Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
2000-07-20
2002-10-01
Jones, Dameron L. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S001110, C424S001650, C424S009100, C424S009300
Reexamination Certificate
active
06458337
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
This invention relates to the Magnetic Resonance Imaging (M.R.I.), a technique used in the medical diagnosis field for a number of years, to rapidly detect a series of anomalies and/or pathological conditions of living human or animal body organs or tissues. (i. e.: Stark D. D., Bradley W. G. Jr., Eds.: “Magnetic Resonance Imaging”, the C.V. Mosby Company, St. Louis, Mo. (USA), 1988). In particular, the invention relates to new chelating agents, especially aminopolycarboxylic acid derivative compounds and to metal chelates thereof with bivalent or trivalent paramagnetic ions and/or salts thereof as well as their use as M.R.I. contrast agents.
BACKGROUND OF THE INVENTION
Diagnostic imaging techniques, such as Magnetic Resonance Imaging have been used in medical diagnosis for a long time. The use of contrast media to improve tissue differentiation, to delineate structures or monitor physiological functions constitutes in some cases a fundamental contribution in the best formulation of some medical diagnosis and a valid support for radiologist work.
The medical use of aminopolycarboxylic acid or carboxylic acid derivatives and metal chelates thereof as M.R.I. contrast agents is well known. Said contrast agents, to simplify, can be seen as pertaining to two main groups: the linear and the cyclic ones.
The present invention relates to linear polyaminopolycarboxylic acid derivatives, as well as their complexes with paramagnetic metal ions, in particular the Gd
3+
ion.
Patent literature is rich in patent and patent applications relating to the use of linear polyaminopolycarboxylic acid derivatives in the preparation of MRI contrast agents. These compounds generally are derived from the simplest one, N,N,N′,N″,N″-diethylenetriamine-pentaacetic acid, (DTPA), of which the Meglumine salt of the Gd
3+
complex has been commercialised for a number of years as MAGNEVIST®. To improve stability, water solubility and selectivity and to reduce toxicity of these contrast agents generally patent literature proposes the preparation of esters or amido derivatives of said acids or the introduction of substituents on the diethylene unit of the diethylenetriamine DTPA skeleton. As an example of said patent literature we can cite: Guerbet EP 661279; Concat Ltd., WO 95/05118; Dibra WO 95/15319; Mallinckrodt WO 94/08630; Green Gross Corp. JP 06016606 and JP 05229998; Mallinckrodt U.S. Pat. No. 5,141,740 and U.S. Pat. No. 5,077,037; Cockbain-Nycomed WO 91/15467 and WO 92/11232; Salutar U.S. Pat. Nos. 4,889,931 and 4,858,451; Abbot Laboratoires EP 279307; Nycomed EP 299795; Metasyn Inc. WO 95/28179; Schering EP 680 464; and document cited in these patent publications. Some documents further exist in which substituents have been introduced in à to one or more carboxylic DTPA groups; for example: Bracco EP-B-230893 and U.S. Pat. No. 5,182,370; Schering WO 96/16928, WO 96/16929, WO 96/26180 and DE 4341724 enclosing à derivatives, generally comprising an aromatic group, particularly useful for the imaging of the hepatobiliary system. In particular, some patent literature further exist, in which the introduction of an aromatic or lipophilic group on the chelant structure is specifically stated to make the contrast agent particularly useful for a best definition of the liver and the biliary duct: the General Hospital Corporation U.S. Pat. No. 4,899,755 and WO-A-86/06605.
Among the other relevant documents disclosing large substituents on a DTPA like skeleton, in particular on the at position to the carboxy groups of DTPA, the following can also be mentioned. U.S. Pat. No. 5,746,995 describes chelates compounds in which the DTPA skeleton is substituted on the &agr; position of one of the carboxy residues of the terminal/lateral part of the molecule. Said substituents are lipophilic radicals that render the claimed compounds particularly useful for the imaging of liver, gallbladder and bile ducts. U.S. Pat. No. 5,672,335 discloses substituted DTPA derivatives, which carry substituents that render the same sufficiently lipophilic to be useful for the imaging of liver and the biliary tracts. These compounds are specific hepatobiliary contrast agents for X-ray imaging (computer tomography). U.S. Pat. No. 5,514,810 discloses a process for preparing complexses substituted in the &agr; position of the central carboxylic acid of the molecule. Said compounds are in any case lipophilic tetraesters of the four terminal carboxylic acids of the skeleton of DTPA. CA 2,177,977 discloses a number of complex derivatives of DTPA which carry huge substituents containing one or more aromatic moieties, which are especially suitable for diagnostic radiology of the liver.
No mention is found in this prior-art on the possibility that said compounds form strong non-covalent bonds with the serum/plasma proteins, turning out to be useful also as blood pool contrast agents. In fact the fact that said compounds are substantially hepatospecific means that they are preferentially, if not selectively taken up by the liver hepatocytes and are then excreted via the biliary route, thus being cleared away from the vessels in a very short time.
SUMMARY OF THE INVENTION
The compounds of the present invention are diethylenetriaminepentaacetic acid derivatives characterised by having a hindering group in a to at least one of the 5 DTPA carboxylic groups wherein said substituent has the dimension of a C
1
-C
20
alkyl, linear or branched, saturated or unsaturated chain, which is substituted or interrupted by at least two cyclic, optionally aromatic, carbocyclic or eterocyclic, saturated or unsaturated, isolated or fused units.
Particularly preferred compounds are those having one hindering group in the &agr; position of the central carboxylic acid of the DTPA skeleton, in particular the ones in which said hindering group is a tyrosine residue.
Said hindering group is probably responsible for the interaction of the paramagnetic chelates with biological components of the fluids in which the agent diffuses, wherein said interaction produces the surprisingly high relaxivity values that we have measured in Human Reconstructed Serum.
Relaxivity values of the contrast agent of the present invention have been tested either in saline or in human serum obtained by Seronorm™ Human, freeze-dried human serum produced by Nycomed Pharma AS, Oslo, Norway. Serum obtained from said Seronorm™ is substantially equivalent to the fresh one, so its use in the relaxivity determination grants a good picture of the “in vivo” behaviour and, further, an excellent reproducibility of this test.
The compounds object of the present invention are characterised by very high r
1
and r
2
relaxivity values. When measured in Seronorm™ Human at 20 MHz, at a temperature of 39° C., and at a concentration comprised from 0 to 1 mM, compounds of the present invention usually have r
1
relaxivity equal to or, preferably, higher than 15
s−1
mM
−1
, thus confirming the formation of unexpectedly strong non-covalent bonds with serum proteins. This feature has been further confirmed by measuring the protein binding of the chelate complexes of the invention to Human Serum Albumin (HSA), whereas an average percent binding value superior to 80% was found. Last, significative amounts of the preferred compounds of the invention have also been found in the urines, showing that, thanks to their binding to HSA, the same are very promising as blood pool diagnostic agents.
DETAILED DISCLOSURE OF THE INVENTION
The present invention relates to novel chelating agents, more particularly linear aminopolycarboxylic acid derivatives chelants, and metal chelates thereof and the use of such chelating agents and chelates in the preparation of diagnostic imaging contrast agents and in particular of contrast agents exhibiting improved serum relaxivity.
Said compounds are polyaminopolycarboxylic acid derivatives of formula (I)
in which:
R is H, or a linear or branched, saturated or unsaturated C
1
-C
20
alkyl, optionally interrupted by one or more
Anelli Pier Lucio
Brocchetta Marino
Fedeli Franco
Lolli Marco
Morosini Pierfrancesco
Dibra S.p.A
Jones Dameron L.
Nixon & Vanderhye P.C.
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