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

• US 6,861,043 B2
• Filed: 05/06/2002
• Issued: 03/01/2005
• 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: Mühler, Andreas, Radüchel, Bernd, Schmitt-Willich, Heribert, Frenzel, Thomas, Platzek, Johannes
• Primary Examiner(s): HUANG, GIGI GEORGIANA
• Application Number:
  US10/138,651
• Publication Number:
  US 20020187101A1
• Time in Patent Office: 1,030 Days
• Field of Search: 424/1.65, 424/1.81, 424/1.21, 424/1.29, 424/9.3, 424/9.36, 424/9.361, 424/9.363, 424/9.364, 424/DIG.16
• US Class Current: 424/1.65
• 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

Cascade polymer complexes with at least 16 ions of an element of atomic numbers 20 to 29, 39, 42, 44 or 57-83, useful NMR or x-ray lymphography imaging.

Claims

1. A method for radiotherapy in a human or animal patient which comprises administering a radiotherapeutic effective amount of a nitrogen-containing cascade polymer having complexing ligands which complex at least 16 ions of a radioisotope of an element of atomic numbers 27, 29, 31, 32, 37-39, 43, 49, 62, 64, 70, 75 or 77, which results in radiotherapy on the patient,

wherein cascade polymer comprising:

a) a complexing ligand of general 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,

K stands for the radical of a complexing agent,

a stands for numbers 2 to 12,

x, y, z and w, independently of one another, stand for numbers 1 to 4,

provided that at least two cascade reproduction units are different and that for the product of the multiplicities,

16≦

a·

x·

y·

z·

w≦

64

holds true,

b) at least 16 ions of an element of atomic numbers 27, 29, 32, 37-39, 43, 49, 62, 64, 70, 75 or 77,

c) optionally one or more cations of inorganic and/or organic bases, amino acids or amino acid amides, and

d) optionally, one or more acylated terminal amino groups.

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

3. The method of claim 1, wherein the cascade polymer is administered parenterally.

4. The method of claim 1, wherein the cascade polymer is administered intravenously.

5. The method of claim 1, wherein in the complexing ligand of formula (I), A means a nitrogen atom,

in which

m and n independently stand for numbers 1 to 10,

p stands for numbers 0 to 10,

U¹ stands for Q¹ or E,

U² stands for Q2 or E with

E meaning the group

whereby

o stands for numbers 1 to 6,

Q¹ stands for a hydrogen atom or Q² and

Q² stands for a direct bond,

M stands for a C₁-C₁₀ alkylene chain which optionally is interrupted by 1 to 3 oxygen atoms and/or optionally is substituted with 1 to 2 oxo groups,

R^o stands for a branched or unbranched C₁-C₁₀ alkyl radical, a nitro, amino, carboxylic acid group or for

whereby the number of Q² elements equals base multiplicity a.

6. The method of claim 1, wherein in the complexing ligand of formula (I), cascade reproduction Units X, Y, Z and W, independently of one another, stand for

E,

in which

U¹ stands for Q¹ or E,

U² stands for Q² or E with

E meaning the group

whereby

o stands for numbers 1 to 6,

Q¹ stands for a hydrogen atom or Q²,

Q² stands for a direct bond,

U³ stands for a C₁-C₂₀ alkylene chain, which optionally is interrupted by 1 to 10 oxygen atoms and/or 1 to 2 —

N(CO)_q—

R² radicals, 1 to 2 phenylene radicals and/or 1 to 2 phenylenoxy radicals and/or optionally is substituted by 1 to 2 oxo, thioxo, carboxy, C₁-C₅ alkylcarboxy, C₁-C₅ alkoxy, hydroxy, C₁-C₅ alkyl groups, whereby

q stands for numbers 0 or 1 and

R² stands for a hydrogen atom, a methyl or an ethyl radical, which optionally is substituted with 1-2 hydroxy or 1 carboxy group(s),

L stands for a hydrogen atom or the group

V stands for methine group

 

if at the same time U⁴ means a direct bond or group M and U⁵ has one of the meanings of U³ or

V stands for group

 

if at the same time U⁴ and U⁵ are identical and mean the direct bond or group M, and

M stands for a C₁-C₁₀ alkylene chain which optionally is interrupted by 1 to 3 oxygen atoms and/or optionally is substituted with 1 to 2 oxo groups.

7. The method of claim 1, wherein in the complexing ligand of formula I, at least one complexing agent radical K bound to the terminal nitrogen atoms of the last generation of reproduction unit W stands for a radical of general formula IA or IB

in which

R¹, independently of one another, stand for a hydrogen atom or a metal ion equivalent of atomic numbers 20-29, 39, 42-44 or 57-83,

R² stands for a hydrogen atom, or a methyl or an ethyl radical, which optionally is substituted with 1-2 hydroxy or 1 carboxy group(s),

R³ stands for a

 

group;

R⁴ stands for a straight-chain, branched, saturated or unsaturated C₁-C₃₀ alkyl chain, which optionally is interrupted by 1-10 oxygen atoms, 1 phenylene group, 1 phenylenoxy group and/or optionally substituted by 1-5 hydroxy, 1-3 carboxy, 1-phenyl group(s),

R⁵ stands for a hydrogen atom or for R⁴,

U⁶ stands for a straight-chain, branched, saturated or unsaturated C₁-C₂₀ alkylene group optionally containing 1-5 imino, 1-3 phenylene, 1-3 phenylenoxy, 1-3 phenylenimino, 1-5 amide, 1-2 hydrazide, 1-5 carbonyl, 1-5 ethylenoxy, 1 urea, 1 thiourea, 1-2 carboxyalkylimino, 1-2 ester groups;

1-10 oxygen, 1-5 sulfur and/or 1-5 nitrogen atom(s) and/or optionally substituted by 1-5 hydroxy, 1-2 mercapto, 1-5 oxo, 1-5 thioxo, 1-3 carboxy, 1-5 carboxyalkyl, 1-5 ester and/or 1-3 amino group(s), whereby the phenylene groups that are optionally contained can be substituted by 1-2 carboxy, 1-2 sulfo or 1-2 hydroxy groups,

T stands for a —

CO-α

, —

NHCO-α

or —

NHCS-α

group and

α

stands for the bonding site to the terminal nitrogen atoms of the last generation, of reproduction unit W.

8. The method of claim 1, wherein the complexing ligand of the formula I, has 2 to 4 generations of reproduction units.

9. The method of claim 1, wherein the cascade polymer has a molecular weight of 15,000 to 40,000 daltons.

10. The method of claim 1, wherein the cascade polymer is administered in a dose of 0.0001 to 5 mmol/kg of patient weight.