Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
1999-12-28
2001-06-05
Hollinden, Gary E. (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C514S184000, C514S836000, C534S016000, C540S465000, C540S474000
Reexamination Certificate
active
06241968
ABSTRACT:
FIELD OF THE INVENTION
The present invention concerns innocuous ingestible or enterally administrable compounds and compositions which are used as contrast enhancer media or agents in nuclear magnetic resonance imaging (MRI) of the gasto-intestinal tract of animal and human patients. It also concerns methods for making the new contrast agents and their application in diagnostic imaging.
BACKGROUND ART
It is well known that MRI enables the direct electronic visualisation of internal organs in living beings and is therefore powerful help and guide in prognosis, medical treatment and surgery. This technique can often advantageously supplement or replace X-ray tomography as well as the use of radioactive tracer compounds which may have obvious undesirable side effects.
The whereabouts of MRI techniques applied to the imaging of body organs are summarised in EP-A-0 502 814 and need not be developed in detail here; suffice to say that the useful parameters pertaining thereto, i.e. the relaxation time factors T
1
and T
2
of the water protons in the direct environment of the organs under investigation are usually not sufficiently differentiated to provide sharp images when the measurements are carried out in the absence of contrast agents. The differences of the relaxation time constants between protons in various parts of the organs can however be enhanced in the presence, in the environment of the hydrated molecules under excitation, of a variety of magnetic species, e.g. paramagnetic (which mainly affect T
1
) and ferromagnetic or superparamagnetic (which mainly affect the T
2
response). The paramagnetic substances include some metals in the ionic or organo-metallic state (e.g. Fe
+3
, Mn
+2
, Gd
+3
and the like, particularly in the form of chelates to decrease the intrinsic toxicity of the free metal ions). Ferromagnetic and superparamagnetic contrast substances preferably include magnetic particles of micronic or submicronic size, i.e. from a few microns down to a few nanometers, for instance particles of magnetite (Fe
3
O
4
), &ggr;-Fe
2
O
3
, ferrites and other magnetic mineral compounds of transition elements.
Until now, MRI contrast agents designed for imaging the digestive tract have mostly included solid magnetic materials generally in particular form. This is so because to be effective, the contrast agents should more or less line the walls of the digestive tract, thus requiring bulk. Obviously paramagnetic species in water-soluble molecular form would not fit the foregoing requirements and, if used, they should be associated with bulk carriers.
For instance, EP-A-0 275 215 discloses MRI contrast enhancers for the investigation of the digestive tract comprising complexes of paramagnetic metal species like gadolinium, iron, manganese and the like associated with mineral particulate carriers such as alkaline-earth polyphosphates and apatite.
EP-A-0 083 760 discloses EDTA, DTPA and NTA chelates of paramagnetic metals chemically bonded to organic polymer carriers such as sepharose, dextran, dextrin, starch and the like.
Also in EP-A-0 299 920 there are disclosed complexes between paramagnetic metals such as Cr, Mn, Fe, Ni, Co, Gd, etc. and polysulfated oligosaccharides like sucrose or maltose, these complexes being used for MRI of the digestive tract.
U.S. Pat. No. 5,466,439 discloses diamidopolymers of conventional alkyleneaminopolycarboxylic chelatants such as EDTA, DTPA and the like, and their addition copolymers with methyl methacrylates. The structure of polyethylene diamide-DTPA obtained from ethylene diamine and DTPA dianhydride is given below for illustration:
The polymeric chelatants are used to immobilize paramagnetic metals, e.g. Cr, Mn, Fe and the lanthanides, e.g. Gd, and the complexes administered orally for imaging the digestive tract.
Although the achievements of the prior art have merit, there is still need for more performant internal paramagnetic MRI contrast agents, more particularly in regard to bioadhesivity and controlled transit time in the digestive tract. The present invention is a forward step in the right direction.
DETAILED DESCRIPTION OF THE INVENTION
The invention provides, as contrast signal generators in MRI imaging of the digestive tract, paramagnetic metal chelates of novel acrylic compounds of formula C(R
1
R
2
)═CR
3
—CO—Z—Z (1) and/or C(R
1
R
2
)═CR
3
—CO—Z—Z—CO—CR
3
═C(R
1
R
2
) (2) in monomer, oligomer, homopolymer and copolymer forms, in which the R
1
, R
2
and R
3
represent H or saturated or unsaturated C
1-10
aliphatic radicals optionally substituted by one or more OH groups; Z is a covalent bond or a linker spacer and A is moiety capable of fixing a paramagnetic metal by chelation.
Compounds of type 1 and/or 2 useful in the present invention are, for instance the polyalkylene-aminopropylcarboxylic acids such as NTA, EDTA, DTPA, DOTA and like structures, possibly involving additional substituents; an example is the compound BOPTA which is a DTPA derivative carrying a benzyloxypropyl group. Suitable mono and difunctional monomers involving DTPA are given below for illustration (formula III and III bis)
In these compounds, one or two of the carboxylic functions of DTPA has been derivatized to be connected to the acrylic moiety via an alkylene diamide bridge.
In other embodiments, other chelating moieties can be similarly associated to (1) and/or (2) such as those disclosed in K. Kumar et al., J. Liquid. Chromatography 17 (1994), 3735-3746 incorporated herein by reference. Preferred compounds are those in which Z is H (DO3A), carboxymethylene (DOTA), —CH
2
—CHOH—CH
3
(HP-DO3A), or gadoteridol when in chelate form with Gd), —CH
2
—CHOH—CHOH—CH
2
OH (gadobutrol when in the form of chelate) and —CH(CH
3
)COOH (DOTMA). Other suitable macrocyclic chelates are disclosed in documents WO87/05030 and WO89/01476 incorporated herein by reference.
A can be for instance a molecule like that of formula I
Z being a bond or a lower aliphatic substituent (C
1-6
) carrying one or more oxygen, nitrogen or sulfur containing functions (e.g. —OH, —SH, —NH
2
, —O—, —S—, —NH—, —CO—, —COOH and the like).
In formula (1) or (2), the —CO— group is preferably linked by reaction to a hydroxy, amine or mercaptan function of Z via ester, amide or thioester bonds. For instance, Z can derive from a lower (C
1-6
) alkylene diamine bridging unit, the N's of which are linked through amide bonds to the —CO—'s of (1) or (2). Formula II and II bis are examples of such connecting way
in which n can be 2 to 6. Alternatively, Z can be derived from corresponding glycols or thioglycols.
In other embodiments, another class of macromolecular chelates useful in the present invention is that derived from “Starburst®” dendrimers exemplified by the structure (IV) above, in which at least one R is the acryloyl portion of formula (1), the other R's being derivatized chelatants of paramagnetic metals, e.g. isothiocyanato-DTPA (ITC-DTPA), SCN-Ph-NH-CO-CH
2
-DO3A (IPA-DO3A), or having the formula
in ionic form. The foregoing dendrimer chelatants are disclosed in detail in the publication of E. C. Wiener et al., Magnetic Resonance in Medicine 31 (1994), 1-8, which is incorporated herein by reference.
The paramagnetic metals retained as complexes in the present polymer chelates include lanthanides, e.g. Gd and some transition elements including Fe, Mn, Cr and the like.
A general method to manufacture the chelatant compounds of the invention is based on the acylation with acryloyl derivatives of hydroxy, thiol, or amino derivatives of the chelating agents. The reaction is exemplified below using for illustration HP-DO3A and an acryloyl halide:
According to variant routes spacer-linkers are derived from alkylene bridges carrying terminal derivatizable functions like —OH, —SH and unsubstituted or monosubstituted amino groups. As an illustration, a bridging alkylene diamine (of which one terminal nitrogen is protected by a protective group [Pr], e.g. benzyl, tosyl, BOC or the like) is reacted with a chelatant N-polycarboxylic an
Bussat Philippe
Tournier Herve
Bracco Research S.A.
Hollinden Gary E.
Nixon & Vanderhye
LandOfFree
Compositions for increasing the MRI contrast in visualizing... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Compositions for increasing the MRI contrast in visualizing..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Compositions for increasing the MRI contrast in visualizing... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2494392