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

• US 20040091426A1
• Filed: 10/17/2003
• Published: 05/13/2004
• Est. Priority Date: 07/04/1995
• Status: Active Grant

• Current Assignee: Bayer Schering Pharma AG (Bayer AG)
• Original Assignee: Bayer Schering Pharma AG (Bayer AG)
• Inventors: Muhler, Andreas, Schmitt-Willich, Heribert, Frenzel, Thomas, Platzek, Johannes, Raduchel, Bernd
• Granted Patent: US 7,211,241 B2
• Time in Patent Office: Days
• US Class Current: 424/9.322
• 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 that contain

a) complexing ligands of general formula I

A-{X—[Y-(Z-(W—K_W)_Z)_y]_x}  (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 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 20 to 29, 39, 42, 44 or 57-83,

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

d) optionally acylated terminal amino groups

are valuable compounds for diagnosis and therapy.

Claims

1. A cascade polymer complex 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 20 to 29, 39, 42, 44 or 57-83,

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 grou

2. A cascade polymer complex according to claim 1 wherein A means a nitrogen atom,

3. A cascade polymer complex according to claim 1, wherein 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 1 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)_qR² 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, or C₁-C₅ alkyl groups, whereby

q stands for numbers 0 or 1

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),

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.

4. A cascade polymer complex according to claim 1, wherein complexing agent radical K bound to the terminal nitrogen atoms of the last generation of reproduction unit W stands for a radical of general formulas IA or IB

5. A cascade polymer complex according to claim 4, wherein the C₁-C₂₀ alkylene chain that stands for U⁶ contains the groups

—

CH₂, —

CH₂NHCO, —

NHCOCH₂O₁—

NHCOCH₂OC₆H₄, —

N(CH₂CO₂H),

—

NHCOCH₂C₆H₄, —

NHCSNHC₆H₄, —

CH₂OC₆H₄, or —

CH₂CH₂O and/or is substituted by groups —

COOH, or —

CH₂COOH.

6. A cascade polymer complex according to claim 4, wherein U⁶ stands for a

—

CH₂, —

CH₂CH₂, —

CH₂CH₂CH₂, —

C₆H₄, —

C₆H₄, —

CH₂C₆H₅,

—

CH₂NHCOCH₂CH(CH₂CO₂H)—

C₆H₄,

CH₂NHCOCH₂OCH₂, or

—

CH₂NHCOCH₂C₆H₄ group.

7. A cascade polymer complex according to claim 3, wherein radical U³ contained in cascade reproduction units X, Y, Z and W stands for

—

CO—

, —

COCH₂OCH₂CO—

, —

COCH₂—

, —

CH₂CH₂—

, —

CONHC₆H₄—

,

—

COCH₂CH₂CO—

, —

COCH₂—

CH₂CH₂CO—

, or —

COCH₂CH₂CH₂CH₂CO—

,

radical U⁴ stands for a direct bond, or for —

CH₂CO—

,

radical U⁵ stands for a direct bond, —

(CH₂)₄—

, —

CH₂CO—

,

—

CH(COOH)—

, CH₂OCH₂CH₂—

, —

CH₂C₆H₄—

, or CH₂—

C₆H₄OCH₂CH₂—

,

radical E stands for a group

8. A cascade polymer complex according to claim 3, wherein cascade reproduction units X, Y, Z and W, independently of one another, stand for

—

CH₂CH₂NH—

;

—

CH₂CH₂N<

;

—

COCH(NH—

)(CH₂)₄NH—

;

—

COCH(N<

)(CH₂N<

;

—

COCH₂OCH₂CON(CH₂CH₂NH—

)₂;

—

COCH₂OCH₂CON(CH₂CH₂N<

)₂;

—

COCH₂N(CH₂CH₂NH—

)₂;

—

COCH₂N(CH₂CH₂N<

)₂;

—

COCH₂NH—

;

—

COCH₂N<

;

—

COCH₂CH₂CON(CH₂CH₂NH—

)₂;

—

COCH₂CH₂CON(CH₂CH₂N<

)₂;

—

COCH₂OCH₂CONH—

C₆H₄—

CH₂[CH₂CON(CH₂CHON(CH₂—

)]₂;

—

COCH₂OCH₂CONH—

C₆H₄—

CH[CH₂CON(CH₂CH₂NH)₂]₂;

—

COCH₂CH₂CO—

NH—

C₆H₄—

CH[CH₂CoN(CH₂CH₂N<

)₂]₂;

COCH₂CH₂CO₂—

NH—

C₆H₄—

CH[CH₂CON(CH₂CH₂NH)₂]₂;

—

CONH—

C₆H₄—

CH[CH₂CON(CH₂CH₂NH—

)₂]₂;

—

CONH—

C₆H₄—

CH[CH₂CON(CH₂CH₂N<

)₂]₂;

—

COCH(NH—

)CH(COOH)NH—

;

—

COCH(N<

)CH(COOH)N<

;

9. A cascade polymer complex according to claim 2, wherein

m stands for numbers 1-3,

n stands for numbers 1-3,

o stands for number 1,

p stands for numbers 0-3,

M stands for a —

CH₂, —

CO or —

CH₂CO group and

R^o stands for a —

CH₂NU¹U², CH₃ or NO₂ group.

10. A pharmaceutical agent comprising at least one cascade polymer complex according to claim 1, and a pharmaceutically acceptable carrier.

11. A method of NMR diagnosis, e.g., imaging or diagnostic radiology, e.g., CT imaging, comprising administering at least one polymer complex according to claim 1.

12. A method for differentiating benign and malignant tumors in regions of the body without blood-brain barriers comprising imaging such tumors by administering a cascade polymer complex according to claim 1.

13. Process for the production of cascade polymer complexes according to claim 1, wherein compounds of general formula I′

A-{X—

[Y-(Z-(W-β

_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,

a stands for numbers 2 to 12,

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

β

stands for the bonding site of the terminal NH groups of the last generation, of reproduction unit W,

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

16≦

a·

x·

y·

z·

w≦

64

holds true,

are reacted with a complex of completing agent K′

of general formula I′

A or I′

B

whereby

R^1′

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

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),

R^3′

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 —

C*O, —

COOH, —

N═

C═

O or —

N═

C=S group, and

C*O stands for an activated carboxyl group provided that—

if K′

stands for a complex—

at least two (in the case of divalent metals) or three (in the case of trivalent metals) of substituents R¹ stand for a metal ion equivalent of the above-mentioned elements and that optionally other carboxyl groups are present in the form of their salts with inorganic and/or organic bases, amino acids or amino acid amides,

optionally present protective groups are cleaved, the thus obtained cascade polymers—

if K′

stands for a complexing agent—

are reacted in a way known in the art with at least one metal oxide or metal salt of an element of atomic numbers 20-29, 39, 42, 44, or 57-83 and optionally then in the cascade polymer complexes thus obtained, acid hydrogen atoms that are still present are completely or partially substituted by cations of inorganic and/or organic bases, amino acids, or amino acid amides and optionally still present free terminal amino groups are optionally acylated—

before or after the metal complexing.

15. Process for the production of pharmaceutical agents according to claim 10, wherein the cascade polymer complexes, dissolved or suspended in water or physiological salt solution, optionally with the additives that are commonly used in galenicals, are brought into a form suitable for enteral or parenteral administration.

14. A compound of general formula I′

A