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Claims for Patent: 6,039,931

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Claims for Patent: 6,039,931

Title: Derivatized DTPA complexes, pharmaceutical agents containing these compounds, their use, and processes for their production
Abstract:Compounds of general Formula I ##STR1## wherein Z.sup.1 and Z.sup.2 in each case independently mean the residue wherein m and n means the numbers 0-20, k, l, q and r means the numbers 0 and 1, and R means a hydrogen atom, an optionally OR.sup.1 -substituted C.sub.1 -C.sub.6 -alkyl residue, or a CH.sub.2 COOR.sup.1 group with R.sup.1 meaning it hydrogen atom, a C.sub.1 -C.sub.6 -alkyl residue, or a benzyl group, X means a hydrogen atom and/or a metal ion equivalent of an element of atomic number 21-29, 42, 44 or 57-83, with the provisos that at least two the substituents X stand for a metal ion equivalent; that one of the substituents Z.sup.1 and Z.sup.2 stands for a hydrogen and the other is not H; that--if n and l each mean the number 0--k and r do not simultaneously mean the number 1; that --(O).sub.r --R is not --OH; and that Z.sup.1 and Z.sup.2 are not --CH.sub.2 --C.sub.6 H.sub.4 --O--CH.sub.2 --COOCH.sub.2 C.sub.6 H.sub.5 or --CH.sub.2 --C.sub.6 H.sub.4 --O--(CH.sub.2).sub.5 --COOCH.sub.2 C.sub.6 H.sub.5, as well as their salts with inorganic and/or organic bases, amino acids or amino acid amides, are valuable pharmaceutical agents, e.g., for NMR.
Inventor(s): Schmitt-Willich; Heribert (Berlin, DE), Platzek; Johannes (Berlin, DE), Gries; Heinz (Berlin, DE), Schumann-Giampieri; Gabrielle (Berlin, DE), Weinmann; Hanns-Joachim (Berlin, DE), Vogler; Hubert (Berlin, DE), Deutsch; Julius (Berlin, DE), Conrad; Juergen (Berlin, DE)
Assignee: Schering Aktiengesellschaft (Berlin, DE)
Application Number:08/319,357
Patent Claims: 1. A method of enhancing an NMR image comprising administering to a patient a compound of the formula ##STR4## wherein one of Z.sup.1 and Z.sup.2 is H and the other is

wherein

m and n, independently, are each 0-20,

k, l, q and r are each, independently, 0 or 1,

R is H, C.sub.1 -C.sub.6 -alkyl, OR.sup.1 -substituted C.sub.1 -C.sub.6 -alkyl or CH.sub.2 COOR.sup.1,

R.sup.1 is H, C.sub.1 -C.sub.6 -alkyl or benzyl; and

X is, in each case, a hydrogen atom or a metal ion equivalent of an element of atomic number 21-29, 42, 44 or 58-70;

with the provisos that:

at least two X groups represent a metal ion equivalent of atomic number 21-29, 42, 44 or 58-70;

when n and l are each 0, then k and r are not each simultaneously 1;

--(O).sub.r -R is not --OH;

Z.sup.1 and Z.sup.2 are not --C.sub.6 H.sub.5, --CH.sub.2 --C.sub.6 H.sub.5, --CH.sub.2 --C.sub.6 H.sub.4 --O--CH.sub.2 --COOCH.sub.2 C.sub.6 H.sub.5 or --CH.sub.2 --C.sub.6 H.sub.4 --O--(CH.sub.2).sub.5 --COOCH.sub.2 C.sub.6 H.sub.5 ; and

at least one of q and l is 1;

or a physiologically acceptable salt thereof with an inorganic and/or organic base, an amino acid or an amino acid amide.

2. A method of claim 1, wherein Z.sup.1 is hydrogen and Z.sup.2 is --(CH.sub.2).sub.m --(C.sub.6 H.sub.4).sub.q --(O).sub.k --(CH.sub.2).sub.n --(C.sub.6 H.sub.4).sub.l --(O).sub.r --R, which is not hydrogen.

3. A method of claim 1, wherein Z.sup.2 is hydrogen and Z.sup.1 is --(CH.sub.2).sub.m --(C.sub.6 H.sub.4).sub.q --(O).sub.k --(CH.sub.2).sub.n --(C.sub.6 H.sub.4).sub.l --(O).sub.r --R, which is not hydrogen.

4. A method of claim 1, wherein Z.sup.1 is --CH.sub.2 --C.sub.6 H.sub.4 --OCH.sub.3, --CH.sub.2 --C.sub.6 H.sub.4 --O--CH.sub.2 --C.sub.6 H.sub.4 --OCH.sub.3, --CH.sub.2 --O--CH.sub.2 --C.sub.6 H.sub.5, --CH.sub.2 --C.sub.6 H.sub.4 --O--CH.sub.2 --COOH, --CH.sub.2 --C.sub.6 H.sub.4 --OC.sub.2 H.sub.5, --CH.sub.2 --C.sub.6 H.sub.4 --OC.sub.4 H.sub.9 or --CH.sub.2 --C.sub.6 H.sub.4 --O--CH.sub.2 --C.sub.6 H.sub.5.

5. A method of claim 4, wherein Z.sup.1 is --CH.sub.2 --C.sub.6 H.sub.4 --OCH.sub.3, --CH.sub.2 --C.sub.6 H.sub.4 --O--CH.sub.2 --C.sub.6 H.sub.4 --OCH.sub.3, --CH.sub.2 --O--CH.sub.2 --C.sub.6 H.sub.5 or --CH.sub.2 --C.sub.6 H.sub.4 --O--CH.sub.2 --COOH.

6. A method of claim 1, wherein Z.sup.2 is --CH.sub.2 --C.sub.6 H.sub.4 --OCH.sub.3, --CH.sub.2 --C.sub.6 H.sub.4 --O--CH.sub.2 --C.sub.6 H.sub.4 --OCH.sub.3, --CH.sub.2 --O--CH.sub.2 --C.sub.6 H.sub.5, --CH.sub.2 --C.sub.6 H.sub.4 --O--CH.sub.2 --COOH, --CH.sub.2 --C.sub.6 H.sub.4 --OC.sub.2 H.sub.5, --CH.sub.2 --C.sub.6 H.sub.4 --OC.sub.4 H.sub.9 or --CH.sub.2 --C.sub.6 H.sub.4 --O--CH.sub.2 --C.sub.6 H.sub.5.

7. A method of claim 6, wherein Z.sup.2 is --CH.sub.2 --C.sub.6 H.sub.4 --OCH.sub.3, --CH.sub.2 --C.sub.6 H.sub.4 --O--CH.sub.2 --C.sub.6 H.sub.4 --OCH.sub.3, --CH.sub.2 --O--CH.sub.2 --C.sub.6 H.sub.5 or --CH.sub.2 --C.sub.6 H.sub.4 --O--CH.sub.2 --COOH.

8. A method of claim 1, wherein at least three X groups represent a Gd ion.

9. A method of claim 4, wherein at least three X groups represent a Gd ion.

10. A method of claim 6, wherein at least three X groups represent a Gd ion.

11. A method of claim 1, wherein said compound is:

gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-methoxybenzyl)undecanedioic acid or a physiologically acceptable salt thereof;

europium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-methoxybenzyl)undecanedioic acid or a physiologically acceptable salt thereof;

iron(III) complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-methoxybenzyl)undecanedioic acid or a physiologically acceptable salt thereof;

gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-5-(4-methoxybenzyl)undecanedioic acid or a physiologically acceptable salt thereof;

gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-[4-(4-methoxybenzyloxy)benzyl]und ecanedioic acid or a physiologically acceptable salt thereof;

gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-benzyloxymethylundecanedioic acid or a physiologically acceptable salt thereof;

gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-carboxymethoxybenzyl)undecaned ioic acid or a physiologically acceptable salt thereof;

gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)undecanedioic acid or a physiologically acceptable salt thereof;

europium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)undecanedioic acid or a physiologically acceptable salt thereof,

iron complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)undecanedioic acid or a physiologically acceptable salt thereof;

gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-butoxybenzyl)undecanedioic acid or a physiologically acceptable salt thereof;

europium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-butoxybenzyl)undecanedioic acid or a physiologically acceptable salt thereof;

iron complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)4-(4-butoxybenzyl)undecanedioic acid or a physiologically acceptable salt thereof,

gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-benzyloxybenzyl)undecanedioic acid or a physiologically acceptable salt thereof;

europium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-benzyloxybenzyl)undecanedioic acid or a physiologically acceptable salt thereof;

iron complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-benzyloxybenzyl)undecanedioic acid or a physiologically acceptable salt thereof.

12. A method of claim 1, wherein the renal system is imaged.

13. A method of claim 1 wherein the hepatobiliary system is imaged.

14. A method according to claim 1, wherein two of the X groups represent manganese(II), iron(II), cobalt(II) or copper(II); or three of the X groups represent chromium(III), praseodymium(III), neodymium(III), samarium(III), ytterbium(III), gadolinium(III), terbium(III), dysprosium(III), holmium(III), erbium(III), or iron(III).

15. A method to claim 1, wherein Z.sup.1 is --C.sub.6 H.sub.4 --O--C.sub.2 H.sub.5 or --C.sub.2 H.sub.4 --C.sub.6 H.sub.4 --O--C.sub.2 H.sub.5.

16. A method according to claim 1, wherein said compound is gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxyphenyl)undecanedioic acid or a physiologically acceptable salt thereof.

17. A method according to claim 1, wherein said compound is a complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxyphenylethyl)undecanedioi c acid and a metal ion of atomic number 21-29, 42, 44 or 57-83, or a physiologically acceptable salt thereof.

18. A method according to claim 1, wherein R is C.sub.1-6 -alkyl or C.sub.1-6 -alkyl substituted by --OR.sup.1.

19. A method according to claim 1, wherein one of Z.sup.1 and Z.sup.2 is --CH.sub.2 --C.sub.6 H.sub.4 --O--(CH.sub.2).sub.n --(C.sub.6 H.sub.4).sub.l --(O).sub.r --R.

20. A method according to claim 1, wherein one of Z.sup.1 and Z.sup.2 is --(CH.sub.2)--C.sub.6 H.sub.4 --O--CH.sub.2 --C.sub.6 H.sub.4 --(O).sub.r --R.

21. A method according to claim 1, wherein the X groups which do not represent a metal ion equivalent of atomic number 21-29, 42, 44 or 57-83 are individually lithium, potassium or sodium, or two such X groups are calcium or magnesium.

22. A method according to claim 1, wherein X groups which are not a metal ion equivalent of an element of atomic number 21-29, 42, 44 or 57-83 represent a salt with ethanolamine, diethanolamine, morpholine, glucamine, N,N-dimethylglucamine, N-methylglucamine, lysine, arginine, ornithine, lysine methylamide, glycine ethylamide or serine methylamide.

23. A method according to claim 11, wherein Z.sup.2 is --C.sub.6 H.sub.4 --OC.sub.2 H.sub.5 or --C.sub.2 H.sub.4 --C.sub.6 H.sub.5 --OC.sub.2 H.sub.5.

24. A method according to claim 1, wherein said compound is administered in a dose of 1 .mu.mole/kg-5 mmole/kg.

25. A method according to claim 24, wherein the dose of said compound is 10 .mu.mole/kg-0.5 mmole/kg.

26. A method according to claim 1, wherein said compound is administered by intravenous injection.

27. A method according to claim 1, wherein said compound is administered orally.

28. A method according to claim 1, wherein at least one of k and r is 1.

29. A method according to claim 1, wherein said compound is administered as a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier.

30. A method according to claim 1, wherein R.sup.1 is H or C.sub.1 -C.sub.6 -alkyl.

31. A method of enhancing an NMR image of the GI tract of a patient comprising administering a compound of the formula ##STR5## wherein one of Z.sup.1 and Z.sup.2 is H and the other is

wherein

m and n independently are 0-20,

k, l, q and r each independently is 0 or 1,

R is hydrogen, optionally OR.sup.1 -substituted C.sub.1 -C.sub.6 -alkyl or CH.sub.2 COOR.sup.1,

R.sup.1 is hydrogen, C.sub.1 -C.sub.6 -alkyl or benzyl, and

X is, in each case, a hydrogen atom or a metal ion equivalent of an element of atomic number 21-29, 42, 44 or 58-70,

with the provisos that:

at least two of the substituents X represent a metal ion equivalent of atomic number 21-29. 42, 44 or 58-70; and

when n and l are each 0, then k and r are not each simultaneously 1;

--(O).sub.r --R is not --OH;

Z.sup.1 and Z.sup.2 are not --C.sub.6 H.sub.5, --CH.sub.2 --C.sub.6 H.sub.5, --CH.sub.2 --C.sub.6 H.sub.4 --O--CH.sub.2 --COOCH.sub.2 C.sub.6 H.sub.5 or --CH.sub.2 --C.sub.6 H.sub.4 --O--(CH.sub.2).sub.5 --COOCH.sub.2 C.sub.6 H.sub.5 ; and

at least one of q and l is 1;

or a physiologically acceptable salt thereof with an inorganic and/or organic base, an amino acid or an amino acid amide.

32. A method according to claim 31, wherein said compound is administered as a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier.

33. A method according to claim 31, wherein R.sup.1 is H or C.sub.1 -C.sub.6 -alkyl.

34. A method of enhancing NMR imaging of a patient having renal insufficiency comprising administering to a patient a compound of the formula ##STR6## wherein one of Z.sup.1 and Z.sup.2 is H and the other is --(CH.sub.2).sub.m --(C.sub.6 H.sub.4).sub.q --(O).sub.k --(CH.sub.2).sub.n --(C.sub.6 H.sub.4).sub.l --(O).sub.r --R,

wherein

m and n, independently, are each 0-20,

k, l, q and r are each, independently, 0 or 1,

R is H, C.sub.1 -C.sub.6 -alkyl, OR.sup.1 -substituted C.sub.1 -C.sub.6 -alkyl or CH.sub.2 COOR.sup.1,

R.sup.1 is H, C.sub.1 -C.sub.6 -alkyl or benzyl; and

X is, in each case, a hydrogen atom or a metal ion equivalent of an element of atomic number 21-29, 42, 44 or 58-70;

with the provisos that:

at least two X groups represent a metal ion equivalent of atomic number 21-29, 42, 44 or 58-70;

when n and l are each 0, then k and r are not each simultaneously 1;

--(O).sub.r --R is not --OH;

Z.sup.1 and Z.sup.2 are not --C.sub.6 H.sub.5, --CH.sub.2 --C.sub.6 H.sub.5, --CH.sub.2 --C.sub.6 H.sub.4 --O--CH.sub.2 --COOCH.sub.2 C.sub.6 H.sub.5 or --CH.sub.2 --C.sub.6 H.sub.4 --O--(CH.sub.2).sub.5 --COOCH.sub.2 C.sub.6 H.sub.5 ; and

at least one of q and l is 1;

or a physiologically acceptable salt thereof with an inorganic and/or organic base, an amino acid or an amino acid amide.

35. In a method of NMR imaging a patient comprising administering an NMR contrast agent to said patient, the improvement wherein said contrast agent is a compound of the formula ##STR7## wherein one of Z.sup.1 and Z.sup.2 is H and the other is --(CH.sub.2).sub.m --(C.sub.6 H.sub.4).sub.q --(O).sub.k --(CH.sub.2).sub.n --(C.sub.6 H.sub.4).sub.l --(O).sub.r --R,

wherein

m and n, independently, are each 0-20,

k, l, q and r are each, independently, 0 or 1,

R is H, C.sub.1 -C.sub.6 -alkyl, OR.sup.1 -substituted C.sub.1 -C.sub.6 -alkyl or CH.sub.2 COOR.sup.1,

R.sup.1 is H, C.sub.1 -C.sub.6 -alkyl or benzyl; and

X is, in each case, a hydrogen atom or a metal ion equivalent of an element of atomic number 21-29, 42, 44 or 58-70;

with the provisos that:

at least two X groups represent a metal ion equivalent of atomic number 21-29, 42, 44 or 58-70;

when n and l are each 0, then k and r are not each simultaneously 1;

--(O).sub.r --R is not --OH;

Z.sup.1 and Z.sup.2 are not --C.sub.6 H.sub.5, --CH.sub.2 --C.sub.6 H.sub.5, --CH.sub.2 --C.sub.6 H.sub.4 --O--CH.sub.2 --COOCH.sub.2 C.sub.6 H.sub.5 or --CH.sub.2 --C.sub.6 H.sub.4 --O--(CH.sub.2).sub.5 --COOCH.sub.2 C.sub.6 H.sub.5 ; and

at least one of q and l is 1;

or a physiologically acceptable salt thereof with an inorganic and/or organic base, an amino acid or an amino acid amide.
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