Iodinated derivatives, their preparation and their use as contra

Details Iodinated derivatives, their preparation and their use as contra Iodinated derivatives, their preparation and their use as contra

1996-05-21

1998-01-20

Kumar, Shailendra

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

057098468

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/FR95/01213, filed Sep. 20, 1995, published as WO96/09281 Mar. 28, 1996.
The present invention relates to contrast agents for X-ray radiology.
These molecules, with a high molecular weight since they comprise at least 12 triiodinated phenyl rings, have a vascular persistence which is markedly greater than that of the contrast agents currently used in diagnostic, such as iobitridol or iohexol, and more or less analogous to that of compositions resulting from grafting of iodinated rings to polymers, which compositions are known to suffer from disadvantages due to the presence of molecules of various molecular weights in the same sample. Thus, it has been observed that, five minutes after intravenous injection in rat of products of the invention or of commercial contrast agents containing the same dose of iodine, the blood iodine concentration of the new compounds was at least three times higher.
Moreover, the aqueous solutions of these new compounds have a viscosity which is compatible with their intravenous administration in man, at usual doses, whereas their osmolality generally has to be raised.
The compounds of the invention have the formula ##STR4## in which Za, Zb, Zc and Zd, which are identical or different, are Tz-Qz-Vz, Tz being attached to A; representing H or C.sub.1 to C.sub.6 alkyl, hydroxyalkyl or polyhydroxyalkyl and Qz represents C.sub.1 to C.sub.6, preferably C.sub.1 to C.sub.4, alkylene, hydroxyalkylene or polyhydroxyalkylene; or else Qz and/or Tz do not exist; ##STR5## and T.sub.1, T'.sub.1, V.sub.1 and V'.sub.1, which are identical or different, are CO-ND' or ND'-CO with D' representing H or C.sub.1 to C.sub.6 alkyl, optionally carrying one or more OH groups; and preferably C.sub.1 to C.sub.4, alkylene optionally carrying one or more OH groups; ##STR6## in which formula III, R is COOH and R' is CO--NR'.sub.1 R'.sub.2 or N(R'.sub.1)--CO--R'.sub.2, R'.sub.1 and R'.sub.2 being H or C.sub.1 to C.sub.8 alkyl, hydroxyalkyl or polyhydroxyalkyl, and containing between them more than 4 OH groups; or in which R and R', which are identical or different, are CO--NR'.sub.1 R'.sub.2 or N(R'.sub.1)--CO--R'.sub.2 and R'.sub.1 and R'.sub.2 are H or C.sub.1 to C.sub.8 alkyl, hydroxyalkyl or polyhydroxyalkyl and R and R' contain between them more than 6 OH groups or, better, more than 8 OH groups and preferably 10 OH groups; N(R'.sub.1)--CO--R'.sub.2, R'.sub.1 and R'.sub.2 being C.sub.1 to C.sub.8 hydroxyalkyl or polyhydroxyalkyl such that they contain between them more than 8 OH groups and preferably more than 10 OH groups; ##STR7## in which formula V, R and R', which are identical or different, respectively are T.sub.2 -Q.sub.2 -V.sub.2 -Ar.sub.2 and T'.sub.2 -Q'.sub.2 -V'.sub.2 -Ar'.sub.2, with T.sub.2, T'.sub.2, Q.sub.2, Q'.sub.2, V.sub.2 and V'.sub.2 respectively having one of the meanings of T.sub.1, Q.sub.1 and V.sub.1 groups and Ar.sub.2 and Ar'.sub.2 having the meanings of formulae III or IV; can have one of the meanings given for formula V; optionally containing one or more heteroatoms selected in particular from oxygen, nitrogen and halogens and particularly iodine, said moiety with a molecular weight of less than 2000, having a structure such that the four Za, Zb, Zc and Zd groups can be linked thereto giving amide or ether groups.
Aliphatic moiety is understood to mean a cyclic or acyclic moiety in which the free bonds are situated on several atoms.
Mention may be made, among the A(Tz) moiety according to the invention, of:
tetrakis derivatives of methane, such as: J. Chem. Soc., 1638 (1922) is described in U.S. Pat. No. 2,401,607 Chem. Soc., 1588-1595 (1938) 1,2,3,4-butanetetracarboxylic acid, of triethylenetetramine, of ethylenediaminetetraacetic acid and of 1,4,7,10-tetraazacyclododecane-N,N'N",N'"-tetraacetic acid.
An aromatic moiety comprises one or several phenyl rings and optionally C.sub.1 to C.sub.4 alkyl groups which can be bonded to the phenyl ring directly or via a functional group such as an ether or an amide group, it being possible for the free bon

REFERENCES:
patent: 4065553 (1977-12-01), Tilly et al.
patent: 4065554 (1977-12-01), Tilly et al.

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