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

• US 6,177,060 B1
• Filed: 03/19/1998
• Issued: 01/23/2001
• 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: Schmitt-Willich, Heribert, Frenzel, Thomas, Platzek, Johannes, Mühler, Andreas, Radüchel, Bernd
• Primary Examiner(s): Hartley, Michael G.
• Application Number:
  US09/044,254
• Time in Patent Office: 1,041 Days
• Field of Search: 424/9.36, 424/9.361, 424/9.363, 424/9.364, 424/9.365, 424/1.65, 424/9.4, 424/9.42, 424/DIG.16, 424/9.322, 424/9.3, 424/9.44, 534/10, 534/11, 534/12, 534/13, 534/14, 534/15, 534/16, 540/465, 540/473, 540/474
• US Class Current: 424/9.36
• 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 contrast enhanced NMR or x-ray lymphography imaging in a human or animal which comprises administering a contrast enhancement effective amount of a contrast agent to the human or animal and generating an enhanced image by NMR or x-ray of at least a part of the lymphatic system thereof, wherein said contrast agent is a nitrogen-containing cascade polymer, said polymer consisting essentially of:

a) a complexing ligand of general formula I

2. 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,

R⁰ 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 the base multiplicity a.

3. 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 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.

4. 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

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.

5. The method of claim 1, wherein the contrast agent has a molecular weight of 10,000 to 80,000 daltons.

6. The method of claim 1, wherein the contrast agent is administered parenterally.

7. The method of claim 1, wherein the contrast agent is administered interstitially.

8. The method of claim 1, wherein the contrast agent is administered subcutaneously.