Cascade polymer complexes, process for their production and pharamceutical agents containing said complexes
First Claim
1. A cascade polymer complex containinga) a complexing ligand of formula I
in whichA 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 a number from 2 to 12,x, y, z and w, independently of one another, stand for a number 1 to 4, andterminal amino groups are optionally acylated, provided that at least two reproduction units are different and that16≦
W-K.sub.W >
.sub.Z).sub.4 !.sub.x }.sub.a (I),
a·
x·
y·
z·
w≦
64,holds true for the product of the multiplicities,b) at least 16 ions of an element of atomic numbers 20 to 29, 39, 42, 44 or 57-83 and,c) optionally cations of inorganic and/or organic bases, amino acids or amino acid amides,wherein at least one of cascade reproduction units X, Y, Z and W, independently of one another, is selected from the group consisting ofE, ##STR23## in which U1 stands for Q1 or E,U2 stands for Q2 or E withE meaning the group ##STR24## in which o stands for a number from 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, 1 to 2 --N(CO)q --R2 radicals, 1 to 2 phenylene radicals, 1 to 2 phenylenoxy radicals or combinations thereof, and optionally is substituted by 1 to 2 oxo, thioxo, carboxy, C1 -C5 alkylcarboxy, C1 -C5 alkoxy, hydroxy or C1 -C5 alkyl groups, in whichq stands for number 0 or 1 andR2 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 ##STR25## V stands for methine group ##STR26## in which case U4 means a direct bond or group M and U5 has one of the meanings of U3orV stands for group ##STR27## in which case U4 and U5 are identical and mean the direct bond or group M where M stands for a C1-10 -alkylene chain which optionally is interrupted by 1 to 3 oxygen atoms and optionally is substituted with 1 to 2 oxo groups, andwherein complexing agent radical K bound to the terminal nitrogen atoms of the last generation of reproduction unit W stand for a radical of general formula IA or IB ##STR28## 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, a methyl or an ethyl radical which optionally is substituted with 1-2 hydroxy or 1 carboxy group(s),R3 stands for a ##STR29## 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 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, or 1-10 oxygen, 1-5 sulfur 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) or combinations thereof, and 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, andα
stands for the bonding site to the terminal nitrogen atoms of the last generation, of reproduction unit W.
2 Assignments
0 Petitions
Accused Products
Abstract
Cascade polymer complexes that contain
a) complexing ligands of general formula I
A-{X- Y-(Z-<W-K.sub.W >.sub.Z).sub.y !.sub.x }.sub.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 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.
82 Citations
14 Claims
- 1. A cascade polymer complex containing
a) a complexing ligand of formula I - space="preserve" listing-type="equation">A-{X- Y-(Z-<
W-K.sub.W >
.sub.Z).sub.4 !.sub.x }.sub.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 a number from 2 to 12, x, y, z and w, independently of one another, stand for a number 1 to 4, and terminal amino groups are optionally acylated, provided that at least two reproduction units are different and that 16≦
a·
x·
y·
z·
w≦
64,holds true for the product of the multiplicities, b) at least 16 ions of an element of atomic numbers 20 to 29, 39, 42, 44 or 57-83 and, c) optionally cations of inorganic and/or organic bases, amino acids or amino acid amides, wherein at least one of cascade reproduction units X, Y, Z and W, independently of one another, is selected from the group consisting of E, ##STR23## in which U1 stands for Q1 or E, U2 stands for Q2 or E with E meaning the group ##STR24## in which o stands for a number from 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, 1 to 2 --N(CO)q --R2 radicals, 1 to 2 phenylene radicals, 1 to 2 phenylenoxy radicals or combinations thereof, and optionally is substituted by 1 to 2 oxo, thioxo, carboxy, C1 -C5 alkylcarboxy, C1 -C5 alkoxy, hydroxy or C1 -C5 alkyl groups, in which q stands for number 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 ##STR25## V stands for methine group ##STR26## in which case U4 means a direct bond or group M and U5 has one of the meanings of U3 or V stands for group ##STR27## in which case U4 and U5 are identical and mean the direct bond or group M where M stands for a C1-10 -alkylene chain which optionally is interrupted by 1 to 3 oxygen atoms and optionally is substituted with 1 to 2 oxo groups, and wherein complexing agent radical K bound to the terminal nitrogen atoms of the last generation of reproduction unit W stand for a radical of general formula IA or IB ##STR28## 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, a methyl or an ethyl radical which optionally is substituted with 1-2 hydroxy or 1 carboxy group(s), R3 stands for a ##STR29## 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 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, or 1-10 oxygen, 1-5 sulfur 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) or combinations thereof, and 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, andα
stands for the bonding site to the terminal nitrogen atoms of the last generation, of reproduction unit W.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)
- 12. A process for the production of a pharmaceutical agent according to claim 8, wherein the cascade polymer complex, dissolved or suspended in water or physiological salt solution, optionally with the additives usual in galenicals, is brought into a form suitable for enteral or parenteral administration.
- 13. A cascade polymer complex according to claim 1, wherein a cascade reproduction unit X, Y, Z or W is E which is --CH2 --CH2 --N(Q1 Q2).
- 14. A cascade polymer complex of claim 1, wherein at least one reproduction unit X, Y, Z or W is of the following formula:
- ##STR37##
- space="preserve" listing-type="equation">A-{X- Y-(Z-<
Specification
-
- Resources
-
Current AssigneeBayer Schering Pharma AG (Bayer AG)
-
Original AssigneeSchering Ag (Merck & Co., Inc.)
-
InventorsSchmitt-Willich, Heribert, Frenzel, Thomas, Platzek, Johannes, Raduchel, Bernd, Muhler, Andreas
-
Primary Examiner(s)Hollinden, Gary E.
-
Assistant Examiner(s)Hartley, Michael G.
-
Application NumberUS08/674,844Time in Patent Office832 DaysField of Search424/1.65, 424/9.322, 424/9.34, 424/9.341, 424/9.36, 424/9.364, 424/9.365, 424/9.361, 534/10, 534/14, 534/15, 534/16, 540/465, 540/473, 540/474, 564/191, 564/198, 528/288, 528/328, 528/332, 528/310, 528/336US Class Current424/9.36CPC Class CodesA61K 49/04 X-ray contrast preparationsA61K 49/085 conjugated systemsA61K 49/124 dendrimers, dendrons, hyper...A61K 51/065 conjugates with carriers be...A61P 43/00 Drugs for specific purposes...C07C 229/76 Metal complexes of amino ca...C07C 237/42 having nitrogen atoms of am...C07D 251/54 Three nitrogen atomsC07D 257/02 not condensed with other ringsC07D 487/08 Bridged systemsC07K 14/001 by chemical synthesisY10S 424/16 Dendrimers and dendritic po...
