Claims
- 1. A cascade polymer complex containing
- a) a complexing ligand of 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 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.ltoreq.a.multidot.x.multidot.y.multidot.z.multidot.w.ltoreq.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 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 ##STR24## in which R.sup.1 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,
- R.sup.2 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.sup.3 stands for a ##STR25## R.sup.4 stands for a straight-chain, branched, saturated or unsaturated C.sub.1 -C.sub.30 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),
- R.sup.5 stands for hydrogen atom or for R.sup.4,
- U.sup.6 stands for a straight-chain, branched, saturated or unsaturated C.sub.1 -C.sub.20 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, 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-.alpha., --NHCO-.alpha. or --NHCS-.alpha. group, and
- .alpha. stands for the bonding site to the terminal nitrogen atoms of the last generation, of reproduction unit W.
- 2. A cascade polymer complex according to claim 1, wherein A means a nitrogen atom, ##STR26## in which m and n independently stand for numbers 1 to 10,
- p stands for numbers 0 to 10,
- U.sup.1 stands for Q.sup.1 or E,
- U.sup.2 stands for Q.sup.2 or E with E meaning the group ##STR27## whereby o stands for numbers 1 to 6,
- Q.sup.1 stands for a hydrogen atom or Q.sup.2 and
- Q.sup.2 stands for a direct bond,
- M stands for a C.sub.1 -C.sub.10 alkylene chain which optionally is interrupted by 1 to 3 oxygen atoms and/or optionally is substituted with 1 to 2 oxo groups,
- R.sup.o stands for a branched or unbranched C.sub.1 -C.sub.10 alkyl radical, a nitro, amino, carboxylic acid group or for ##STR28## the number of Q.sup.2 elements equals the base multiplicity a.
- 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, ##STR29## in which U.sup.1 stands for Q.sup.1 or E,
- U.sup.2 stands for Q.sup.2 or E with E meaning the group ##STR30## whereby o stands for numbers 1 to 6,
- Q.sup.1 stands for a hydrogen atom or Q.sup.2,
- Q.sup.2 stands for a direct bond,
- U.sup.3 stands for a C.sub.1 -C.sub.20 alkylene chain, which optionally is interrupted by 1 to 10 oxygen atoms and/or 1 to 2 --N(CO).sub.q --R.sup.2 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, C.sub.1 -C.sub.5 alkylcarboxy, C.sub.1 -C.sub.5 alkoxy, hydroxy, or C.sub.1 -C.sub.5 alkyl groups, whereby
- q stands for numbers 0 or 1, and
- R.sup.2 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),
- U.sup.4 stands for a direct bond or a group M,
- U.sup.5 stands for a direct bond, a group M or has one of the meanings for U.sup.3,
- L stands for a hydrogen atom or the group ##STR31## V stands for methine group ##STR32## if at the same time U.sup.4 means a direct bond or group M and U.sup.2 has one of the meanings of U.sup.3 or
- V stands for group ##STR33## if at the same time U.sup.4 and U.sup.5 are identical and mean the direct bond or group M, and
- M stands for a C.sub.1 -C.sub.10 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 the C.sub.1 -C.sub.20 alkylene chain that stands for U.sup.6 contains the groups
- --CH.sub.2, --CH.sub.2 NHCO, --NHCOCH.sub.2 O, --NHCOCH.sub.2 OC.sub.6 H.sub.4, --N(CH.sub.2 CO.sub.2 H),
- --NHCOCH.sub.2 C.sub.6 H.sub.4, --NHCSNHC.sub.6 H.sub.4, --CH.sub.2 OC.sub.6 H.sub.4, or --CH.sub.2 CH.sub.2 O and/or is substituted by groups --COOH, or --CH.sub.2 COOH.
- 5. A cascade polymer complex according to claim 1, wherein U.sup.6 stands for a
- --CH.sub.2, --CH.sub.2 CH.sub.2, --CH.sub.2 CH.sub.2 CH.sub.2, --C.sub.6 H.sub.4, --C.sub.6 H.sub.10, --CH.sub.2 C.sub.6 H.sub.5,
- --CH.sub.2 NHCOCH.sub.2 CH(CH.sub.2 CO.sub.2 H)--C.sub.6 H.sub.4,
- --CH.sub.2 NHCOCH.sub.2 OCH.sub.2, or
- --CH.sub.2 NHCOCH.sub.2 C.sub.6 H.sub.4 group.
- 6. A cascade polymer complex according to claim 3, wherein radical U.sup.3 contained in cascade reproduction units X, Y, Z and W stands for
- CO, COCH.sub.2 OCH.sub.2 CO--, --COCH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CONHC.sub.6 H.sub.4 --,
- --COCH.sub.2 CH.sub.2 CO--, --COCH.sub.2 --CH.sub.2 CH.sub.2 CO--, or --COCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CO--,
- radical U.sup.4 stands for a direct bond, or for --CH.sub.2 CO--,
- radical U.sup.5 stands for a direct bond, --(CH.sub.2).sub.4 --, --CH.sub.2 CO--,
- --CH(COOH)--, CH.sub.2 OCH.sub.2 CH.sub.2 --, --CH.sub.2 C.sub.6 H.sub.4 --, or CH.sub.2 --C.sub.6 H.sub.4 OCH.sub.2 CH.sub.2 --,
- radical E stands for a group ##STR34##
- 7. A cascade polymer complex according to claim 1, wherein cascade reproduction units X, Y, Z and W, independently of one another, stand for --CH.sub.2 CH.sub.2 NH--; --CH.sub.2 CH.sub.2 N<;
- --COCH(NH--)(CH.sub.2).sub.4 NH--; --COCH(N<)(CH.sub.2).sub.4 N<;
- --COCH.sub.2 OCH.sub.2 CON(CH.sub.2 CH.sub.2 NH--).sub.2 ; --COCH.sub.2 OCH.sub.2 CON(CH.sub.2 CH.sub.2 N<).sub.2 ;
- --COCH.sub.2 N(CH.sub.2 CH.sub.2 NH--).sub.2 ; --COCH.sub.2 N(CH.sub.2 CH.sub.2 N<).sub.2 ;
- --COCH.sub.2 NH--; --COCH.sub.2 N<;
- --COCH.sub.2 CH.sub.2 CON(CH.sub.2 CH.sub.2 NH--).sub.2 ; --COCH.sub.2 CH.sub.2 CON(CH.sub.2 CH.sub.2 N<).sub.2 ;
- --COCH.sub.2 OCH.sub.2 CONH--C.sub.6 H.sub.4 --CH[CH.sub.2 CON(CH.sub.2 CH.sub.2 NH--).sub.2 ].sub.2 ;
- --COCH.sub.2 OCH.sub.2 CONH--C.sub.6 H.sub.4 --CH[CH.sub.2 CON(CH.sub.2 CH.sub.2 N<).sub.2 ].sub.2 ;
- --COCH.sub.2 CH.sub.2 CO--NH--C.sub.6 H.sub.4 --CH[CH.sub.2 CON(CH.sub.2 CH.sub.2 NH--).sub.2 ].sub.2 ;
- --COCH.sub.2 CH.sub.2 CO--NH--C.sub.6 H.sub.4 --CH[CH.sub.2 CON(CH.sub.2 CH.sub.2 N<).sub.2 ].sub.2 ;
- --CONH--C.sub.6 H.sub.4 --CH[CH.sub.2 CON(CH.sub.2 CH.sub.2 NH--).sub.2 ].sub.2 ;
- --CONH--C.sub.6 H.sub.4 --CH[CH.sub.2 CON(CH.sub.2 CH.sub.2 N<).sub.2 ].sub.2 ;
- --COCH(NH--)CH(COOH)NH--; --COCH(N<)CH(COOH)N<; ##STR35##
- 8. A cascade polymer complex according to claim 2, wherein m stands for a number from 1-3,
- n stands for a number from 1-3,
- o stands for 1,
- p stands for a number from 0-3,
- M stands for a --CH.sub.2, --CO or --CH.sub.2 CO group and
- R.sup.o stands for a --CH.sub.2 NU.sup.1 U.sup.2, CH.sub.3 or NO.sub.2 group.
- 9. A pharmaceutical agent comprising at least one cascade polymer complex according to claim 1, and a pharmaceutically acceptable carrier.
- 10. A process for the production of a pharmaceutical agent according to claim 9, 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.
- 11. A cascade polymer complex according to claim 1, wherein a cascade reproduction unit X, Y, Z or W is --CH.sub.2 --CH.sub.2 --N(Q.sup.1 Q.sup.2).
- 12. A cascade polymer complex according to claim 1, wherein at least one reproduction unit X, Y, Z or W is of the formula: ##STR36##
- 13. A process for the production of a cascade polymer complex according to claim 1, wherein: a) a compound of general formula I'
- A--{X--[Y--(Z--<W-.beta..sub.W >.sub.z).sub.y ].sub.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 a number from 2 to 12,
- x, y, z and w, independently of one another, stand for a number from 1 to 4 and
- .beta. 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.ltoreq.a.multidot.x.multidot.y.multidot.z.multidot.w.ltoreq.64
- holds true, is reacted with a complex or complexing agent K' of general formula I'A or I'B ##STR37## wherein R.sup.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, wherein K' stands for a complex when at least two, in the case of divalent metals, or three, in the case of trivalent metals, of substituents R.sup.1' stand for a metal ion equivalent of the above-mentioned elements and K' is otherwise a complexing agent,
- R.sup.2 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.sup.3' stands for a ##STR38## R.sup.4 stands for a straight-chain, branched, saturated or unsaturated C.sub.1 -C.sub.30 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),
- R.sup.5 stands for a hydrogen atom or for R.sup.4,
- U.sup.6 stands for a straight-chain, branched, saturated or unsaturated C.sub.1 -C.sub.20 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, 1-5 nitrogen atom(s) or combinations thereof and optionally substituted by 1-5 hydroxy, 1-2 mercapto, 1-5 oxo, 1-5 thioxo, 1-3 carboxy, 1-5 carboxyalkyl, 1-5 ester, 1-3 amino group(s) or combinations thereof, 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.dbd.C.dbd.O or --N.dbd.C.dbd.S group, and
- C*O stands for an activated carboxyl group, and optionally, other carboxyl groups are present in the form of their salts with inorganic bases, organic bases, amino acids or amino acid amides,
- b) optionally present protective groups are cleaved,
- c) if K' is a complexing agent, it is reacted with at least one metal oxide or metal salt of an element of atomic numbers 20-29, 39, 42, 44, or 57-83 to obtain a cascade polymer complex,
- d) optionally, 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
- e) optionally, still present free terminal amino groups are acylated before or after step c).
- 14. A method for NMR diagnosis which comprises administering to a patient at least one cascade polymer complex according to claim 1 and subjecting the patient to an NMR diagnosis.
- 15. The method of claim 14, wherein the cascade polymer complex is administered in a dose of 0.001-5 mmol/kg of the patient.
- 16. The method of claim 14, wherein the NMR diagnosis is NMR imaging.
- 17. A method for diagnostic radiology which comprises administering to a patient at least one cascade polymer complex according to claim 1 and subjecting the patient to a radiology diagnosis.
- 18. The method of claim 17, wherein the cascade polymer complex is administered in a dose of 0.1-5 mmol/kg of the patient.
- 19. The method of claim 14, wherein the radiology diagnosis is computer tomography imaging.
- 20. A diagnostic method for differentiating between benign and malignant tumors which comprises administering to a patient at least one cascade polymer complex according to claim 1 and subjecting the patient to an NMR or radiology diagnosis which indicates differentiation between benign and malignant tumors.
Priority Claims (1)
Number |
Date |
Country |
Kind |
195 25 924 |
Jul 1995 |
DEX |
|
Parent Case Info
This ia continuation, of application Ser. No. 08/674,844 filed Jul. 3, 1996, now U.S. Pat. No. 5,820,849.
US Referenced Citations (15)
Foreign Referenced Citations (4)
Number |
Date |
Country |
2179624 |
Jun 1995 |
CAX |
2181070 |
Sep 1995 |
CAX |
2187921 |
Nov 1995 |
CAX |
2194560 |
Jan 1996 |
CAX |
Non-Patent Literature Citations (1)
Entry |
"Dendrimer-based Metal Chelates: A New Class of Magnetic Resonance Imaging Contrast Agents," Magnetic Resonance in Medicine 31(1):1-8, Jan. 1, 1994. |
Continuations (1)
|
Number |
Date |
Country |
Parent |
674844 |
Jul 1996 |
|