Monofunctionalised EDTA, DTPA and TTHA derivatives and their use

Details Monofunctionalised EDTA, DTPA and TTHA derivatives and their use Monofunctionalised EDTA, DTPA and TTHA derivatives and their use

1998-06-29

2000-06-27

Geist, Gary

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

514530, 560121, 560169, A01N 3702, A01N 3708, C07C 6974, C07C22924

Patent

active

060807857

DESCRIPTION:

BRIEF SUMMARY
FIELD OF INVENTION

The invention relates to new monofunctionalized EDTA, DTPA and TTHA derivatives and their use for the production of pharmaceutical agents.
Metal complexes that consist of an open-chain chelating agent (ligands) and metal ions are known pharmaceutical agents, which have a variety of uses in medical diagnosis and therapy of heavy metal poisoning. Thus, i.a., the meglumine salt of the gadolinium(III) complex of diethylenetriaminepentaacetic acid (DTPA) was approved under the trade name Magnevist.RTM. as a contrast medium for MR tomography.
For the development of new preparations, it is often necessary to bond one or more ligands that are capable of chelation, such as, e.g, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA) or triethylenetetraaminehexaacetic acid (TTHA) to another molecule. Thus, it is possible, e.g., to bond a DTPA radical to a monoclonal antibody, which for its part has a specificity relative to tumors in order to label and thus to detect the latter, using a complexed radioactive metal ion. Such a process was described by, e.g., Kuhlmann and Steinstrasser (Nucl. Med. Biol. 15 (1988), pp. 617-627). In addition, it is possible to bond several complexing agent radicals to a polymeric parent substance and thus to increase the number of metal ions, which are present as opacifying components in the molecule. Compounds of this type are described in, for example, European Patent Application EP 331616.
For the production of such compounds, appropriately prepared monofunctionalized complexing agent derivatives are always required. Thus, e.g., Kuhlmann and Steinstrasser use the bis-anhydride of DTPA (Int. J. Radiat. Isot. 33 (1982), pp. 327-332) that is described for the first time by Hnatowich. The main problem when using bis-anhydride of DTPA is, however, its poor solubility in organic solvents, which entails a host of other problems.
Another problem of use of the bis-anhydride of DTPA for linking DTPA to amine-containing molecules is the unavoidable crosslinking, as was documented by a critical study by Maisano et al. (Bioconj. Chem. 3 (1992), pp. 212-217). For this reason, the inventors of European Patent Application EP 331616 propose the use of a monoanhydride, which also carries an ethyl ester (see Example 13a), that is obtained from the bis-anhydride. This derivative shows a better, but still always unsatisfactory solubility and at the same time exhibits a radical with the ethyl ester group that is easy to saponify unintentionally and is therefore difficult to handle. Moreover, the synthesis is expensive, i.a., because of the necessary chromatographic separations.
The partial alkaline saponification of DTPA-pentamethyl ester, as it is described in U.S. Pat. No. 5,252,317, invariably leads to product mixtures, since saponification by nature proceeds statistically.


SUMMARY OF THE INVENTION

The object of this invention was therefore to make available new derivatives of EDTA, DTPA and TTHA, which make possible selective coupling to additional molecules. They are also to be easy to manufacture and to have better solubility than the known derivatives. At the same time, they are to carry carboxylic acid protective groups, which if desired can be readily and selectively cleaved, but which are not unintentionally cleaved during the course of further manipulations of the molecule.
This object is achieved by this invention, especially by the new materials and the production process of this invention. Advantageous embodiments of the invention are also disclosed.
The subjects of this invention are therefore compounds of general formula I ##STR1## in which n stands for numerical values 0, 1 or 2, stand for --(CH.sub.2).sub.m --, in which m can assume numerical values 3 to 6, provided that R.sup.1 and R.sup.2 only then together stand for --(CH.sub.2).sub.m --, if n stands for value 0.
Formula I relates to EDTA-(n=0), DTPA-(n=1) and TTHA-(n=2) derivatives, in which in each case a terminal acetic group is substituted by hidrogen but preferably DTPA derivative

REFERENCES:
patent: 5514810 (1996-05-01), Platzek et al.
patent: 5618513 (1997-04-01), Srinivasan
Journal of Medicinal Chemistry, Aug. 30, 1996.

Affiliated with

Also associated with

Rating

Monofunctionalised EDTA, DTPA and TTHA derivatives and their use does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Monofunctionalised EDTA, DTPA and TTHA derivatives and their use, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Monofunctionalised EDTA, DTPA and TTHA derivatives and their use will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-1785189