Cascade polymer bound complexing compounds, their complexes and conjugates, process for their production, and pharmaceutical agents containing them

• US 6,054,117 A
• Filed: 09/17/1998
• Issued: 04/25/2000
• Est. Priority Date: 11/21/1989
• Status: Expired due to Fees

• Current Assignee: Bayer Schering Pharma AG (Bayer AG)
• Original Assignee: Schering Ag (Merck & Co., Inc.)
• Inventors: Schmitt-Willich, Heribert, Platzek, Johannes, Bauer, Hans, Weinmann, Hanns-Joachim, Gries, Heinz, Schuhmann-Giampieri, Gabriele, Vogler, Hubert
• Primary Examiner(s): Hollinden, Gary E.
• Application Number:
  US09/156,047
• Time in Patent Office: 586 Days
• Field of Search: 424/9.363, 424/9.36, 424/9.364, 534/16, 540/465, 540/474, 556/50, 556/55, 556/63, 556/77, 556/105, 556/116, 556/134, 556/148, 436/173, 436/806, 514/492, 514/502, 514/836, 514/184, 600/420
• US Class Current: 424/9.363
• CPC Class Codes: A61K 49/0002 General or multifunctional contrast agents, e.g. chelated agents
• CPC Class Codes: A61K 49/04 X-ray contrast preparations
• CPC Class Codes: A61K 49/06 Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
• CPC Class Codes: A61K 49/085 conjugated systems
• CPC Class Codes: A61K 49/124 dendrimers, dendrons, hyperbranched compounds
• CPC Class Codes: A61K 51/04 Organic compounds
• CPC Class Codes: A61K 51/065 conjugates with carriers being macromolecules
• CPC Class Codes: C08G 83/003 Dendrimers
• CPC Class Codes: C08G 85/00 General processes for preparing compounds provided for in this subclass
• CPC Class Codes: Y10T 436/24 Nuclear magnetic resonance, electron spin resonance or other spin effects or mass spectrometry

Abstract

Cascade polymers, containing complex-forming ligands, optionally at least five ions of an element of atomic numbers 21-29, 39, 42, 44 or 57-83, as well as, if desired, cations of inorganic and/or organic bases, amino acids or amino acid amides, are valuable complexing compounds and complexes for diagnostics and therapy.

Claims

1. A cascade polymer complex having a size sufficiently large for its retention in the blood vessels for a time sufficient to provide contrast in NMR imaging but sufficiently small for physiologically acceptable excretion and having sufficient loading of paramagnetic atoms chelated by macrocyclic complex-forming ligands to achieve blood pool imaging by NMR.

2. The cascade polymer of claim 1, which is of the formula I ##STR22## wherein A represents a nitrogen-containing cascade nucleus of basis multiplicity b,

S represents a reproduction unit, independently for each generation,

N represents a nitrogen atom,

Z¹ and Z² for the first to penultimate generation, independently each represent, ##STR23## but for the last generation, Z¹ represents a hydrogen atom, a C₁ -C₁₀ -alkyl, C₂ -C₁₀ -acyl or C₁ -C₁₀ -alkylsulfonyl radical optionally containing 1 to 3 carboxy groups, from 1 to 3 sulfonic acid groups, from 1 to 5 hydroxy groups and/or 1 to 3 oxygen atoms, or represents the radical of a complex former or complex K and

Z² represents the radical of a complex K,

b represents a number 1 to 50, and

s represents a number 1 to 3,

wherein K represents a radical of the formula IB bonded to the terminal nitrogen atoms of the last generation via V:

##STR24## k represents the numbers 1, 2, 3, 4 or 5, l represents the numbers 0, 1, 2, 3, 4 or 5,

q represents the numbers 0, 1 or 2,

U represents CH₂ X or V,

X represents the radicals --COOH, optionally in the form of an ester or an amide thereof,

B, D and E which are identical or different represents the group --(CH₂)_a, wherein a represents the numbers 2, 3, 4 or 5,

R¹ represents V or a hydrogen atom,

with the proviso that R¹ represents V only when U at the same time represents CH₂ X, and that

U represents V only when R'"'"' at the same time represents a hydrogen atom,

V representing a straight-chain, branched, saturated or unsaturated C₁ -C₂₀ -alkenylene group optionally containing imino, phenylene, phenyleneoxy, phenyleneimino, amide, hydrazide, ureido, thioureido, carbonyl ester groups(s) and oxygen, sulphur and/or nitrogen atom(s), and optionally substituted by hydroxy, mercapto, imino, epoxy, oxo, thioxo and/or by amino group(s),

wherein the reproduction units S have to be identical only for one generation and the number of generations is from 2 to 10, and wherein radicals K are complexed with at least five ions of an element of atomic number 21 to 29, 39, 42, 44 or 57 to 83 and optionally cations of inorganic and/or organic bases, amino acids or amino acid amides.

3. A cascade polymer complex of claim 1, wherein the cascade polymer complex is based on a cascade polymer of 4 or 5 generations.

4. A cascade polymer complex of claim 2, wherein the cascade polymer complex is based on a cascade polymer of 4 or 5 generations.

5. The cascade polymer complex of claim 1, wherein the cascade polymer complex is based on a cascade polymer of 1-10 generations.

6. The cascade polymer complex of claim 1, wherein the cascade polymer complex is based on a cascade polymer of 2-9 generations.

7. The cascade polymer complex of claim 1, wherein the cascade polymer complex is based on a cascade polymer of 2-6 generations.

8. The cascade polymer complex of claim 1, wherein the cascade polymer complex is based on a cascade polymer of 3-6 generations.

9. The cascade polymer complex of claim 1, wherein the cascade polymer complex is based on a cascade polymer of 3-5 generations.

10. The cascade polymer complex of claim 1, wherein the cascade polymer complex is based on a cascade polymer of 3 or 4 generations.

11. The cascade polymer complex of claim 1, wherein the cascade polymer complex is based on a cascade polymer providing 20-64 terminal nitrogen atoms.

12. The cascade polymer complex of claim 1, wherein the cascade polymer complex is based on a cascade polymer providing 24-48 terminal nitrogen atoms.

13. The cascade polymer complex of claim 1, which contains more than 15% by weight of the elements of atomic numbers 21-29, 39, 42, 44 and 57-83.

14. The cascade polymer complex of claim 1, which contains at least one complexed gadolinium ion.

15. The cascade polymer complex of claim 1, wherein all of the complexed paramagnetic ions are gadolinium ions.

16. The cascade polymer complex of claim 2, wherein the radicals K contain a tetraazacyclododecane macrocyclic ring.

17. A cascade polymer complex according to claim 2, wherein S is

18. A cascade polymer complex according to claim 2, wherein A is a nitrogen atom, ##STR26## wherein R², R³ and R⁴ are, in each case independently of one another, a covalent bond or ##STR27## g is the number 2, 3, 4 or 5, t is the number 1, 2, 3, 4, 5, 6, 7 or 8,

l is the number 0, 1, 2, 3, 4 or 5,

r is the number 0 or 1,

n is the number 0, 1, 2, 3 or 4,

m is the number 0, 1, 2, 3 or 4,

k is the number 1, 2, 3, 4 or 5,

a is the number 2, 3, 4 or 5,

W is CH, CH₂, NH or a nitrogen atom,

C₁ is ##STR28## C₂, C₃, C₄ and C₅ are, in each case independently, a hydrogen atom or ##STR29## f is the number 1, 2, 3, 4 or 5, j is the number 6, 7 or 8,

Y¹ and Y² are, in each case independently of each other, a hydrogen atom, ##STR30## and Y³ is a nitrogen atom, ##STR31## a and g are as defined above, ##STR32## means a single or double bond, with the proviso that, if Y³ is a nitrogen atom,

Y¹ and Y² are hydrogen.

19. A cascade polymer complex according to claim 2, wherein V is ##STR33## wherein R⁺ and R^y stand for natural amino acid residues;

##STR34##