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

• US 6,193,950 B1
• Filed: 02/22/2000
• Issued: 02/27/2001
• 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:
  US09/510,363
• Time in Patent Office: 371 Days
• Field of Search: 424/9.363, 424/9.364, 424/9.365, 424/9.36, 514/492, 514/502, 514/836, 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, 600/420
• 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 cascade polymer containing complex-forming ligands, optionally at least five ions of an element of atomic numbers 21-29, 39, 42, 44 or 57-83 complexed therewith, as well as optionally cations of inorganic and/or organic bases, amino acids or amino acid amides, which 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, to an extent of 96-100%, the residue of a radical of a complex former or complex K, and, to an extent of 0-4%, V′

where V′

is the residue of a group V defined below with a terminal functional group or, linked via a functional group, a bio- or macro-molecule,

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 the group V;

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 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 a hydrogen atom, and

V represents a straight-chain, branched, saturated or unsaturated C₁-C₂₀-alkylene 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), provided that V does not represent —

CH₂—

CO—

(NH—

(CH₂)₂—

(C₆H₄)_0,1—

NH—

CH₂—

CO)_0,1—

or —

CH₂—

CO—

NH—

(CH₂)₂—

(C₆H₄)_0,1—

NH—

CS—

, where for both the —

CH₂—

CO—

side is bonded to the radical of formula IB.

2. The cascade polymer of claim 1, wherein the cascade nucleus A is nitrogen atom,

wherein

R², R³ and R⁴ mean, in each case independently of one another, a covalent bond or

g means the number 2, 3, 4 or 5,

t means the number 1, 2, 3, 4, 5, 6, 7 or 8,

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

r means the number 0 or 1,

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

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

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

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

W means CH, CH₂, NH or a nitrogen atom,

C₁ means

C₂, C₃, C₄ and C₅ mean, in each case independently, a hydrogen atom or

f means the number 1, 2, 3, 4 or 5,

j means the number 6, 7 or 8,

Y¹ and Y² mean, in each case independently of each other, a hydrogen atom,

and

Y³ is a nitrogen atom,

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 mean hydrogen.

3. The cascade polymer of claim 1, wherein the cascade nucleus A is:

tris(aminoethyl)amine;

tris(aminopropyl)amine;

diethylenetriamine;

triethylenetetramine;

tetraethylenepentamine;

H₂N—

CH₂—

C₆H₄—

CH₂—

NH—

CH₂—

C₆H₄—

NH₂;

1,3,5-tris(aminomethyl)benzene;

2,4,6-tris(aminomethyl)pyridine;

1,4,7-triazacyclononane;

1,4,7,10-tetraazacyclododecane;

1,4,7,10,13-pentaazacyclopentadecane;

1,4,8,11-tetraazacyclotetradecane;

1,4,7,10,13,16,19,22,25,28-decaazacyclotriacontane;

6,6′

,6″

,6′

″

,6″

″

,6′

″

″

-hexaamino-6,6′

,6″

,6′

″

,6″

″

,6′

″

″

-hexadeoxy-α

-cyclodextrin;

6,6′

,6″

,6′

″

,6″

″

,6′

″

″

,6″

″

″

-heptaamino-6,6′

,6″

,6′

″

,6″

″

,6′

″

″

,6″

″

″

-heptadeoxy-β

-cyclodextrin;

6,6′

,6″

,6′

″

,6″

″

,6′

″

″

-hexa-(1-amino-2-hydroxypropyl)-α

-cyclodextrin hexaether;

2,2′

,2″

,2′

″

,2″

″

,2′

″

″

,6,6′

,6″

,6′

″

,6″

″

,6′

″

″

-dodeca-(1-amino-2-hydroxypropyl)-α

-cyclodextrin;

dodecaether.

4. The cascade polymer of claim 1, wherein at least one reproduction unit S is of one of the following formulae

wherein

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

α

and β

in each case mean a hydrogen atom or (CH₂)_o,

γ

means (CH₂)_f,

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,

f means the number 1, 2, 3, 4 or 5, and

r means the number 0 or 1,

with the proviso that o and 1 are not both zero at the same time.

5. The cascade polymer of claim 1, wherein at least one reproduction unit S is of one of the following formulae

6. The cascade polymer of claim 1, wherein at least one complex former or complex K is a tetraazacyclododecanetetraacetic acid residue.

7. The cascade polymer of claim 1, wherein the polymer is complexed with at least 5 ions of the elements of atomic numbers 21-29, 42, 44 and 58-70.

8. The cascade polymer of claim 1, wherein at least one group V is of one of the following formulae, where the left side of the formula is attached to the radical of the formula IB:

—

CH₂—

CH(OH)—

CH₂—

O—

CH₂CH₂—

;

—

CH₂—

CH(OH)—

CH₂—

;

—

CH₂—

CH(OH)—

CH₂—

OCH₂—

C₆H₄—

NH—

CO—

CH₂—

;

—

CH₂—

CH(OH)—

CH₂—

OCH₂—

C₆H₄—

NH—

CO—

CH₂—

S—

(CH₂)₄—

S—

;

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)₂NHCS—

;

—

CH₂—

CH(OH)—

CH₂—

O—

(CH₂)₂—

NH—

CO—

CH₂—

;

—

CH₂—

CH(OH)—

CH₂—

O—

C₆H₄—

NHCS—

;

—

CH₂—

CH(OH)—

CH₂—

O—

C₆H₄—

NHCO—

;

—

CH₂—

CH(OH)—

CH₂—

O—

CH₂—

C₆H₄—

NHCS—

;

—

CH₂—

O—

C₆H₄—

CH₂;

—

CH₂—

CH(OH)—

CH₂—

O—

C₆H₄CH₂—

;

—

C(═

NH)—

O—

C₆H₄—

CH₂—

;

—

(CH₂)₄—

NH—

CO—

CH₂—

O—

C₆H₄—

CH₂—

;

—

(CH₂)₄—

NH—

CH₂—

CH(OH)—

CH₂—

O—

C₆H₄—

CH₂—

;

—

(CH₂)₃—

O—

C₆H₄—

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—

;

—

(CH₂)₃—

NH—

groups.

9. A method for NMR or x-ray imaging a patient which comprises administering to the patient a solution comprising a cascade polymer of claim 1, which is complexed with at least five ions of an element of atomic numbers 21-29, 39, 42, 44 or 57-83, and conducting NMR or x-ray imaging.

10. The method of claim 9, wherein the cascade nucleus A is nitrogen atom,

wherein

R², R³ and R⁴ mean, in each case independently of one another, a covalent bond or

g means the number 2, 3, 4 or 5,

t means the number 1, 2, 3, 4, 5, 6, 7 or 8,

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

r means the number 0 or 1,

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

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

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

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

W means CH, CH₂, NH or a nitrogen atom,

C₁ means

C₂, C₃, C₄ and C₅ mean, in each case independently, a hydrogen atom or

f means the number 1, 2, 3, 4 or 5,

j means the number 6, 7 or 8,

Y¹ and Y² mean, in each case independently of each other, a hydrogen atom,

and

Y³ is a nitrogen atom,

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 mean hydrogen.

11. The method of claim 9, wherein the cascade nucleus A is

tris(aminoethyl)amine;

tris(aminopropyl)amine;

diethylenetriamine;

triethylenetetramine;

tetraethylenepentamine;

H₂N—

CH₂—

C₆H₄—

CH₂—

NH—

CH₂—

C₆H₄—

NH₂;

1,3,5-tris(aminomethyl)benzene;

2,4,6-tris(aminomethyl)pyridine;

1,4,7-triazacyclononane;

1,4,7,10-tetraazacyclododecane;

1,4,7,10,13-pentaazacyclopentadecane;

1,4,8,11-tetraazacyclotetradecanei

1,4,7,10,13,16,19,22,25,28-decaazacyclotriacontane;

6,6′

,6″

,6′

″

,6″

″

,6′

″

″

-hexaamino-6,6′

,6″

,6′

″

-6″

″

,6′

″

″

-hexadeoxy-α

-cyclodextrin;

6,6′

,6″

,6′

″

,6″

″

,6′

″

″

,6″

″

″

-heptaamino-6,6′

,6″

,6′

″

,6″

″

,6′

″

″

,6″

″

″

-heptadeoxy-β

-cyclodextrin;

6,6′

,6″

,6′

″

,6″

″

,6′

″

″

-hexa-(1-amino-2-hydroxypropyl)-α

-cyclodextrin hexaether;

2,2′

,2″

,2′

″

,2″

″

,2′

″

″

,6,6′

,6″

,6′

″

,6″

″

,6′

″

″

-dodeca-(1-amino-2-hydroxypropyl)-α

-cyclodextrin;

dodecaether.

12. The method of claim 9, wherein at least one reproduction unit S is of one of the following formulae

wherein

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

α

and β

in each case mean a hydrogen atom or (CH₂)_o,

γ

means (CH₂)_f,

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,

f means the number 1, 2, 3, 4 or 5, and

r means the number 0 or 1,

with the proviso that o and 1 are not both zero at the same time.

13. The method of claim 9, wherein at least one reproduction unit S is of one of the following formulae

—

(CH₂)₂—

CONH—

(CH₂)₂—

;

—

CH₂—

CH(OH)—

CH₂—

;

—

CH₂—

₂—

CH(OH)—

CH₂—

O—

(CH₂)₂—

;

14. The method of claim 9, wherein at least one complex former or complex K is a tetraazacyclododecanetetraacetic acid residue.

15. The method of claim 9, wherein the polymer is complexed with at least 5 ions of the elements of atomic numbers 21-29, 42, 44 and 58-70 and the method is for NMR imaging.

16. The method of claim 9, wherein at least one group V is of one of the following formulae, where the left side of the formula is attached to the radical of the formula IB:

—

CH₂—

CH(OH)—

CH₂—

O—

CH₂CH₂—

;

—

CH₂—

CH(OH)—

CH₂—

;

—

CH₂—

CH(OH)—

CH₂—

OCH₂—

C₆H₄—

H—

CO—

CH₂—

;

—

CH₂—

CH(OH)—

CH₂—

OCH₂—

C₆H₄—

NH—

CO—

CH₂—

S—

(CH₂)₄—

S—

;

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)₂NHCS—

;

—

CH₂—

CH(OH)—

CH₂—

O—

(CH₂)₂—

NH—

CO—

CH₂—

;

—

CH₂—

CH(OH)—

CH₂—

O—

C₆H₄—

NHCS—

;

—

CH₂—

CH(OH)—

CH₂—

O—

C₆H₄—

NHCO—

;

—

CH₂—

CH(OH)—

CH₂—

O—

CH₂—

C₆H₄—

NHCS—

;

—

CH₂—

O—

C₆H₄—

CH₂—

;

—

CH₂—

CH(OH)—

CH₂—

O—

C₆H₄—

CH₂—

;

—

C(═

NH)—

O—

C₆H₄—

CH₂—

;

—

(CH₂)₄—

NH—

CO—

CH₂—

O—

C₆H₄—

CH₂—

;

—

(CH₂)₄—

NH—

CH₂—

CH(OH)—

CH₂—

O—

C₆H₄—

CH₂—

;

—

(CH₂)₃—

O—

C₆H₄—

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—

;

—

(CH₂)₃—

NH—

groups.

17. The method of claim 9, wherein the complexed cascade polymer is administered in a does of 0.0001-5 mmol/kg weight of the patient.

18. The method of claim 15, wherein the complexed cascade polymer is administered in a does of 0.0001-5 mmol/kg weight of the patient.