Chelated complexes of paramagnetic metals with low toxicity

Details Chelated complexes of paramagnetic metals with low toxicity Chelated complexes of paramagnetic metals with low toxicity

2000-06-20

2001-01-23

Shah, Mukund J. (Department: 1624)

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

Organic compounds

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

C540S465000, C534S016000

Reexamination Certificate

active

06177562

ABSTRACT:

The present invention relates to the field of the diagnostic technique known as Magnetic Resonance Imaging (M.R.I.), a renowned, powerful diagnostic procedure used in medical practice to detect anomalies in organs or tissues of the human or animal body (see: Rocklage S. M., Watson A. D. and Carvlin M. J., Magnetic Resonance Imaging, Chap. 14, Vol. 1, Second Ed., 1992; Stark D. D. and Bradley W. G. Eds.). Particularly, the invention relates to novel compounds able to chelate paramagnetic metal ions, to their chelated complexes and to the physiologically acceptable salts thereof as well as the use of these compounds as M.R.I contrast agents.
Lanthanide ions are known to be among the most toxic paramagnetic metal ions in vivo. It is therefore necessary to administer said ions in the form of chelated complexes to the subject undergoing such a diagnostic procedure, as chelation by an electron donor ligand appreciably decreases the toxicity of the metal ion. On the other hand, this often also decreases undesirably the relaxivity properties, as accessibility by the water protons to the inner coordination sphere of the metal ion is reduced. The relaxivity of a chelated complex is generally significantly lower than that of the corresponding metal ion (The British Journal of Radiology, 68, 225-247, 1995).
It is therefore important for the paramagnetic chelated complex to have a high stability, i.e. a high thermodynamic stability constant, in order to have a low toxicity. A higher stability can be obtained, for example, using macrocyclic ligands, in which the metal ion is incorporated in a rigid structure; Gd-DOTA (Dotarem®) or Gd-HP-DO3A (ProHance®) are, for example, known to have a higher stability than Gd-DTPA (Investigative Radiology, 27 (Suppl.1), S1-S6, 1992; Topics in Magnetic Resonance Imaging, 7(3), 181-195, 1995). Gd-DOTA and Gd-HP-DO3A are macrocyclic ligand contrast agents commercially available at present.
The thermodynamic stability being the same, other factors affecting the toxicity of a contrast agent are the osmolality of the solution (in case of injectable formulations) and the intrinsic toxicity of the molecule, or molecular toxicity (Toxicology Letters, 64/65, 705-715, 1992). The osmolality of the solution particularly affects the toxicity of the contrast agent after intravenous administration; the molecular toxicity should, in its turn, be specifically considered when the contrast agent is administered to patients with impaired permeability of the blood-brain barrier, for example patients affected by cerebrovascular disorders, cerebral metastases, traumas and the like, in that the contrast agent can enter the tissues of central nervous system (Investigative Radiology, 25, S49-S50, 1990; M. Nadjmi Ed., XVth Congress of the European Society of Neuroradiology, W{umlaut over (u)}rzburg, Sep. 13-17th, 1988, 581-584—Springer-Verlag Berlin Heidelberg 1989); this can, in fact, result in the appearance of even remarkable neurotoxic effects. Molecular toxicity can be evaluated by tests carried out either in vitro (histamine release, inhibition of enzymatic activity and of coagulation); or in vivo, administering the compound directly to the nervous tissue, which is the substrate most sensitive to molecular toxicity.
DL
50
values after intracerebral administration (intracisternal, intracerebroventricular), for example in the mouse and in the rat, can therefore be taken as a highly sensitive index of the molecular toxicity of the contrast agent (Toxicology Letters, cited ref.). In particular, the intracerebroventricular administration seems to be the most sensitive to discriminate the neurotoxicity of the compounds (Proceedings of the 10th National Congress of the Italian Toxicology Society, Pavia, Sep. 21-24th, 100, 1994).
The “neurotoxicity index” is defined by the following ratio:
neurotoxicity
⁢
 
⁢
index
=
DL
50
⁢
i
.
v
.
DL
50
⁢
i
.
c
.
It is evident that, DL
50
s values after intravenous administration being the same, the higher the DL
50
value after intracerebral administration, the lower the neurotoxicity index of the compound.
Generally speaking, open-chain paramagnetic chelates have a cerebral toxicity different than the corresponding macrocyclic chelates; in particular, chelates such as Magnevist® (gadopentetate dimeglumine) and Omniscan® (gadodiamide) showed a better tolerability, after intracisternal administration, than such macrocyclic chelates as Dotarem® (gadoterate), gadobutrol and ProHance® (gadoteridol) (European Journal of Radiology, 21, 1-10, 1995).
Researches in the field of M.R.I. contrast agents are therefore directed to discovery of chelating agents having a high stability to paramagnetic metal ions, with a consequent decrease in toxicity deriving from the release of the free metal ion, which keep a good relaxivity and a low effective dose and which, above all in case of specific uses, have a low neurotoxicity index. This proves of paramount importance when the administration of high doses of contrast agent is necessary in order to improve the imaging of some lesions, such as infections, metastases or cerebral neoplasms, subacute cerebral infarction, head and neck tumors (Topics in Magnetic Resonance Imaging, 7(3), 181-195, 1995; The British Journal of Radiology, 68, 225-247, 1995).
The present invention relates to chelated complexes of paramagnetic metals characterized by an extremely favourable neurotoxicity profile. In particular, the paramagnetic chelated complexes of the present invention showed, after intracerebroventricular administration to the mouse, extremely high DL
50
values compared with the teachings of the prior art. The compound described in example 1 (gadolinium complex of 10-[2-[[2-(2-hydroxyethoxy)ethyl]amino]-2-oxoethyl]-&agr;,&agr;′,&agr;″-tris(hydroxymethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic) acid has, for example, a DL
50
of 0.23 mmol/kg after intracerebroventricular administration to the mouse. The compounds described in example 2 (gadolinium complex of &agr;,&agr;′,&agr;″-tris(hydroxymethyl)-10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid) and in Example 4 (Na
+
Gd[THM-DOTA]
−
) have a very good tolerability as well, with a DL
50
, after intracerebroventricular administration to the mouse, of 0.170 and 0.150 mmol/kg, respectively; the corresponding value for Gd-DOTA being 0.064 mmol/kg. This strongly suggests the possible use of the compounds of the present invention for imaging of cerebral lesions such as tumors, metastases, in highly safe conditions for the patient.
The present invention relates to the compounds of formula (I), both in the racemic and optically active forms:
wherein:
R is a (C
1
-C
15
) straight or branched alkyl chain, optionally interrupted by one or more oxygen, nitrogen, sulfur atoms, as well as by —CO—, —CONH—, —NHCO—, —SO—, —SO
2
—, —SO
2
NH— groups, or optionally substituted by one or more NH
2
, OH, halogen, COOH groups and corresponding ester or amide derivatives; said chain being optionally interrupted and/or substituted by one or more 5- or 6- membered cyclic, saturated, carbocyclic or heterocyclic groups, in which said cyclic groups are optionally substituted by one or more X groups, which can be the same or different, in which X is —OH, halogen, —NH
2
, —NHR
5
, —N(R
5
)
2
, —O—R
5
, —S—R
5
, —CO—R
5
, wherein R
5
, which can be the same or different, are a (C
1
-C
5
) straight or branched alkyl, optionally substituted by one or more hydroxy, alkoxy, carboxy groups, or X is a COOH group, or an ester or amide derivative thereof, or a —SO
3
H group or an amide derivative thereof,
R
1
, which can be the same or different, are a hydrogen atom or a —CH
2
OH group,
with the provisos that:
R is different from: unsubstituted alkyl, —CH
2
COOH,
 at least two of the R
1
substituents are —CH
2
OH.
The invention also relates to the compounds of formula (II), both in the racemic and optically active forms:
wherein:
R
2
is a hydrogen atom, or a (C
1
-C
15
) straight

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