide, such as
186
Re/
188
Re,
90
Y, and
153
Sm, to a target site within a mammalian host. This method comprises providing to cells a therapeutically effective dose of a chelate compound of the present invention.
Other aspects of the

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