Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – X-ray contrast imaging agent
Patent
1997-03-21
1998-12-22
Hollinden, Gary E.
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
X-ray contrast imaging agent
564153, 514616, A61K 4904, C07C23365
Patent
active
058515119
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to compounds which can be used as contrast agents for X-ray radiology.
These compounds, which comprise at least 6 phenyl rings bearing 3 or 4 iodine atoms, give aqueous solutions whose concentration of iodine atoms is of the order of those generally used clinically, from 5 to 40 g of iodine per 100 ml, and which have a viscosity which is acceptable for parenteral administration, despite a molecular weight of more than 3,000. They are, moreover, eliminated from the blood circulation, after intravascular administration, markedly more slowly than the known compounds, with the exclusion of polymers on which iodo molecules are grafted as described in EP-A-354,836 and WO 93/10824, but whose clinical use is still not established, in particular due to the polydispersity of their molecular weights.
Thus, after intravenous injection into an animal of the same dose, expressed as weight of iodine, of a monomer of the invention or of a contrast agent commonly used clinically--such as iobitridol or iohexol--it is observed that the concentration of iodine in the blood decreases much less quickly for the compounds of the invention in the first minutes following the administration. For example, in rats, after 5 minutes, the concentration for a compound according to the invention is generally at least 3 times higher. Since, moreover, the presence of hydrophilic groups which are properly distributed on the molecule affords these compounds good water solubility, greater than 25 g of iodine per liter, they are useful as contrast agents for X-ray imaging of the vascular compartment.
The compounds of the invention have formula I: ##STR3## in which: T.sub.i, V.sub.i, T'.sub.i and V'.sub.i, which are identical or different, with i=0, 1 or 2, are selected from the group consisting of O, CO--ND and ND--CO, and D is selected from the group consisting of H, C.sub.1 to C.sub.6 alkyl and C.sub.1 to C.sub.6, preferably C.sub.1 to C.sub.4, hydroxyalkyl or polyhydroxyalkyl; are selected from the group consisting of C.sub.1 to C.sub.6 alkylene and C.sub.1 -C.sub.6, preferably C.sub.1 or C.sub.2, hydroxyalkylene or polyhydroxyalkylene; are selected from the group consisting of:
either formula II ##STR4## in which R is COOH and R' is selected from the group consisting of CONR'.sub.1 R'.sub.2 and N(R'.sub.1)COR'.sub.2, R'.sub.1 and R'.sub.2 being selected from the group consisting of H, C.sub.1 to C.sub.4 alkyl and C.sub.1 to C.sub.8 hydroxyalkyl or polyhydroxyalkyl and together comprising more than 4 hydroxyls and preferably more than 6 hydroxyls, or consisting of CONR'.sub.1 R'.sub.2 and N(R'.sub.1)COR'.sub.2, R'.sub.1 and R'.sub.2 being selected from the group consisting of H, C.sub.1 to C.sub.4 alkyl and C.sub.1 to C.sub.8 hydroxyalkyl or polyhydroxyalkyl and together comprising at least 6 hydroxyls and preferably more than 8 hydroxyls, and better at least 10 hydroxyls,
or formula III ##STR5## in which the groups T.sub.i, Q.sub.i and V.sub.i with i=3 or 4 have one of the meanings of the case i=0 and R.sub.i and R'.sub.i with i=3 or 4 have one of the meanings of R and R' in formula II or are T--Q--V--Ar with Ar being formula II and T, Q and V having the meanings of T.sub.i, Q.sub.i and V.sub.i, molecular weight less than 1200, optionally comprising hetero atoms chosen from oxygen, nitrogen and iodine, having two free valences such as to give with T.sub.0 and T'.sub.0 an amide or ether group, as well as pharmaceutically acceptable salts with bases of these acids, such as alkali metal salts, salts of aliphatic amines such as N-methylglucamine or salts of amino acids such as lysine.
The alkyl groups may be linear or branched.
The structure of A is not critical insofar as, depending on the case, A can form with T.sub.0 and T'.sub.0 two amide and/or oxide ether groups.
Among the suitable aliphatic radicals A, mention may be made of derivatives the alkylene chain optionally being interrupted by an oxygen atom or an amide group and possibly substituted by one or more hydroxyls; HOOC--(CH.sub.2).sub.n --COOH in which n
REFERENCES:
patent: 4065553 (1977-12-01), Tilly et al.
patent: 4065554 (1977-12-01), Tilly et al.
patent: 4283381 (1981-08-01), Speck et al.
patent: 5709846 (1998-01-01), Le!Lem et al.
le Lem Gael
Meyer Dominique
Guerbet S.A.
Hollinden Gary E.
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