Metal chelates of substituted polyaminocarboxylic...

Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound

Reexamination Certificate

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C424S009363, C424S009420, C540S465000, C540S474000, C514S184000, C514S836000

Reexamination Certificate

active

06187285

ABSTRACT:

The present invention relates to chelates formed from macrocyclic polyaminocarboxylic acids with metal cations and to their use in diagnostic imaging, in particular magnetic resonance imaging (MRI) for magnetic cations.
The relaxivities r
1
and r
2
and particularly the first give a measure of the magnetic efficacy of such a chelate and make it possible to assess its use as a contrast agent. For the products currently marketed, r
1
does not exceed 6 mM
−1
s
−1
(at 20 MHz and 37° C.), whether the chelates are linear (gadopentetate or DTPA and gadoversetamide) or macrocyclic (gadoterate or DOTA and gadoteridol). In addition, when these compounds are administered intravenously, they diffuse rapidly from the vascular domain into the extracellular interstitial compartment and there is not yet a product on the market which remains sufficiently localized in blood vessels to allow an accurate evaluation of tissue perfusion, of capillary permeability or of the blood volume.
Substituted macromolecules resulting from the grafting of a standard chelate onto a biocompatible polymer, such as that obtained by attaching gadopentetate to polyethylene glycol or polylysine, or of gadopentetate and gadoterate onto a polysaccharide, which have been described for more than 10 years and which have been tested on animals, have still not been developed in man.
It has since been proposed to graft these standard chelates (DTPA or DOTA) onto branched polymers of unique molecular mass, known as cascade polymers or dendrimers, consisting of varied repeating units, such as, for example, in EP-A-430,863 or EP-A-607222. It is mentioned that the relaxivities of these products are high and that they have a certain level of vascular retention, but these results remain limited since, for example, the polyamines bearing 24 or 48 gadopentetate molecules described in EP-A-430,863 have, despite their size, only a relaxivity r
1
of about 13 mM
−1
s
−1
for 4.8 mM
−1
s
−1
for gadopentetate alone; in addition, it appears to be difficult to isolate a single compound during the synthesis, i.e. to obtain the substitution of all of the end groups of such a polyamine, assuming that it was possible to obtain it in uniform molecular weight, which would avoid the dispersity of the physicochemical and pharmacokinetic properties of the components of the dose administered, which is a known drawback of the standard substituted polymers, which has limited their development.
In the most recent studies aimed at obtaining molecules with high relaxivity, of unique molecular weight and containing only one chelating group, mention may be made of EP-A-661,279 and WO 97/01359, which underline the advantage of introducing, into the known molecular structures, at least 3 hydrophilic side arms with a weight of greater than 200 onto the side groups of the donor nitrogen atoms which bear the other coordinating groups, whether they are acidic groups or substituted groups; in particular, it is mentioned that the gadolinium complexes of the substituted compounds of the gadoterate of formula
in which
have a relaxivity r
1
>20 mM
−1
s
−1
at 20 MHz and 37° C.
As compounds with high relaxivity and having a certain level of vascular retention, mention should also be made of those described in WO 96/23526, which are substantially different in structure from the above compounds, one of the representatives of which, MS325, a gadolinium complex of the compound of formula
binds reversibly to albumin in plasma such that its relaxivity r
1
in this medium is virtually 10 times that of the gadopentetate from which it is derived, for a half-life multiplied by 4 and a distribution volume divided by 2.5 in rabbits, according to Acad. Radiol. S356-S358 (1996).
In contrast with MS325 and its homologues, the paramagnetic metal complexes of the present invention have high relaxivities, even in water, since r
1
therein is greater than 30 mM
−1
s
−1
(20 MHz, 37° C.); in addition, although they hardly bind to plasmatic albumin at all, they show marked vascular localization and are mainly eliminated via the kidneys, such that they can advantageously be used in MRI as contrast agents, for revealing the circulatory system.
According to a first aspect, the invention relates to the paramagnetic, or radioactive, metal ion chelates of the polyaminocarboxylic macrocycles of formula
in which
m is 1 or 2,
R′ is H, an optionally hydroxylated C
1
-C
4
alkyl group, a CH
2
—COOH group, a group CH
2
—CONZ
1
Z
2
, Z
1
and Z
2
being, independently of each other, H or an optionally hydroxylated C
1
-C
4
alkyl group,
or R′ is a group HOOC—CH—(CH
2
)
m
—CONHR,
in which a is 1 or 2
Z is a bond, CH
2
, CH
2
—CO—NH or (CH
2
)
2
—NHCO
Z′ is a bond, O, S, NQ, CH
2
, CO, CO—NQ, NQ—CO, NQ—CO—NQ, CO—NQ—CH
2
—CONQ
Z″ is CO—NQ, NQ—CO, CO—NQ—CH
2
—CO—NQ or NQ—CO—CH
2
—NQ—CO
where Q is H or an optionally hydroxylated C
1
-C
4
alkyl group
R
1
, R
2
, R
3
, R
4
and R
5
, independently of each other, are selected from the group consisting of H, Br, Cl, I, CO—NQ
1
Q
2
or N(Q
1
)—CO—Q
2
and Q
1
and Q
2
, which may be identical or different, are selected from C
2
-C
6
alkyl groups which are optionally hydroxylated and optionally interrupted by an oxygen atom, such that Q
1
and Q
2
together contain from 4 to 10 OH groups,
with the proviso that at least 1, and not more than 2, groups R
1
, R
2
, R
3
, R
4
and R
5
are amido groups.
The metal cations complexed in the chelates of the invention are selected from the paramagnetic cations generally used in MRI, especially trivalent cations including Fe
3+
, Cr
3+
, Eu
3+
, Gd
3+
, Tb
3+
, and particularly Gd
3+
, or, for use in scintigraphy, from the cations of radio isotopes such as
99m
Tc or
111
In.
Inorganic bases which may give a pharmacologically acceptable salt with the optional free acid group of a metal complex of the compound of formula I are preferably selected from alkali metal (K
+
, Na
+
) or alkaline-earth metal (Ca
++
, Mg
++
) hydroxides and carbonates, while the organic bases are chosen from amines such as aminoethanol, thromethamine or N-methylglucamine, of from amino acids such as lysine, glycine or arginine.
The preferred compounds are those in which m is 2 and a is 1, R′ is not H or alkyl, Z is a bond, CH
2
or CH
2
CONH, Z′ is CONH, NHCO, CONHCH
2
CONH or NHCONH, Z″ is CONH or CONHCH
2
CONH with R
3
=CONQ
1
Q
2
and R
1
, R
2
, R
4
and R
5
are, independently, H, Br, Cl or I, or R
2
=R
4
=CONQ
1
Q
2
in which case R
1
, R
3
and R
5
are, independently, H, Br, Cl or I,
or Z″ is NHCO with R
3
=N(Q
1
)COQ
2
and R
1
, R
2
, R
4
and R
5
are, independently, H, Br, Cl or I, or R
2
=R
4
=N(Q
1
)COQ
2
, in which case R
1
, R
3
and R
5
are, independently, H, Br, Cl or I.
Among these, the preferred compounds are those in which Z′ is CONH, CONHCH
2
CONH or NHCONH, and, better still, those in which Z′ is CONH, shorter bond, R
1
, R
3
and R
5
are all Br or I and R
2
=R
4
=CONQ
1
Q
2
where Q
1
and Q
2
are C
2
-C
6
hydroxyalkyl groups together containing 6 to 10 OH groups or, if Q
1
and/or Q
2
is interrupted by an oxygen atom, they contain from 4 to 8 OH groups.
According to a second aspect, the invention relates to a process for preparing metal chelates of the compounds of formula I, which consists in reacting a chelate II of the metal cation M
3+
and of the compound of formula
with an amine of formula
in which the letters have the same meanings as in formula I, in the presence of a coupling agent, in particular those used in peptide synthesis, which is suited to the aqueous or organic reaction medium in which the compounds of formulae II and III are, at least partially, in solution. Under these conditions, the protected carboxylic acid groups located on the carbon atoms alpha to the nitrogen atoms in compound II do not react.
According to another aspect, the invention rel

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