1,4,7,10-tetraazacyclododecane-1,4-diacetic acid derivatives...

Details 1,4,7,10-tetraazacyclododecane-1,4-diacetic acid derivatives... 1,4,7,10-tetraazacyclododecane-1,4-diacetic acid derivatives...

2000-08-25

2002-01-29

Ford, John M. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C540S472000, C540S474000

Reexamination Certificate

active

06342597

ABSTRACT:

The present invention relates to the novel 1,4,7,10-tetraazacyclododecane-1,4-diacetic acid derivatives of formula (I), their complexes with paramagnetic metal ions and physiologically compatible salts thereof, as well as to the preparation thereof and the use thereof for the preparation of chelating agents.
In particular the present invention relates to the derivatives of the novel compound, 1,4,7,10-tetraazacyclododecane-1,4-diacetic acid of formula (X), its chelated complex salts with pararnagnetic metal ions and the physiologically compatible salts thereof, as well as to the preparation thereof and the use thereof for the preparation of chelating agents.
The compounds of general formula (I), and in particular the compound of formula (X), are novel chelating agents for bi- trivalent metal ions and are also important intermediates for the synthesis of 1,4,7,10-tetraazacyclododecane derivatives chelating agents, symmetrically functionalized at the 1- and 4-positions.
The compounds of general formula (I) are therefore the starting material for the synthesis of multidentate derivatives which are capable of complexing different metals, some of which have applications in the biomedical field, such as gadolinium complexes of said derivatives, which are used in diagnostic as contrast agents for the magnetic resonance technique (Magnetic Resonance Imaging, MRI).
In particular, the medical diagnosis by means of “Magnetic Resonance Imaging” (M.R.I.), which is known to be a powerful diagnostic means in the clinical practice (Stark, D. D., Bradley, W. G., Jr., Eds. “Magnetic Resonance Imaging” The C. V. Mosby Company, St. Louis, Mo. (USA), 1988), mainly makes use of paramagnetic pharmaceutical compositions, preferably containing chelated complex salts of bi- and trivalent paramagnetic metal ions with aminopolycarboxylic acids and/or derivatives or analogues thereof.
Presently some of them are used in clinic as M.R.I. contrast agents (Gd-DTPA, N-methylglucamine salt of the gadolinium complex with diethylenetriaminopentaacetic acid, MAGNEVIST®, Schering; Gd-DOTA, N-methylglucamine salt of the gadolinium complex with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, DOTAREM®, Guerbet).
A list of significant patent literature for illustrating the prior art in this diagnostic field, although only exemplary and incomplete, is the following: EP 71564 (Schering), U.S. Pat. No. 4,639,365 (Sherry), U.S. Pat. No. 4,615,879 (Runge), DE-A-3401052 (Schering), EP 130934 (Schering), EP 65728 (Nycomed), EP 230893 (Bracco), U.S. Pat. No. 4,826,673 (Mallinckrodt), U.S. Pat. No. 4,639,365 (Sherry), EP 299795 (Nycomed), EP 258616 (Salutar), WO 8905802 (Bracco).
Object of the present invention are the compounds of general formula (I):
in which
R is a hydrogen atom, a straight or branched or cyclic C
1
-C
6
alkyl group, unsubstituted or substituted by 1 to 10 oxygen atoms, or a C
1
-C
20
alkyl group, optionally interrupted by a phenylene, in its turn substituted by a straight or branched C
1
-C
6
alkyl group, unsubstituted or substituted by 1 to 3 C
1
-C
7
groups; the aromatic group being unsubstituted or substituted by alkoxy, carboxy, sulfamoyl, hydroxyalkyl, amino groups; as well as their complexes with bi-trivalent metal ions having atomic number variable from 20 to 31, 39, 42, 43, 44, 49, or from 57 to 83, as well as their salts with anions of physiologically acceptable organic acids, selected, for example, from acetate, succinate, citrate, fumarate, maleate, oxalate, or with anions of inorganic acids such as halo acids ions, namely chlorides, bromides, iodides. Metal ions suitable for preparing complex salts with the novel chelating agents of general formula (I) are mainly bivalent or trivalent ions of the elements having atomic number variable from 20 to 31, 39, 42, 43, 44, 49, or from 57 to 83; particularly preferred being Fe
(2+)
, Fe
(3+)
, Cu
(2+)
, Cr
(3+)
, Gd
(3+)
, Eu
(3+)
, Dy
(3+)
, La
(3+)
, Yb
(3+)
or Mn
(2+)
or also radioisotopes as
51
Cr,
67
Ga,
68
Ga,
111
In,
99m
Tc,
140
La,
175
Yb,
153
Sm,
166
Ho,
90
Y,
149
Pm,
177
Lu,
47
Sc,
142
Pr,
159
Gd,
212
Bi.
Preferably R can be selected from the group consisting of: H or a straight or branched alkyl group, such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, in its turn substituted by hydroxy groups or interrupted by oxygen atoms, as defined above.
When an aromatic group is present in R, particularly preferred are the phenyl and benzyl groups.
Particularly preferred are the compounds of formula (I) selected from the group consisting of: &agr;,&agr;′-dimethyl-1,4,7,10-tetraazacyclododecane-1,4-diacetic acid; &agr;,&agr;′-diethyl-1,4,7,10-tetraazacyclododecane-1,4-diacetic acid; and &agr;,&agr;′-dibenzyl-1,4,7,10-tetraazacyclododecane-1,4-diacetic acid.
Preferred anions of inorganic acids suitable for salifying the chelated complexes of the invention comprise, in particular, halo acids ions such as chlorides, bromides, iodides or other ions, such as sulfate.
Preferred anions of organic acids suitable for the above aim comprise those of the acids conventionally used in pharmaceutical technique for the salification of basic substances, such as acetate, succinate, citrate, fumarate, maleate.
Preferred amino acids anions comprise, for example, those of taurine, glycine, lysine, arginine or ornithine, or of aspartic and glutamic acids.
The formation of the complex metal salt is carried out conventionally, preferably in water or in a suitable water-alcohol mixture, by reacting compounds (I) with a metal salt (oxide or halide), whereas the temperature can range from 25° C. to 100° C., preferably from 40° C. to 80° C.
The choice of the metal ion and of any neutralizing ion is closely related to the intended use of the complex to be prepared.
The preparation of the novel compound, manganese complex of 1,4,7,10-tetraazacyclododecane-1,4-diacetic acid, which is in the neutral form and therefore does not require the formation of a physiologically compatible salt, is described in the Experimental section.
The novel compounds of the present invention have a good tolerability; moreover, their water solubility and the low osmolality of their solutions are a further advantageous characteristic which makes them particularly suitable for use in nuclear magnetic resonance.
Both soluble and less soluble compounds are useful for the oral and enteral administrations and, therefore, for the imaging of the GI tract.
As far as the parenteral administration is concerned, the compounds are preferably formulated as a sterile aqueous solution or suspension, whose pH can range for instance from 6.0 to 8.5.
These aqueous solutions or suspensions can be administered in concentrations ranging from 0.002 to 1.0 mol.
These formulations can be lyophilized and supplied as they are for reconstitution before use. For the GI use or for the injection in the body cavities, such agents can be formulated as a solution or suspension containing suitable additives, for example thickeners.
In the oral administration they can be formulated according to preparation methods commonly used in the pharmaceutical practice possibly as coated formulations in order to get additional protection from the stomach acid pH, by preventing the release of the chelated metal ion occurring in particular at pH typical of gastric juices.
Other excipients, for instance sweeteners and/or flavouring agents, can also be added according to known techniques of pharmaceutical formulation.
The chelated complex salts of this invention can also be used as radioharmaceuticals in nuclear medicine, both in the diagnostic and therapeutic sector.
In this case, however, the metal ion which is chelated is a radioisotope, for instance
51
Cr,
67
Ga,
68
Ga,
111
In,
99m
Tc,
140
La,
175
Yb,
153
Sm,
166
Ho,
90
Y,
149
Pm,
177
Lu,
47
Sc,
142
Pr,
159
Gd and
212
Bi.
The compounds of the invention can optionally be chemically conjugated with suitable macromolecules or included in suitable carriers.
It is also an o

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