Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-08
2002-08-27
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S465000, C514S300000, C534S010000, C534S014000, C534S016000
Reexamination Certificate
active
06440956
ABSTRACT:
The present invention relates to metal chelates derived from a tetranitrogenous macrocycle condensed with a pyridyl nucleus, to their processes of preparation and to their application in medical imaging.
The use in imaging of chelates, with a paramagnetic or radioactive cation, of certain derivatives of this condensed macrocycle has been proposed on various occasions. Reference may be made to Patents EP-A-0,438,206, EP-A-0,570,575 and EP-A-0,579,802, which disclose compounds of formula
in which X can be a carboxylate or phosphate group and R can be an alkyl or phenyl group or one of the R groups is a group forming a bond with a biological macromolecule.
Among these compounds, that for which A═B═CH, R=H, X=CO
2
−
and M=Gd, known as PCTA, has been the subject of in-depth studies, described in Inorganic Chemistry, 36(14), 2992-3000 (1997) and Magn. Reson. Chem., 36, S200-208 (1998); the authors indicate in particular that PCTA is noteworthy in that it has a particularly high longitudinal relaxation r
1
, since it is approximately “2 times” that of the gadolinium chelates used as contrast agents in magnetic resonance imaging in man.
It is known that r
1
characterizes the effectiveness of paramagnetic products in generating a strong contrast of the images and it is especially advantageous and unexpected that the paramagnetic products of the invention exhibit relaxations r
1
of 10 to 15 times greater than that of the commercial compounds, not only for a magnetic field of 0.5 tesla but also of 1 tesla, the field of most current imaging devices, and even at 1.5 tesla, the field of the devices with the best performances.
As these novel chelates, in addition to their favourable magnetic properties, are stable in vitro and in vivo, in particular with respect to possible breakdown of the complex, have a low osmolality and a good therapeutic index, and, according to the nature of the R group, can exhibit an excellent vascular persistence or an organ specificity, they will advantageously be used in man as contrast agents for magnetic resonance imaging or in nuclear medicine, when the metal ion is a radioelement.
The present invention relates to metal chelates of the compound of formula
in which
R has the formula
and
Z is a bond or a group selected from the CH
2
, CH
2
—CO—NH or (CH
2
)
2
—NH—CO groups,
Z′ is a bond or a group selected from the O, S, NQ, CH
2
, CO, CO—NQ, NQ—CO, NQ—CO—NQ or CO—NQ—CH
2
—CO—NQ groups,
Z″ is a bond or a group selected from the CO—NQ, NQ—CO or CO—NQ—CH
2
—CO—NQ groups,
p and q are integers, the sum of which has a value from 0 to 3,
R
1
, R
2
, R
3
, R
4
and R
5
, independently of one another, are selected from the H, Br, Cl, I, CO—NQ
1
Q
2
and NQ
1
—CO—Q
2
groups, Q
1
and Q
2
, which are identical or different, being H or (C
1
-C
6
)alkyl optionally interrupted by one or more oxygen atoms and at least one of the R
1
to R
5
groups being an amido group,
or R
1
, R
3
and R
5
are, independently of one another, H, Br, Cl or I, and
R
2
and R
4
have the formula
such that
Z′″ is a group selected from the CO—NQ, CONQ—CH
2
, CO—NQ—CH
2
—CO—NQ, CO—NQ—(CH
2
)
2
—NQ—CO and NQ—CO—NQ groups and R′
1
, R′
3
and R′
5
, which are identical or different, are H, Br, Cl or I and Q′
1
and Q′
2
, which are identical or different, are H or (C
1
-C
6
)alkyl optionally interrupted by one or more oxygen atoms,
Q is H or (C
1
-C
4
)alkyl,
the alkyl groups being optionally mono- or polyhydroxylated.
The metal ions can be paramagnetic ions, such as Gd
3+
, Fe
3+
, Tb
3+
, Mn
2+
, Dy
3+
or Cr
3+
, or radioactive ions, such as
99m
Tc,
67
Ga or
111
In; the ions which form less stable chelates, which can give rise to transmetallation, such as Ca
2+
or Zn
2+
, also form part of the invention; the paramagnetic chelates of Gd
3+
and Mn
2+
are particularly suited to magnetic resonance imaging. The paramagnetic chelates of Gd
3+
are very particularly preferred.
It is preferable, for better hydrophilicity and biocompatibility of the compounds, for the R
1
to R
5
groups on the same phenyl ring together to comprise from 6 to 20 OH groups or even for any CONQ
1
Q
2
group present, or, depending on the situation, CONQ′
1
Q′
2
, to comprise from 6 to 10 OH groups; it is also preferable for R
2
and R
4
to be identical and to be CO—NQ
1
Q
2
, which each comprise 6 to 10 OH groups, or the III group, in which each CONQ′
1
Q′
2
comprises from 6 to 10 OH groups; preference is also given to the compounds in which R
1
, R
3
and R
5
are selected from iodine or bromine atoms, as well as R′
1
, R′
3
and R′
5
, when they are present.
The relaxation of the compounds and their in vivo pharmacokinetics depend in particular on their number of phenyl ring. For example, it is possible to distinguish the compounds in which p and q are 0, in particular when R
2
and R
4
are CO—NQ
1
Q
2
, and those in which the sum of p and q has a value from 1 to 3 or better still 1 or 2 and R
2
and R
4
are or have not the formula III.
When, in the compounds of formula I, R
2
and R
4
are CONQ
1
Q
2
, Q
1
and Q
2
are preferably C
2
to C
6
alkyl groups optionally interrupted by an oxygen atom.
Furthermore, preference is given, among the compounds of formula I, to those in which Q is H and, among these, to those in which Z is CH
2
or CH
2
CONH, Z′ is a group selected from CONH, CONHCH
2
CONH or NHCONH and Z″ from CONH and CONHCH
2
CONH, and it is also preferable, when it is present, for Z′″ to be CONH or CONHCH
2
CONH.
Finally, another group of specific compounds is composed of that in which, p and q being equal to 1, Z is CH
2
or CH
2
CONH, Z′ and Z″ are selected from CONH and CONHCH
2
CONH, and R
2
and R
4
are CONQ
1
Q
2
, with R
1
, R
3
and R
5
preferably selected from Br and I.
Other preferred compounds are those defined in points (i) to (ix) hereinbelow:
(i) chelate of the compound of formula I in which p and q are 0 and R
2
and R
4
, which are identical, are —CO—NQ
1
Q
2
, each —CO—NQ
1
Q
2
group comprising from 6 to 10 —OH groups;
(ii) chelate of the compound of formula I in which p and q are 0, R
1
, R
3
and R
5
are identical and are selected from Br and I, and R
2
and R
4
, which are identical, are —CO—NQ
1
Q
2
, each —CO—NQ
1
Q
2
group comprising from 6 to 10 —OH groups;
(iii) chelate of the compound of formula I in which the sum p+q is not 0, any —CO—NQ
1
Q
2
group present comprises from 6 to 10 —OH groups, and R
2
and R
4
have not the formula III. Among these compounds, those for which p+q is 1 or 2 are more preferred.
(iv) Chelate of the compound of formula I in which the sum p+q is not 0, R
1
, R
3
and R
5
are identical and are selected from Br and I, and R
2
and R
4
, which are identical, are —CO—NQ
1
Q
2
, R
2
and R
4
each comprising from 6 to 10 —OH groups. Among these compounds, those for which p+q is 1 or 2 are more preferred.
(v) Chelate of the compound of formula I in which Z is CH
2
or CH
2
—CO—NH, Z′ is a group selected from CO—NH, CO—NH—CH
2
—CO—NH and NH—CO—NH, Z″ is a group selected from CO—NH and CO—NH—CH
2
—CO—NH, R
2
and R
4
, which are identical, are —CO—NQ
1
Q
2
, R
2
and R
4
each comprising from 6 to 10 —OH groups, and R
1
, R
3
and R
5
are identical and are selected from Br and I. Among these compounds, those for which p+q is 1 or 2 are more preferred.
(vi) Chelate of the compound of formula I in which Z is CH
2
or CH
2
—CO—NH, Z′ is a group selected from CO—NH, CO—NH—CH
2
—CO—NH or NH—CO—NH, Z″ is selected from CO—NH and CO—NH—CH
2
—CO—NH, Z′″, when it is present, is CO—NH or CO—NH—CH
2
—CO—NH, and the sum p+q is 1 or 2;
(vii) chelate of the compound of formula I in which R
2
and R
4
are CONQ
1
Q
2
and Q
1
and Q2 are polyhydroxylated C
2
to C
6
alkyl groups optionally interrupted by an oxygen atom;
(viii) chelate of the compound of formula
Guerbet
Habte Kahsay
Jacobson & Holman PLLC
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