Cascade polymer complexes, process for their production and pharmaceutical agents containing said complexes

• US 7,211,241 B2
• Filed: 10/17/2003
• Issued: 05/01/2007
• Est. Priority Date: 07/04/1995
• Status: Expired due to Fees

• Current Assignee: Bayer Schering Pharma AG (Bayer AG)
• Original Assignee: Schering Ag (Merck & Co., Inc.)
• Inventors: Schmitt-Willich, Heribert, Frenzel, Thomas, Platzek, Johannes, Raduchel, Bernd, Muhler, Andreas
• Primary Examiner(s): Hartley; Michael G.
• Assistant Examiner(s): SCHLIENTZ, LEAH H
• Application Number:
  US10/686,717
• Publication Number:
  US 20040091426A1
• Time in Patent Office: 1,292 Days
• Field of Search: 424/9.36, 424/9.364, 424/9.365, 424/1.65, 424/9.4, 424/9.42, 534/10, 534/14, 534/15, 534/16, 540/465, 540/473, 540/474
• US Class Current: 424/9.363
• CPC Class Codes: A61K 49/04 X-ray contrast preparations
• CPC Class Codes: A61K 49/085 conjugated systems
• CPC Class Codes: A61K 49/124 dendrimers, dendrons, hyperbranched compounds
• CPC Class Codes: A61K 51/065 conjugates with carriers being macromolecules
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 229/76 Metal complexes of amino carboxylic acids
• CPC Class Codes: C07C 237/42 having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
• CPC Class Codes: C07D 251/54 Three nitrogen atoms
• CPC Class Codes: C07D 257/02 not condensed with other rings
• CPC Class Codes: C07D 487/08 Bridged systems
• CPC Class Codes: C07K 14/001 by chemical synthesis
• CPC Class Codes: Y10S 424/16 Dendrimers and dendritic polymers

Abstract

Described are new cascade polymer complexes, compositions containing them and use of the complexes in diagnosis and therapy, particularly for magnetic resonance imaging and computer tomography imaging.

Claims

1. A method for identification of underperfused regions in a human or animal patient which comprises administering an effective amount of a nitrogen-containing cascade polymer having complexing ligands which complex at least 16 ions of an element of atomic numbers 20–

29, 39, 42, 44 or 57–

83, and performing NMR diagnosis on the patient to identify the underperfused regions, wherein the nitrogen-containing cascade polymer having complexing ligands is of the following formula (I);

A—

{X—

[Y—

(Z—

(W—

K_w)_z)_y]_x}_a 

 

(I),

in which

A stands for a nitrogen-containing cascade nucleus of base multiplicity a;

X and Y, independently of one another, stand for a direct bond or a cascade reproduction unit of reproduction multiplicity x or y;

Z and W, independently of one another, stand for a cascade reproduction unit of reproduction multiplicity z or w;

a stands for numbers 2 to 12;

x, y, z, and w, independently of one another, stand for numbers 1 to 4, provided that the product of the multiplicities,

16≦

a·

x·

y·

z·

w≦

64

holds true;

K stands for the radical of a complexing agent of the formula (IA);

2. The method of claim 1, wherein the nitrogen-containing cascade polymer with complexed complexing ligands has a molecular weight of 10,000 to 80,000 daltons.

3. The method of claim 1, wherein the method is for identification of underperfused regions in the myocardium of the patient.

4. The method of claim 1, wherein the at least 16 ions of an element of atomic numbers 20–

29, 39, 42, 44 or 57–

83 are Gd ions.

5. The method of claim 1, wherein the K radicals of formula (IA) are 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane radicals wherein at least 16 are complexed with ions of an element of atomic numbers 20–

29, 39, 42, 44 or 57–

83.

6. The method of claim 5, wherein the at least 16 ions of an element of atomic numbers 20–

29, 39, 42, 44 or 57–

83 are Gd ions.

7. The method of claim 1, wherein, in formula (I), A is trimesic acid triamide.

8. The method of claim 5, wherein, in formula (I), A is trimesic acid triamide.

9. The method of claim 1, wherein the nitrogen-containing cascade polymer has 2-(trilysylamino)-ethyl repeating units.

10. The method of claim 5, wherein the nitrogen-containing cascade polymer has 2-(trilysylamino)-ethyl repeating units.

11. The method of claim 5, wherein the nitrogen-containing cascade polymer having complexing ligands which complex at least 16 ions of an element of atomic numbers 20–

29, 39, 42, 44 or 57–

83 is a 24-mer-Gd-complex of N-(5-(1,4,7-tris (carboxymethyl)-1,4,7,10-tetraazacyclododecane)-yl-4-oxo-3-azahexanoyl)-cascade polyamide based on N,N,N′

,N′

,N″

,N″

-hexakis [2-(trilysylamino)-ethyl]-trimesic acid triamide.

12. An angiography method for diagnosis of vascular disease in a human or animal patient which comprises administering an effective amount of a nitrogen-containing cascade polymer having complexing ligands which complex at least 16 ions of an element of atomic numbers 20–

29, 39, 42, 44 or 57–

83, and performing an angiography diagnosis on the patient, wherein the nitrogen-containing cascade polymer having complexing ligands is of the following formula;

A—

{X—

[Y(Z—

(W—

K_w)_z)_y]_x}_a 

 

(I),

in which

A stands for a nitrogen-containing cascade nucleus of base multiplicity a;

X and Y, independently of one another, stand for a direct bond or a cascade reproduction unit of reproduction multiplicity x or y;

Z and W, independently of one another, stand for a cascade reproduction unit of reproduction multiplicity z or w;

a stands for numbers 2 to 12;

x, y, z, and w, independently of one another, stand for numbers 1 to 4, provided that the product of the multiplicities,

16≦

a·

x·

y·

z·

w≦

64

holds true;

K stands for the radical of a complexing agent of the formula (IA);

13. The method of claim 12, wherein the nitrogen-containing cascade polymer with complexed complexing ligands has a molecular weight of 10,000 to 80,000 daltons.

14. The method of claim 12, wherein the at least 16 ions of an element of atomic numbers 20–

29, 39, 42, 44 or 57–

83 are Gd ions.

15. The method of claim 12, wherein the K radicals of formula (IA) are 1,4,7-tris(carboxymethyl)- 1,4,7,10-tetraazacyclododecane radicals wherein at least 16 are complexed with ions of an element of atomic numbers 20–

29, 39, 42, 44 or 57–

83.

16. The method of claim 15, wherein the at least 16 ions of an element of atomic numbers 20–

29, 39, 42, 44 or 57–

83 are Gd ions.

17. The method of claim 12, wherein, in formula (I), A is trimesic acid triamide.

18. The method of claim 15, wherein, in formula (I), A is trimesic acid triamide.

19. The method of claim 12, wherein the nitrogen-containing cascade polymer has 2-(trilysylamino)-ethyl repeating units.

20. The method of claim 15, wherein the nitrogen-containing cascade polymer has 2-(trilysylamino)-ethyl repeating units.