Ligands and metal complexes thereof

Details Ligands and metal complexes thereof Ligands and metal complexes thereof

1996-08-09

2003-12-09

Hartley, Michael G. (Department: 1616)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

C424S001690, C560S168000, C564S225000, C564S226000, C564S227000, C534S010000, C534S014000

Reexamination Certificate

active

06660246

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel compounds and to novel complexes of these compounds with metals. The novel compounds and complexes of the present invention find utility in diagnostic and therapeutic methods.
BACKGROUND OF THE INVENTION
Metal complexes, such as those containing radioactive metals, are finding increasing use as diagnostic and therapeutic agents. Of particular interest are those complexes containing bioactive moieties capable of being selectively taken up at a desired site to facilitate evaluation or treatment of a subject.
The present invention addresses the need in the art for such complexes and the ligands from which they are prepared.
SUMMARY OF THE INVENTION
The present invention provides novel compounds, also referred to herein as ligands, of the following formula I:
where
Q is the group —(C(RR))
m1
—(Y
1
)
n
—(C(RR))
m2
—(Y
2
—(C(RR))
m3
)
n1
—, Y
1
and Y
2
are each independently —NR—, —O—, —S—, —SO—, —SO
2
— or —Se—; n and n1 are each independently 0 or 1; and m1, m2 and m3 are each independently 0 or an integer from 1 to 4; provided that m1 and m2 are not both 0, that m1+m2+n+n1 is less than 6 and that a carbon atom bearing an R group is not directly bonded to more than one heteroatom;
each R and R* group is independently:
(i) R
1
;
(ii) alkoxy;
(iii) hydroxy;
(iv) halogen, especially fluoro;
(v) haloalkyl;
(vi) —OR
1
;
(vii) —C(O)—OR
1
;
(viii) —C(O)—N(R
1
)
2
;
(ix) —N(R
1
)
2
—;
(x) —N(R
1
)—COR
1
;
(xi) -alkyl-C(O)—OR
1
;
(xii) -alkyl-C(O)—N(R
1
)
2
;
(xiii) -alkyl-N(R
1
)
2
—;
(xiv) -alkyl-N(R
1
)—COR
1
;
(xv) -aryl-C(O)—OR
1
;
(xvi) -aryl-C(O)—N(R
1
)
2
;
(xvii) -aryl-N(R
1
)
2
—;
(xviii) -aryl-N(R
1
)—COR
1
;
(xix) nitrile;
(xx) acyl;
(xxi) acyloxy;
(xxii) heterocyclo;
(xxiii) hydroxyalkyl;
(xxiv) alkoxyalkyl;
(xxv) hydroxyaryl;
(xxvi) arylalkyl;
(xxvii) —SO
2
—R
1
;
(xxviii) -alkyl-SO
2
—R
1
;
(xxix) —(A)
p
—R
a
, where A is a linking group, p is 0 or a positive integer, and R
a
is a bioactive moiety or a reactive group capable of forming a covalent bond to a bioactive moiety; or
(xxx) two of the groups, taken together with one or more atoms to which they are bonded, form a saturated or unsaturated, spiro or fused, carbocyclic (such as fused 1,2-phenyl) or heterocyclic ring which may be unsubstituted or substituted by one or more groups selected from the groups (i) to (xxix) above;
each R
1
is independently hydrogen, alkyl, alkenyl, alkynyl or aryl; and
G
1
and G
2
are each independently —OH or —N(R
2
)
2
, provided that at least one of G
1
or G
2
is —N(R
2
)
2
, where each R
2
is independently hydrogen, alkyl, aryl, acyl or —(A)
p
—R
a
.
The present invention also provides complexes of the aforementioned compounds of the formula I with metals, preferably rhenium or technetium, and the use of these complexes in diagnostic and therapeutic methods. Further provided by the present invention are kits for preparing the metal complexes of the present invention.
In certain embodiments, the present invention provides complexes, without a specific bioactive moiety, that localize selectively in an organ or organ system and may be useful for heart, brain, hepatobiliary or other organ imaging. In other embodiments, the present invention provides complexes containing bioactive moieties, such as receptor or hypoxia-localizing moieties, which retain the biochemical behavior and affinity of the free moieties and which are capable of rapidly providing increased amounts of a desired radionuclide selectively to targeted areas. Certain complexes of the invention may be labeled at ambient temperature with suitable, easy-to-use radionuclides; and some complexes may be membrane permeable, allowing intracellular delivery.
DESCRIPTION OF THE INVENTION
The present invention is described further as follows.
Definitions
Listed below are definitions of terms used to describe the present invention. These definitions apply to the terms as they are used throughout the specification unless otherwise indicated.
The terms “alkyl” or “alk”, as used herein alone or as part of another group, denote optionally substituted, straight and branched chain saturated hydrocarbon groups, preferably having 1 to 12 carbons in the normal chain. Most preferably, these groups are lower alkyl groups. Exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. Exemplary substituents include one or more of the following groups: halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, hydroxy, carboxyl (—COOH), amino, alkylamino, dialkylamino, formyl, alkylcarbonyloxy, alkylcarbonyl, heterocyclo or thiol (—SH). Preferred alkyl groups are unsubstituted alkyl, haloalkyl, arylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, aryloxyalkyl and hydroxyalkyl groups.
The terms “lower alkyl” or “lower alk”, as used herein, denote optionally substituted groups as described above for alkyl but having only 1 to 4 carbon atoms in the normal chain.
The terms “alkoxy” or “alkylthio” denote an alkyl group as described above bonded through an oxygen linkage (—O—) or a sulfur linkage (—S—), respectively. The term “alkylcarbonyl”, as used herein, denotes an alkyl group bonded through a carbonyl group. The term “asalkylcarbonyloxy”, as used herein, denotes an alkyl group bonded through a carbonyl group which is, in turn, bonded through an oxygen linkage.
The term “alkenyl”, as used herein alone or as part of another group, denotes optionally substituted, straight and branched chain hydrocarbon groups containing at least one carbon to carbon double bond in the chain, and preferably having 2 to 10 carbons in the normal chain. Exemplary unsubstituted alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl and the like. Exemplary substituents include one or more alkyl groups as described above, and/or one or more groups described above as alkyl substituents.
The term “alkynyl”, as used herein alone or as part of another group, denotes optionally substituted, straight and branched chain hydrocarbon groups containing at least one carbon to carbon triple bond in the chain, and preferably having 2 to 10 carbons in the normal chain. Exemplary unsubstituted alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. Exemplary substituents include one or more alkyl groups as described above, and/or one or more groups described above as alkyl substituents.
The term “cycloalkyl”, as used herein alone or as part of another group, denotes optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring. Exemplary unsubstituted cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl and adamantyl. Exemplary substituents include one or more alkyl groups as described above, and/or one or more groups described above as alkyl substituents.
The term “cycloalkenyl”, as used herein alone or as part of another group, denotes such optionally substituted groups as described above for cycloalkyl, further containing at least one carbon to carbon double bond forming a partially unsaturated ring.
The term “aryl”, as used herein alone or as part of another group, denote optionally substituted, homocyclic aromatic groups, preferably containing 1 or 2 rings and 6 to 12 ring carbons. Exemplary unsubstituted aryl groups include phenyl, biphenyl and naphthyl. Exemplary substituents include one or more, preferably three or fewer, nitro groups, alkyl groups as described above and/or groups described above as alkyl substituents. Preferred aryl groups are unsubstituted aryl and hydroxyaryl.
The term “carbocyclic”, as used herein alone or as part of another group, denotes optionally substituted saturated, partially unsaturated or aromatic homocyclic hydrocarb

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