1,4,7,10-tetraazacyclododecane derivatives, their use, pharmaceu

Details 1,4,7,10-tetraazacyclododecane derivatives, their use, pharmaceu 1,4,7,10-tetraazacyclododecane derivatives, their use, pharmaceu

1996-12-06

1999-07-06

Shah, Mukund J.

Drug, bio-affecting and body treating compositions

In vivo diagnosis or in vivo testing

Magnetic imaging agent

514184, 514836, 540474, 540541, 534 14, 534 15, 534 16, C07D25702, A61K 4900, A61B 5055

Patent

active

059194316

DESCRIPTION:

BRIEF SUMMARY
The invention relates to the object characterized in the claims, i.e., new 1,4,7,10-tetraazacyclododecane derivatives, their metal complexes, pharmaceutical agents containing these compounds, their use in diagnosis and treatment as well as process for the production of these compounds and agents.
In diagnosis and radiotherapy, metal complexes have already been used for some time to supply otherwise toxic metals to the body. Representatives of these metal complexes or complexing agents or their precursors are described, for example, in EP-A 0 545 511, EP-A 0 071 564, 0 255 471, 0 448 191 and in DE-A 34 01 052. The metal complexes described there are distinguished partly already by good compatibility. The described chelates partly can also be dosed higher, which is advantageous especially for the detection of certain diseases outside the central nervous system with the help of nuclear spin tomography (NMR diagnosis), but quite especially in the use of chelates as x-ray contrast media.
In comparison to iodinated x-ray contrast media, chelates can offer the advantage that they show radiation absorption in the higher-energy range and thus result in a reduction of the radiation exposure for the patient. This also results in an improvement of the requirements for the energy subtraction method. A further advantage is the avoidance of contrast media reactions, such as, e.g., the so-called allergy-like or cardiovascular side effects.
In addition to open-chain ligands, cyclic chelating agents are also used as complexing agents. WO 91/08272 thus discloses macrocycles that contain heteroatoms as well as their use as additives to liquid crystal mixtures.
WO 93/02045 describes, i.a., tetraazamacrocycles with aminomethylene sulfo groups that are subject to the risk of thermal decomposition in the case of heat sterilization. This is true in the same way for the macrocycles that contain N-methylenesulfonate groups described in WO 93/12097. Also, the SO.sub.3 group contained in these compounds is largely unsuitable for complexing metal ions such as, e.g., gadolinium.
The chelates are to meet the following requirements: strong influencing of the NMR signals; under in vivo conditions; or suspension; medium solution or suspension.
These requirements apply to a varying extent and in a varying way, but basically to all uses of the above-mentioned complexes in in-vivo diagnosis as well as partially in radiotherapy.
New complexing agents or complexes of the above-described type, which are to be improved with respect to the basic hydrophilia, i.e., in their water-solubility and with respect to their compatibility in the organism, are the object of this invention.
This object is achieved with the 1,4,7,10-tetraazacyclododecane derivatives according to claim 1.
The latter are 1,4,7,10-tetraazacyclododecane derivatives of general formula I ##STR2## in which R.sup.1, independently of one another, stand for H, a C.sub.1 -C.sub.6 alkyl radical or a metal ion equivalent, radical, C.sub.2 -C.sub.23 alkylene group interrupted by one or more oxygen atoms, by one or more hydroxy radicals and/or lower alkoxy radicals and/or contain one or more carbonyl functions, and
V means a radical of formula II ##STR3## in which R.sup.3 stands for a hydrogen atom, for a saturated, unsaturated, straight-chain or branched-chain alkyl, aryl or aralkyl radical or cyclic hydrocarbon radical with up to 40 carbon atoms, hydrogen represent a saturated 5- or 6-ring optionally containing another heteroatom, functions and/or are interrupted by one or more oxygen atoms and/or by one or more >N--CH.sub.2 --COOR.sup.1 groups and/or are substituted by one or more O.dbd.C.dbd.N--, S.dbd.C.dbd.N groups, or hydroxy, alkoxy, carboxylato, carbonyl, --CHO, halogen, amido or amino radicals, whereby the hydroxy groups are present in free or protected form.
These substances and the solutions prepared from them meet the requirements to be set for pharmaceutically usable chelates. They have an effectiveness that is strong and can be matched by the selection of suitable metal atom

REFERENCES:
patent: 5631368 (1997-05-01), Schultze et al.
Pulukkody et al. J. Chem. Soc., Perkin Trans 2., 1993., No. 4., pp. 605-620 .

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