Dimeric contrast agents

1. A compound of formula (I)

where:

R is —CH(R 1 )—COOH, where:

R 1 is H or a C 1 -C 3 alkyl chain that is optionally substituted by a C 1 -C 3 alkoxy or C 1 -C 3 hydroxyalkoxy group;

n is 1 or 2;

d is 0 or 1;

R 2 is a C 1 -C 5 alkyl substituted by from 1 to 3 groups X where:

X is a group of formula —O—[CH(CH 2 O—) 2 ] s (R 3 ) s+1 or —O—(CH 2 CH 2 O—) r —R 3 ,

in which:

R 3 is H or a C 1 -C 3 alkyl group, bound to the respective oxygen atom(s) of terminal units —CH(CH 2 O—) or —(CH 2 CH 2 O—) of X;

r is 1, 2, 3, 4, 5, 6, 7 or 8; and

s is 1, 2 or 3;

with the proviso that when the C 1 -C 5 alkyl in R 2 is substituted by a single group X, r and s are not 1,

as well as individual diastereoisomers and their racemic mixtures, and solved enantiomers of the same, and the physiologically acceptable salts thereof.

2. The compound according to claim 1 in which R 1 is H.

3. The compound according to claim 1 in which, in the formula (I) d is 0, having the formula (II)

4. The compound according to claim 3 in which, in the formula (II), R 2 is a C 1 -C 5 alkyl substituted by a single group X, having the formula

in which:

p is 1, 2, 3, 4, or 5; and

X is as defined in claim 1 .

5. The compound according to claim 4 where X is a group of formula —O—(CH 2 CH 2 O—) r R 3 , having the following formula (III A)

in which:

p is 1, 2, or 3;

r is an integer from 2 to 8; and

R 3 is H, or a C 1 -C 3 alkyl selected from methyl and ethyl.

6. The compound according to claim 5 in which, in the formula (III A)

p is 2;

r is from 2 to 5; and

R 3 is H, or methyl.

7. The compound according to claim 4 where X is a group of formula —O—[CH(CH 2 O—) 2 ] s (R 3 ) s+1 , having the following formula (III B)

in which:

p is 1, 2, or 3;

s is 2 or 3; and

R 3 is H, or a C 1 -C 3 alkyl selected from methyl and ethyl.

8. The compound according to claim 3 in which, in the formula (II), R 2 is a C 1 -C 5 alkyl substituted by two groups X, selected from the group consisting of

or a C 1 -C 5 alkyl substituted by three groups X, selected from

where X is defined in claim 1 .

9. The compound according to claim 8 , having the formula (IV)

in which n and X are as defined in claim 1 .

10. The compound according to claim 9 , having the formula (IV A)

in which:

r is an integer from 1 to 8;

n is 1 or 2, and

R 3 is H or a C 1 -C 3 alkyl selected from methyl and ethyl.

11. The compound according to claim 9 , having the formula (IV B)

or the formula (VI B)

in which:

s is 1 or 2, and

R 3 is H or a C 1 -C 3 alkyl selected from methyl and ethyl.

12. The compound according to claim 1 in which, in the formula (I) d is 1, having the formula (VII)

13. The compound according to claim 12 having the formula (VIII)

in which

p is 1, 2 or 3;

r is an integer from 1 to 8;

n is 1 or 2, and

R 3 is H or a C 1 -C 3 alkyl selected from ethyl and methyl.

14. The compound according to claim 1 in which in the formula (I) n is 1 and R 3 is H.

15. The compound according to claim 1 in which in the formula (I) n is 1 and R 3 is methyl.

16. A chelated complex of a compound according to claim 1 with two paramagnetic metal ions selected from the group consisting of Fe 2+ , Fe 3+ , Cu 2+ , Cr 3+, Gd 3+ , Eu 3+ , Dy 3+ , La 3+ , Yb 3+ and Mn 2+ , or a physiologically acceptable salt thereof.

17. The chelated complex according to claim 16 , wherein the paramagnetic metal ions are Gd 3+ ions.

18. The chelated complex according to claim 16 with bivalent metal ion(s), wherein the physiologically acceptable salt is with a cation of (i) an inorganic base selected from an alkali metal and alkaline-earth metal, (ii) an organic base selected from ethanolamine, diethanolamine, morpholine, glucamine, N-methylglucamine, and N,N-dimethylglucamine or (iii) an amino acid selected from lysine, arginine and ornithine.

19. A method of MR imaging comprising:

administering the chelated complex as defined in claim 16 to a patient;

submitting the patient to a radiation frequency selected to excite non-zero proton spin nuclei of the chelated complex; and

recording a MR signal from said nuclei.

20. A pharmaceutical composition comprising a chelated complex of claim 16 in combination with one or more pharmaceutically acceptable carriers, diluents or excipients.

21. The compound according to claim 1 of formula:

22. A compound of formula (1)

where:

R is CH(R 1 )—COOC(CH 3 ) 3 , where:

R 1 is H or a C 1 -C 3 alkyl chain that is optionally substituted by a C 1 -C 03 alkoxy or a C 1 -C 3 hydroxyalkoxy group;

n is 1 or 2;

d is 0 or 1;

R 2 is a C 1 -C 5 alkyl substituted by from 1 to 3 groups X where:

X is a group of formula —O—[CH(CH 2 O—) 2 ] s (R 3 ) s+1 or —O—(CH 2 CH 2 O—) r R 3 ,

in which:

R 3 is H or a C 1 -C 3 alkyl group, bound to the respective oxygen atom(s) of terminal units —(CH(CH 2 O—) or —(CH 2 CH 2 O—) of X;

r is 1, 2, 3, 4, 5, 6, 7 or 8; and

s is 1, 2, or 3;

with the proviso that when the C 1 -C 5 alkyl in R 2 is substituted by a single group X,

r and s are not 1.