Cascade polymer bound complexing compounds for MRI

• US 5,911,971 A
• Filed: 11/04/1996
• Issued: 06/15/1999
• 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:
  US08/743,535
• Time in Patent Office: 953 Days
• Field of Search: 424/9.363, 424/9.36, 424/9.364, 514/492, 514/502, 514/836, 534/16, 540/465, 540/474, 436/173, 436/806, 128/653.4, 128/654, 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 method for NMR imaging the blood vessels of a patient which comprises administering, as a contrast agent, 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, which is of the formula I ##STR20## 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, ##STR21## 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:

##STR22## 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 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, amnide, hydrazide, ureido, thioureido, carbonyl ester groups(s), 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.

2. A method according to claim 1, wherein in the cascade polymer complex at least one generation of S is

--(CH₂)₂ --CONH--(CH₂)_a -- or ##STR23## wherein a is 2, 3, 4 or 5,

α

and β

each independently is a hydrogen atom or (CH₂)_o,

γ

means (CH₂)_f, each f independently is the number 1, 2, 3, 4 or 5, and

r is the number 0 or 1, and

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

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

o is 0, 1, 2, 3, 4 or 5,

with the proviso that l and o are not both zero at the same time.

3. A method according to claim 1, wherein in the cascade polymer complex A is a nitrogen atom, ##STR24## wherein R², R³ and R⁴ are, in each case independently of one another, a covalent bond or ##STR25## 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 ##STR26## C₂, C₃, C₄ and C₅ are, in each case independently, a hydrogen atom or ##STR27## 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, ##STR28## and Y³ is a nitrogen atom, ##STR29## a and g are as defined above, - - - means a single or double bond,

with the proviso that, if Y³ is a nitrogen atom, Y¹ and Y² are hydrogen.

4. A method according to claim 1, where the cascade polymer complex contains at least five ions of an element of atomic numbers 21-29, 39, 42, 44 or 57-83 bound to the complexing agent K.

5. A method according to claim 1, wherein in the cascade polymer complex V is ##STR30## wherein R⁺ and R^Y stand for natural amino acid residues;

--CH₂ --CH(OH)--CH₂ --O--(CH₂)₂ --NHCS--;

--CH₂ --CH(OH)--CH₂ --NHCS--;

--CH₂ --CH(OH)--CH₂ --O--(CH₂)₂ --O--(CH₂)₂ NHCS--;

--CH₂ --CH(OH)--CH₂ --O--(CH₂)₂ --NH--CO--CH₂ --;

--CH₂ --CH(OH)--CH₂ --O--C₆ H₄ --NHCS--;

--CH₂ --CH(OH)--CH₂ --O--C₆ H₄ --NHCO--;

--CH₂ --CH(OH)--CH₂ --O--CH₂ --C₆ H₄ --NHCS--;

--CH₂ --O--C₆ H₄ --CH₂ --;

--CH₂ --CH(OH)--CH₂ --O--C₆ H₄ --CH₂ --;

--C(═

NH)--O--C₆ H₄ --CH₂ --;

--(CH₂)₄ --NH--CO--CH₂ --O--C₆ H₄ --CH₂ --;

--(CH₂)₄ --NH--CH₂ --CH(OH)--CH₂ --O--C₆ H₄ --CH₂ --;

--(CH₂)₃ --O--C₆ H₄ --CH₂ --;

--CH₂ --CO--NH--(CH₂)₃ --O--CH₂ --;

--CH₂ --CO--NH--NH--;

--CH₂ --CONH--(CH₂)₂ --;

--CH₂ --CO--NH--(CH₂)₁₀ --;

--CH₂ --CONH--(CH₂)₂ --S--;

--(CH₂)₄ --NH--CO--(CH₂)₈ --;

--CH₂ --CO--NH--(CH₂)₃ --NH--;

or --(CH₂)₃ --NH--.

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

7. A method of claim 1, wherein the cascade polymer complex is based on a cascade polymer of 1-10 generations.

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

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

10. A method of claim 1, wherein the cascade polymer complex is based on a cascade polymer of 3-6 generations.

11. A method of claim 1, wherein the cascade polymer complex is based on a cascade polymer of 3-5 generations.

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

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

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

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

16. A method of claim 1, 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 1, wherein the cascade polymer complex contains at least one complexed gadolinium ion.

18. A method of claim 1, wherein all of the radicals K are complexed with gadolinium ions.

19. A method of claim 1, wherein the radicals K contain a tetraazacyclododecane macrocyclic ring.

20. A method of claim 18, wherein the radicals K contain a tetraazacyclododecane macrocyclic ring.

21. A method for NMR imaging the vasal space of a patient which comprises administering, as a contrast agent, a cascade polymer complex, having a size large enough to be able to leave the vasal space only after a sufficient time to provide contrast in NMR imaging but small enough to pass through the kidney capillaries, which is of the formula I:

##STR31## 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, ##STR32## 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;

##STR33## 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 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), 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.