Enhanced relaxivity monomeric and multimeric compounds

Details Enhanced relaxivity monomeric and multimeric compounds Enhanced relaxivity monomeric and multimeric compounds

1994-05-11

2004-02-17

Raymond, Richard L. (Department: 1624)

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

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C540S474000

Reexamination Certificate

active

06693190

ABSTRACT:

BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, novel monomeric and multimeric compounds having enhanced relaxivities are provided. These compounds are useful, for example, as metal-chelating ligands. The compounds are also useful in the form of metal complexes as diagnostic contrast agents. When the metal in the complex is paramagnetic, the diagnostic contrast agents are especially suitable for magnetic resonance imaging (MRI).
In one embodiment of the invention, certain specific compounds comprise a tetraazacyclododecane macrocycle, and are represented by the formula I:
wherein
each m, n, o and p is independently 1 or 2;
q is 0 or 1;
each G is independently —COOR″, —P(O)(OR″)
2
, —P(O)(OR″)(R″) or —C(O)N(R″)
2
;
each R′ is independently hydrogen or alkyl, alkoxy, cycloalkyl, hydroxyalkyl or aryl, each of which is optionally substituted, or a functional group capable of forming a conjugate with a biomolecule or of forming a multimer of said compound of formula I;
each R″ is hydrogen;
each R
13
through R
20
is independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl or a functional group capable of forming a conjugate with a biomolecule or of forming a multimer of said compound of the formula I;
or R
13
together with R
15
, and R
17
together with R
18
, independently form, together with the carbon atoms in the tetraazacyclododecane macrocycle to which they are attached, a fused fully or partially saturated non-aromatic cyclohexyl ring which may be unsubstituted or substituted by one or more halogen, alkyl, ether, hydroxy or hydroxyalkyl groups, and which may be further fused to a carbocyclic ring, or R
13
and R
15
are each hydrogen and R
17
, together with R
18
, forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above, or R
13
, together with R
15
, forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above and R
17
and R
18
are hydrogen; provided that (a.) when G is always —COOR″ and (i.) R′, R″, R
14
and R
16
through R
20
are all hydrogen, then R
13
and R
15
are other than hydrogen; (ii.) R″ and R
13
through R
20
are all hydrogen, and m, n, o, p and q are each 1, then (CR′R′) is other than (CH
2
) and (CHCH
3
); (iii.) R′, R″, R
13
, R
14
, R
17
and R
20
are all hydrogen, then at least two of R
15
, R
16
, R
18
and R
19
are other than methyl; and (iv.) R″, R
16
, R
19
and R
20
are all hydrogen, and each (CR′R′) is independently (CHR′) or (CH
2
CHR′), then R
13
and R
15
, and R
17
and R
18
, are other than a fused ring; and (b.) when G is always —P(O)(OR″)
2
, —P(O)(OR″)(R″) or —C(O)N(R″)
2
, then at least one R′ or R
13
through R
20
is other than hydrogen;
or a salt or multimeric form thereof.
DETAILED DESCRIPTION OF THE INVENTION
Listed below are definitions of various terms used in the description of this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.
The expression “relaxivity” refers to the effectiveness of a metal chelate to reduce the relaxation time of bulk water in contact with the metal chelate.
The expression “immobilized relaxivity” refers to the relaxivity measured when a chelate moiety can undergo only slow molecular reorientation because of rigid attachment to a large moiety or a physiological surface, or because it is dissolved in a medium of high viscosity.
The expression “water relaxivity” refers to relaxivity in water where a chelate moiety possesses a relaxivity dominated by overall molecular reorientation.
The expression “enhanced relaxivity” refers to relaxivity values made greater than those of well characterized prior art molecules by 1.) altering the electronic relaxation rate, &tgr;
s
, through modifications of the metal-donor atom bond vibration frequencies and/or amplitudes, (this being accomplished, for example, by increasing the steric bulk and/or orientation of organic elements bonded to the donor atoms and/or the macrocyclic carbon atoms), 2.) in a multimer by decreasing the internal molecular motion of one monomer unit relative to another (this being accomplished, for example, by increasing the steric bulk of the organic groups linking the monomer units) or 3.) by decreasing the molecular reorientation of a monomer or a multimer attached to a large moiety or a physiological surface.
The term “stability” refers to the equilibrium formation constant (K) of the reaction M+L→M(L) where K=[M(L)]/[M][L], M is a metal ion, L is a chelating ligand and M(L) is a chelate complex of a metal and a ligand.
The term “alkyl” refers to both straight and branched, unsubstituted chains of carbon atoms. Those chains having 1 to 5 carbon atoms are preferred. Methyl is the most preferred alkyl group.
The term “cycloalkyl” refers to cyclic hydrocarbon groups of 3 to 8 carbon atoms. The groups may be unsubstituted or substituted by, for example, alkyl, halogen, hydroxy, hydroxyalkyl, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthiol, nitro, cyano, carboxy, carbamoyl, alkoxycarbonyl, alkylsulfonyl, sulfonamido and the like.
The term “alkoxy” refers to -alkyl(O). Methoxy is the most preferred alkoxy group.
The term “aryl” refers to phenyl, pyridyl, furanyl, thiophenyl, pyrrolyl, imidazolyl and the like, all of which may be substituted. Preferred substituted aryl groups are those substituted with 1, 2 or 3 halogen, nitroamino, maleimido, isothiocyanato, hydroxy, hydroxyalkyl, alkyl, alkoxy, carbamoyl, carboxamide, acylamino or carboxy moieties.
“Hydroxyalkyl” refers to straight and branched alkyl groups including one or more hydroxy radicals such as —CH
2
CH
2
OH, —CH
2
CH
2
OHCH
2
OH, —CH(CH
2
OH)
2
and the like. (See, for example, Sovak, M., Editor,
Radiocontrast Agents
, Springer-Verlag, 1984, pp. 1-125).
The term “aralkyl” refers to an aryl group bonded through an alkyl group.
The term “carbocyclic ring” refers to a ring system in which all the ring atoms are carbon, e.g., phenyl or cyclohexyl. The ring may be unsubstituted or substituted by, for example, alkyl, halogen, hydroxy, hydroxyalkyl, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthiol, nitro, cyano, carboxy, carbamoyl, alkoxycarbonyl, alkylsulfonyl, sulfonamido and the like.
The term “halogen” refers to bromo, chloro, fluoro or iodo.
The term “alkanoyl” refers to the group alkyl-C(O)—.
The term “alkanoyloxy” refers to the group alkyl-C(O)—O—.
The term “amino” refers to the group —NH
2
.
The term “alkylamino” refers to the group —NHR where R is alkyl.
The term “dialkylamino” refers to the group —NRR′ where R and R′ are each, independently, alkyl.
The term “alkanoylamino” refers to the group alkyl-C(O)—NH—.
The term “thiol” refers to the group —SH.
The term “alkylthiol” refers to the group —SR where R is alkyl.
The term “nitro” refers to the group —NO
2
.
The term “cyano” refers to the group —CN.
The term “carboxy” refers to the group —C(O)OH or the group —C(O)OR where R is alkyl.
The term “alkoxycarbonyl” refers to the group alkoxy-C—(O)—.
The term “alkylsulfonyl” refers to the group alkyl-SO
2
—.
The term “sulfonamido” refers to the group —SO
2
NH
2
, the group —SO
2
NHR or the group —SO
2
NRR′ where R and R′ are each, independently, alkyl, cycloalkyl or aryl.
The term “carbamoyl” refers to the group —C(O)NH
2
, the group —C(O)NHR or the group —C(O)NRR′ where R and R′ are each, independently, alkyl, alkoxy or hydroxyalkyl.
The term “carboxamide” refers to the group —C(O)NH
2
, the group —C(O)NHR or the group —C(O)NRR′ where R and R′ are each, independently, alkyl.
The term “acylamino” refers to the group —NH—C(O)—R where R is alkyl.
The expressions “bioactive group” and “bioactive moiety” denote a group which is

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