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

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

2000-07-14

2002-07-09

Raymond, Richard L. (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

06417354

ABSTRACT:

The present invention relates to the novel compound, acid 1,4,7,10-tetraazacyclododecane-1,4-diacetic of formula (I), its 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.
The compound of formula (I) is a novel chelating agent for bi-trivalent metal ions and is also an important intermediate for the synthesis of 1,4,7,10-tetraazacyclododecane derivatives chelating agents, functionalized at the 1-and 4-positions with the acetic residue.
The compound of formula (I) is 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).
Such complexes have been described, inter alia, in EP 325762.
Therefore, the object of the present invention is the compound of formula (I):
as well as its chelated complex salts with bi-trivalent metal ions having atomic number 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 from, for example, acetate, succinate, citrate, fumarate, maleate, oxalate, or with anions of inorganic acids such as halo acids ions, specificallychlorides, bromides, iodides.
Metal ions suitable for preparing chelated complex salts with the novel chelating agent (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+)
also radioisotopes such 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.
The novel compounds of the present invention have a good tolerability; moreover, their water solubility and the limited 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 gastronitestinal (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 which can control viscosity.
In the oral administration they can be formulated according to preparation methods commonly used in the pharmaceutical practice, possibly also 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 which are typical of gastric juices.
Other excipients, for instance sweeteners and/or flavouring agents, can also be added according to known techniques of pharmaceutical formulation.
In the diagnostic field, the chelated complex salts of this invention can be used as contrast agents, while as radiopharmaceuticals in nuclear medicine, they are useful 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 object of the present invention can optionally be chemically conjugated with suitable macromolecules or included in suitable carriers.
Preferred anions of inorganic acids suitable for salifying the chelated complex salts 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 acid anions comprise, for example, those of taurine, glycine, lysine, arginine or ornithine, or of aspartic and glutamic acids.
The chelated complex salts of compound (I) with the metal ions defined above are prepared according to procedures known in literature, by reacting compound (I) with the oxide or the halide of the selected metal ion.
More specifically, the reaction is carried out in water or in a suitable water-alcohol mixture, and 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 chelated 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 compound of formula (I) was surprisingly prepared starting from octahydro-2a,4a,6a,8a-tetraazapentalen[1,6-cd]pentalene (CAS RN 54364-78-2) of formula (II), and from 1,2,3,4,6,7,8,9-octahydro-5H-4a,7,9a-triaza-2a-azoniacycloocta[cd] pentalene chloride of formula (IV), both obtainable according to known methods from 1,4,7,10-tetraazacyclododecane (III) (commonly named Cyclen), according to the following Scheme 1, through the formation of the novel compound of formula (V), 1,4,7,10-tetraazabicyclo[8.2.1 ]tridecane-13-on-4,7-diacetic acid, which is also an object of the invention:
The compound of formula (II) quickly and reversibly dissociates in water to give the compound of formula (IV), the respective preparations of said compounds being already disclosed in U.S. Pat. No. 3,932,451 and in a paper (Richman et Simmons, Tetrahedron, 30, 1769, 1974), for the use of both of them in photography.
The compound of formula (II) is obtainable by benzene extraction from the alkalinized solution of compound (IV), which can easily be prepared in quantitative yields from 1,4,7,10-tetraazacyclododecane (commercial product, commonly named Cyclen) of formula (III), by reaction with ethyl orthocarbonate and an equivalent of hydrochloric acid in ethanol, as shown in the following Scheme:
The compound of formula (IV) is in prototropic equilibrium at room temperature with compound (II) and with the dicationic compound (VI). This equilibrium is also of conformational type, thus causing the magnetic equivalence of protons of compound (II).
U.S. Pat. No. 3,932,451 discloses the preparation of these compounds starting from 2,3,5,6-tetraidro-1H-imidazo[1,2a]-imidazole, as shown in the following Scheme:
The compound of formula (II) quickly reconverts to compound (VII) by reaction with ethyl chloroformate, thus giving further structural evidences.
From such a behaviour of the compounds of formula (II) and (IV), documented in literature, no uses of these compounds as useful intermediates for the synthesis of 1,4-disubstituted 1,4,7,10-tetraazacyclododecane derivatives could be expected.
It is a further object of the invention the process for the preparation of the novel compound of formula (I), starting from known compounds of formula (II) or (IV), through the formation of the novel compound of formula (V), comprising the following steps represented in Scheme 2:
in which
step a) is the alkylation reaction in basic conditions with an acetic acid reactive derivative, XCH
2
COOH, in which X is a halogen;
step b) is the

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