Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
2000-07-07
2002-06-11
Jones, Dameron L. (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S009100, C424S009300, C424S009360, C424S001650
Reexamination Certificate
active
06403055
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 amide 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. Nos. 5,141,740 and 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 (&agr;) 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 &agr; derivatives, generally comprising an aromatic group, particularly useful for the imaging of the hepatobiliary system. In particular, some patent literature further exists, in which the introduction of an aromatic or lipophilic group on the chelant structure is specifically stated to make the contrast agent as 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.
Further relevant documents disclosing DTPA derivatives which carry substituents in &agr; position to the carboxy groups of the DTPA skeleton exist. Among the others, U.S. Pat. No. 5,885,548 describes DTPA analogs carrying a radicals which comprise at least one aryl group. No alicyclic substituents are indicated as possible substituents. The chelate complex of the invention are strongly preferred for the imaging of the liver, the bile ducts and the gallbladder, wichever the diagnostic technique is. U.S. Pat. No. 5,853,699 describes a range of compounds similar to the preceiding ones. In this case the preferred and strongly recommended ones are tetraazamacrocycles and are described and claimed only as contrast agents for the imaging of the liver by using the Computer Tomography, i. e. X-rays. No mention of a possible use with the Magnetic Resonance is done nor even suggested. DTPA derivatives &agr; substituted, whereas the possible &agr; substituents are only lower alkyl groups, and where said derivatives are in any case mono or diamido compounds are also disclosed in U.S. Pat. No. 5,453,264. No mention of possible cyclic moieties in the &agr; substituents is done or suggested. Also U.S. Pat. No. 5,672,335 discloses DTPA derivatives with possible substituents, comprising at least one aromatic ring, in &agr; position to the carboxy groups. Even this patent only suggests the imaging of the liver and bile ducts by using the X-rays (Computer Tomography), not magnetic resonance. The general teaching of the prior-art concerns the possibility of finding compounds that are particularly useful for the imaging of liver, bile ducts, gall bladder provided that lipophilic substituents are attached to the chelating moiety. More lipophilic substituents are highly preferred
eeded for obtaining liver specificity. No mention, nor even suggestion is made to the possibility that such DTPA derivatives can show very high relaxivity values in serum, and, on consequence, the capability of strongly bonding to the serum proteins.
SUMMARY OF THE INVENTION
The compounds of the present invention are diethylenetriaminepentaacetic acid derivatives characterised in having substituents at the a position to the carboxy group of two or three of the five acetic groups of DTPA. More precisely, the compounds can have two substituents (the same or different from each other) in &agr; to the carboxyls of the two acetic groups respectively bound to the two side nitrogen atoms of DTPA; or they can have three substituents (the same or different from each other) in &agr; to the carboxyl groups of three acetic groups respectively bound to the three nitrogen atoms of DTPA.
Therefore, the compounds of the present invention are characterized in having some sterical hindrance, due to the presence of two or three substituents at the above mentioned positions. The minimum size of the substituents is that of a chain having at least three carbon atoms.
Said hindering groups are probably responsible for the interactions of the paramagnetic chelates with biological components of the fluids in which the agent diffuses, said interactions substantially consisting in the formation of strong non-covalent bonds with the proteins present in such fluids. In particular said tight bonding is detectable in plasma, showing a great affinity of the compounds of the invention with the plasma proteins. This feature is particularly unexpected in view of the general teaching of the art. Actually it is well known that when a compound is hepatospecific, it is preferentially/selectively taken up by the liver hepatocytes and then it is excreted via the biliary route, in such way being cleared from the palsma. The compounds of the present invention, on the contrary, showed such an affinity with the plasma proteins to give extremely high values of relaxivity in serum (thus confirming the formation of strong bonds with serum proteins). Accordingly one of their preferential and strongly recommended use is as potential blood pool contrast agents, said caracteristic feature giving the possibility of a long period of permanence inside the vessels even administering substantially lower doses.
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 in
Calabi Luisella
Lolli Marco
Maiocchi Alessandro
Rebasti Fabrizio
Dibra S.p.A.
Jones Dameron L.
Nixon & Vanderhye
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