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

• US 6,855,309 B2
• Filed: 12/11/2002
• Issued: 02/15/2005
• 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): JONES, DAMERON LEVEST
• Application Number:
  US10/316,094
• Publication Number:
  US 20030232017A1
• Time in Patent Office: 797 Days
• Field of Search: 424/1.11, 424/1.65, 424/9.1, 424/9.3, 424/9.36, 424/9.361, 424/9.363, 424/9.364, 424/9.365, 424/9.4, 424/9.42, 534 10- 16, 514/492, 514/501, 514/502, 514/495, 514/496, 514/499
• US Class Current: 424/9.36
• 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 method for radiodiagnosis and/or radiotherapy of a patient, comprising conducting radiodiagnosis and/or radiotherapy of a patient who has been administered a cascade polymer complex having complex-forming ligands complexing at least five ions of an element of atomic numbers 27, 29, 31, 32, 37-39, 43, 49, 62, 64, 70, 75 or 77, as well as, optionally, cations of inorganic and/or organic bases, amino acids or amino acid amides.

2. A method of claim 1, wherein the complex is administered in a dose of 0.0001-5 mmol/kg weight of the patient.

3. A method of claim 1, wherein the cascade polymer complex contains more than 15% by weight of the elements of atomic numbers 27, 29, 31, 32, 37-39, 43, 49, 62, 64, 70, 75 or 77.

4. A method of claim 1, wherein at least one complex-forming ligand is a macrocyclic ligand.

5. A method of claim 4, wherein the at least one macrocyclic complex-forming ligand is a tetraazacyclododecane macrocyclic ring ligand.

6. The method of claim 1, wherein the cascade polymer complex is of the formula I

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,

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.

7. The method of claim 6, wherein in formula (I), K represents a radical of the formula IA, IB or IC bonded to the terminal nitrogen atoms of the last generation via V:

wherein

n and m in each case independently are 0, 1, 2, 3 or 4;

n and m adding up to no more than 4,

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 CH₂X 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 CH₂X, and that U represents V only when R¹ 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).

8. A method for detecting tumors in a patient, comprising conducting MRI-, x-ray- or radio-diagnosis of a patient who has been administered a cascade polymer complex having complex-fanning ligands complexing at least five ions of an element of atomic numbers 21-29, 31, 32, 37-39, 42,43, 44,49 or 57-83, as well as, optionally, cations of inorganic and/or organic bases, amino acids or amino acid amides.

9. The method of claim 8, wherein the method comprises conducting MRI-diagnosis, the cascade polymer complex is complexed with at least five ions of an element of atomic numbers 21-29, 39, 42, 44 or 57-83 and the cascade polymer complex is administered in a dose of below 1 mg per kg body weight of the patient.

10. A method of claim 8, wherein the cascade polymer complex contains more than 15% by weight of the elements of atomic numbers 21-29,31, 32, 37-39, 42, 43, 44, 49 or 57-83.

11. A method of claim 8, wherein the cascade polymer complex contains at least one complexed gadolinium ion.

12. A method of claim 8, wherein all of the complexed paramagnetic ions are gadolinium ions.

13. A method of claim 8, wherein at least one complex-forming ligand is a macrocyclic ligand.

14. A method of claim 13, wherein the at least one macrocyclic complex-forming ligand is a tetraazacyclododecane macrocyclic ring ligand.

21. The method of claim 8, wherein the cascade polymer complex is of the formula I

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,

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 of a complex K,

b represents a number 1 to 50, and

s represents a number 1 to 3.

22. The method of claim 21, wherein in formula (I), K represents a radical of the formula IA, LB or IC bonded to the terminal nitrogen atoms of the last generation via V:

wherein

n and m in each case independently are 0, 1, 2, 3 or 4;

n and m adding up to no more than 4,

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 CH₂X 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 CH₂X, and that U represents V only when R¹ 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).

15. A method for susceptibility imaging comprising imaging a patient by in vivo NMR spectroscopy to whom a susceptibility reagent has been administered, wherein said susceptibility reagent is a cascade polymer complex having complex-forming ligands complexing at least five ions of an element of atomic numbers 21-29, 39, 42, 44 or 57-83, as well as, optionally, cations of inorganic and/or organic bases, amino acids or amino acid amides.

16. A method of claim 15, wherein the cascade polymer complex contains more than 15% by weight of the elements of atomic numbers 21-29, 39, 42, 44 and 57-83.

17. A method of claim 15, wherein the cascade polymer complex contains at least one complexed gadolinium ion.

18. A method of claim 15, wherein all of the complexed paramagnetic ions are gadolinium ions.

19. A method of claim 15, wherein at least one complex-forming ligand is a macrocyclic ligand.

20. A method of claim 19, wherein the at least one macrocyclic complex-forming ligand is a tetraazacyclododecane macrocyclic ring ligand.

23. The method of claim 15, wherein the cascade polymer complex is of the formula I

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,

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.

24. The method of claim 23, wherein in formula (I), K represents a radical of the formula IA, IB or IC bonded to the terminal nitrogen atoms of the last generation via V:

wherein

n and m in each case independently are 0, 1, 2, 3 or 4;

n and m adding up to no more than 4,

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 CH₂X 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 CH₂X, and that U represents V only when R¹ 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).