Cascade polymer bound complexing compounds, their complexes and conjugates, processes for their production, and pharmaceutical agents containing them
First Claim
Patent Images
1. A cascade polymer containing complex-forming ligands, optionally at least five ions of an element of atomic numbers 21-29, 39, 42, 44 or 57-83 complexed therewith, as well as optionally cations of inorganic and/or organic bases, amino acids or amino acid amides, which is of the formula I:
-
whereinA represents a nitrogen-containing cascade nucleus of basis multiplicity b, S represents a reproduction unit, independently for each generation, N represents a nitrogen atom, Z1 and Z2 for the first to penultimate generation, independently each represent,
but for the last generation, Z1 represents a hydrogen atom, a C1-C10-alkyl, C2-C10-acyl or C1-C10-alkylsulfonyl radical optionally containing 1 to 3 carboxy groups, from 1 to 3 sulfonic acid groups, from 1 to 5 hydroxy groups and/or 1 to 3 oxygen atoms, or represents the radical of a complex former or complex K, and Z2 represents, to an extent of 96-100%, the residue of a radical of a complex former or complex K, and, to an extent of 0-4%, V′
where V′
is the residue of a group V defined below with a terminal functional group or, linked via a functional group, a bio- or macro-molecule, b represents a number 1 to 50, and s represents a number 1 to 3, wherein K represents a radical of the formula IB bonded to the terminal nitrogen atoms of the last generation via the group V;
k represents the numbers 1, 2, 3, 4 or 5, l represents the numbers 0, 1, 2, 3, 4 or 5, q represents the numbers 0, 1 or 2, U represents V, X represents the radicals —
COOH, optionally in the form of an ester or an amide thereof, B, D and E which are identical or different represents the group —
(CH2)a wherein a represents the numbers 2, 3, 4 or 5, R1 represents a hydrogen atom, and V represents a straight-chain, branched, saturated or unsaturated C1-C20-alkylene group optionally containing imino, phenylene, phenyleneoxy, phenyleneimino, amide, hydrazide, ureido, thioureido, carbonyl ester groups(s) and oxygen, sulphur and/or nitrogen atom(s), and optionally substituted by hydroxy, mercapto, imino, epoxy, oxo, thioxo and/or by amino group(s), provided that V does not represent —
CH2—
CO—
(NH—
(CH2)2—
(C6H4)0,1—
NH—
CH2—
CO)0,1—
or —
CH2—
CO—
NH—
(CH2)2—
(C6H4)0,1—
NH—
CS—
, where for both the —
CH2—
CO—
side is bonded to the radical of formula IB.
1 Assignment
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Accused Products
Abstract
Cascade polymers, containing complex-forming ligands, optionally at least five ions of an element of atomic numbers 21-29, 39, 42, 44 or 57-83, as well as, if desired, cations of inorganic and/or organic bases, amino acids or amino acid amides, are valuable complexing compounds and complexes for diagnostics and therapy.
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Citations
18 Claims
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1. A cascade polymer containing complex-forming ligands, optionally at least five ions of an element of atomic numbers 21-29, 39, 42, 44 or 57-83 complexed therewith, as well as optionally cations of inorganic and/or organic bases, amino acids or amino acid amides, which is of the formula I:
-
wherein A represents a nitrogen-containing cascade nucleus of basis multiplicity b, S represents a reproduction unit, independently for each generation, N represents a nitrogen atom, Z1 and Z2 for the first to penultimate generation, independently each represent,
but for the last generation,Z1 represents a hydrogen atom, a C1-C10-alkyl, C2-C10-acyl or C1-C10-alkylsulfonyl radical optionally containing 1 to 3 carboxy groups, from 1 to 3 sulfonic acid groups, from 1 to 5 hydroxy groups and/or 1 to 3 oxygen atoms, or represents the radical of a complex former or complex K, and Z2 represents, to an extent of 96-100%, the residue of a radical of a complex former or complex K, and, to an extent of 0-4%, V′
where V′
is the residue of a group V defined below with a terminal functional group or, linked via a functional group, a bio- or macro-molecule,b represents a number 1 to 50, and s represents a number 1 to 3, wherein K represents a radical of the formula IB bonded to the terminal nitrogen atoms of the last generation via the group V;
k represents the numbers 1, 2, 3, 4 or 5, l represents the numbers 0, 1, 2, 3, 4 or 5, q represents the numbers 0, 1 or 2, U represents V, X represents the radicals —
COOH, optionally in the form of an ester or an amide thereof,B, D and E which are identical or different represents the group —
(CH2)a wherein a represents the numbers 2, 3, 4 or 5,R1 represents a hydrogen atom, and V represents a straight-chain, branched, saturated or unsaturated C1-C20-alkylene group optionally containing imino, phenylene, phenyleneoxy, phenyleneimino, amide, hydrazide, ureido, thioureido, carbonyl ester groups(s) and oxygen, sulphur and/or nitrogen atom(s), and optionally substituted by hydroxy, mercapto, imino, epoxy, oxo, thioxo and/or by amino group(s), provided that V does not represent —
CH2—
CO—
(NH—
(CH2)2—
(C6H4)0,1—
NH—
CH2—
CO)0,1—
or —
CH2—
CO—
NH—
(CH2)2—
(C6H4)0,1—
NH—
CS—
, where for both the —
CH2—
CO—
side is bonded to the radical of formula IB.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18)
wherein R2, R3 and R4 mean, in each case independently of one another, a covalent bond or g means the number 2, 3, 4 or 5, t means the number 1, 2, 3, 4, 5, 6, 7 or 8, l means the number 0, 1, 2, 3, 4 or 5, r means the number 0 or 1, n means the number 0, 1, 2, 3 or 4, m means the number 0, 1, 2, 3 or 4, k means the number 1, 2, 3, 4 or 5, a means the number 2, 3, 4 or 5, W means CH, CH2, NH or a nitrogen atom, C1 means C2, C3, C4 and C5 mean, in each case independently, a hydrogen atom or f means the number 1, 2, 3, 4 or 5, j means the number 6, 7 or 8, Y1 and Y2 mean, in each case independently of each other, a hydrogen atom, and Y3 is a nitrogen atom, a and g are as defined above, means a single or double bond, with the proviso that, if Y3 is a nitrogen atom, Y1 and Y2 mean hydrogen. -
3. The cascade polymer of claim 1, wherein the cascade nucleus A is:
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tris(aminoethyl)amine;
tris(aminopropyl)amine;
diethylenetriamine;
triethylenetetramine;
tetraethylenepentamine;
H2N—
CH2—
C6H4—
CH2—
NH—
CH2—
C6H4—
NH2;
1,3,5-tris(aminomethyl)benzene;
2,4,6-tris(aminomethyl)pyridine;
1,4,7-triazacyclononane;
1,4,7,10-tetraazacyclododecane;
1,4,7,10,13-pentaazacyclopentadecane;
1,4,8,11-tetraazacyclotetradecane;
1,4,7,10,13,16,19,22,25,28-decaazacyclotriacontane;
6,6′
,6″
,6′
″
,6″
″
,6′
″
″
-hexaamino-6,6′
,6″
,6′
″
,6″
″
,6′
″
″
-hexadeoxy-α
-cyclodextrin;
6,6′
,6″
,6′
″
,6″
″
,6′
″
″
,6″
″
″
-heptaamino-6,6′
,6″
,6′
″
,6″
″
,6′
″
″
,6″
″
″
-heptadeoxy-β
-cyclodextrin;
6,6′
,6″
,6′
″
,6″
″
,6′
″
″
-hexa-(1-amino-2-hydroxypropyl)-α
-cyclodextrin hexaether;
2,2′
,2″
,2′
″
,2″
″
,2′
″
″
,6,6′
,6″
,6′
″
,6″
″
,6′
″
″
-dodeca-(1-amino-2-hydroxypropyl)-α
-cyclodextrin;
dodecaether.
-
-
4. The cascade polymer of claim 1, wherein at least one reproduction unit S is of one of the following formulae
wherein a is a number 2, 3, 4 or 5, α - and β
in each case mean a hydrogen atom or (CH2)o,γ
means (CH2)f,k is 1, 2, 3, 4 or 5, l is 0, 1, 2, 3, 4 or 5, o is 0, 1, 2, 3, 4 or 5, f means the number 1, 2, 3, 4 or 5, and r means the number 0 or 1, with the proviso that o and 1 are not both zero at the same time.
- and β
-
5. The cascade polymer of claim 1, wherein at least one reproduction unit S is of one of the following formulae
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6. The cascade polymer of claim 1, wherein at least one complex former or complex K is a tetraazacyclododecanetetraacetic acid residue.
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7. The cascade polymer of claim 1, wherein the polymer is complexed with at least 5 ions of the elements of atomic numbers 21-29, 42, 44 and 58-70.
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8. The cascade polymer of claim 1, wherein at least one group V is of one of the following formulae, where the left side of the formula is attached to the radical of the formula IB:
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—
CH2—
CH(OH)—
CH2—
O—
CH2CH2—
;
—
CH2—
CH(OH)—
CH2—
;
—
CH2—
CH(OH)—
CH2—
OCH2—
C6H4—
NH—
CO—
CH2—
;
—
CH2—
CH(OH)—
CH2—
OCH2—
C6H4—
NH—
CO—
CH2—
S—
(CH2)4—
S—
;
wherein R+ and Ry stand for natural amino acid residues;
—
CH2—
CH(OH)—
CH2—
O—
(CH2)2—
NHCS—
;
—
CH2—
CH(OH)—
CH2—
NHCS—
;
—
CH2—
CH(OH)—
CH2—
O—
(CH2)2—
O—
(CH2)2NHCS—
;
—
CH2—
CH(OH)—
CH2—
O—
(CH2)2—
NH—
CO—
CH2—
;
—
CH2—
CH(OH)—
CH2—
O—
C6H4—
NHCS—
;
—
CH2—
CH(OH)—
CH2—
O—
C6H4—
NHCO—
;
—
CH2—
CH(OH)—
CH2—
O—
CH2—
C6H4—
NHCS—
;
—
CH2—
O—
C6H4—
CH2;
—
CH2—
CH(OH)—
CH2—
O—
C6H4CH2—
;
—
C(═
NH)—
O—
C6H4—
CH2—
;
—
(CH2)4—
NH—
CO—
CH2—
O—
C6H4—
CH2—
;
—
(CH2)4—
NH—
CH2—
CH(OH)—
CH2—
O—
C6H4—
CH2—
;
—
(CH2)3—
O—
C6H4—
CH2—
;
—
CH2—
CO—
NH—
(CH2)3—
O—
CH2—
;
—
CH2—
CO—
NH—
NH—
;
—
CH2—
CONH—
(CH2)2—
;
—
CH2—
CO—
NH—
(CH2)10—
;
—
CH2—
CONH—
(CH2)2—
S—
;
—
(CH2)4—
NH—
CO—
(CH2)8—
;
—
CH2—
CO—
NH—
(CH2)3—
NH—
;
—
(CH2)3—
NH—
groups.
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9. A method for NMR or x-ray imaging a patient which comprises administering to the patient a solution comprising a cascade polymer of claim 1, which is complexed with at least five ions of an element of atomic numbers 21-29, 39, 42, 44 or 57-83, and conducting NMR or x-ray imaging.
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10. The method of claim 9, wherein the cascade nucleus A is nitrogen atom,
wherein R2, R3 and R4 mean, in each case independently of one another, a covalent bond or g means the number 2, 3, 4 or 5, t means the number 1, 2, 3, 4, 5, 6, 7 or 8, l means the number 0, 1, 2, 3, 4 or 5, r means the number 0 or 1, n means the number 0, 1, 2, 3 or 4, m means the number 0, 1, 2, 3 or 4, k means the number 1, 2, 3, 4 or 5, a means the number 2, 3, 4 or 5, W means CH, CH2, NH or a nitrogen atom, C1 means C2, C3, C4 and C5 mean, in each case independently, a hydrogen atom or f means the number 1, 2, 3, 4 or 5, j means the number 6, 7 or 8, Y1 and Y2 mean, in each case independently of each other, a hydrogen atom, and Y3 is a nitrogen atom, a and g are as defined above, means a single or double bond, with the proviso that, if Y3 is a nitrogen atom, Y1 and Y2 mean hydrogen. -
11. The method of claim 9, wherein the cascade nucleus A is
tris(aminoethyl)amine; -
tris(aminopropyl)amine;
diethylenetriamine;
triethylenetetramine;
tetraethylenepentamine;
H2N—
CH2—
C6H4—
CH2—
NH—
CH2—
C6H4—
NH2;
1,3,5-tris(aminomethyl)benzene;
2,4,6-tris(aminomethyl)pyridine;
1,4,7-triazacyclononane;
1,4,7,10-tetraazacyclododecane;
1,4,7,10,13-pentaazacyclopentadecane;
1,4,8,11-tetraazacyclotetradecanei 1,4,7,10,13,16,19,22,25,28-decaazacyclotriacontane;
6,6′
,6″
,6′
″
,6″
″
,6′
″
″
-hexaamino-6,6′
,6″
,6′
″
-6″
″
,6′
″
″
-hexadeoxy-α
-cyclodextrin;
6,6′
,6″
,6′
″
,6″
″
,6′
″
″
,6″
″
″
-heptaamino-6,6′
,6″
,6′
″
,6″
″
,6′
″
″
,6″
″
″
-heptadeoxy-β
-cyclodextrin;
6,6′
,6″
,6′
″
,6″
″
,6′
″
″
-hexa-(1-amino-2-hydroxypropyl)-α
-cyclodextrin hexaether;
2,2′
,2″
,2′
″
,2″
″
,2′
″
″
,6,6′
,6″
,6′
″
,6″
″
,6′
″
″
-dodeca-(1-amino-2-hydroxypropyl)-α
-cyclodextrin;
dodecaether.
-
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12. The method of claim 9, wherein at least one reproduction unit S is of one of the following formulae
wherein a is a number 2, 3, 4 or 5, α - and β
in each case mean a hydrogen atom or (CH2)o,γ
means (CH2)f,k is 1, 2, 3, 4 or 5, l is 0, 1, 2, 3, 4 or 5, o is 0, 1, 2, 3, 4 or 5, f means the number 1, 2, 3, 4 or 5, and r means the number 0 or 1, with the proviso that o and 1 are not both zero at the same time.
- and β
-
13. The method of claim 9, wherein at least one reproduction unit S is of one of the following formulae
— - (CH2)2—
CONH—
(CH2)2—
;
—
CH2—
CH(OH)—
CH2—
;
—
CH2—
2—
CH(OH)—
CH2—
O—
(CH2)2—
;
- (CH2)2—
-
14. The method of claim 9, wherein at least one complex former or complex K is a tetraazacyclododecanetetraacetic acid residue.
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15. The method of claim 9, wherein the polymer is complexed with at least 5 ions of the elements of atomic numbers 21-29, 42, 44 and 58-70 and the method is for NMR imaging.
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16. The method of claim 9, wherein at least one group V is of one of the following formulae, where the left side of the formula is attached to the radical of the formula IB:
-
—
CH2—
CH(OH)—
CH2—
O—
CH2CH2—
;
—
CH2—
CH(OH)—
CH2—
;
—
CH2—
CH(OH)—
CH2—
OCH2—
C6H4—
H—
CO—
CH2—
;
—
CH2—
CH(OH)—
CH2—
OCH2—
C6H4—
NH—
CO—
CH2—
S—
(CH2)4—
S—
;
wherein R+ and Ry stand for natural amino acid residues;
—
CH2—
CH(OH)—
CH2—
O—
(CH2)2—
NHCS—
;
—
CH2—
CH(OH)—
CH2—
NHCS—
;
—
CH2—
CH(OH)—
CH2—
O—
(CH2)2—
O—
(CH2)2NHCS—
;
—
CH2—
CH(OH)—
CH2—
O—
(CH2)2—
NH—
CO—
CH2—
;
—
CH2—
CH(OH)—
CH2—
O—
C6H4—
NHCS—
;
—
CH2—
CH(OH)—
CH2—
O—
C6H4—
NHCO—
;
—
CH2—
CH(OH)—
CH2—
O—
CH2—
C6H4—
NHCS—
;
—
CH2—
O—
C6H4—
CH2—
;
—
CH2—
CH(OH)—
CH2—
O—
C6H4—
CH2—
;
—
C(═
NH)—
O—
C6H4—
CH2—
;
—
(CH2)4—
NH—
CO—
CH2—
O—
C6H4—
CH2—
;
—
(CH2)4—
NH—
CH2—
CH(OH)—
CH2—
O—
C6H4—
CH2—
;
—
(CH2)3—
O—
C6H4—
CH2—
;
—
CH2—
CO—
NH—
(CH2)3—
O—
CH2—
;
—
CH2—
CO—
NH—
NH—
;
—
CH2—
CONH—
(CH2)2—
;
—
CH2—
CO—
NH—
(CH2)10—
;
—
CH2—
CONH—
(CH2)2—
S—
;
—
(CH2)4—
NH—
CO—
(CH2)8—
;
—
CH2—
CO—
NH—
(CH2)3—
NH—
;
—
(CH2)3—
NH—
groups.
-
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17. The method of claim 9, wherein the complexed cascade polymer is administered in a does of 0.0001-5 mmol/kg weight of the patient.
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18. The method of claim 15, wherein the complexed cascade polymer is administered in a does of 0.0001-5 mmol/kg weight of the patient.
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Specification