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US 5,859,214 AGranted
DTPA monoamides, pharmaceutical agents containing these compounds, their use and process for their production
AssigneeSchering Aktiengesellshaft
InventorsHeinz Gries, Erich Klieger, Bernd Raduchel, Heribert Schmitt-Willich, Hanns-Joachim Weinmann, Hubert Vogler, Gabriele Schuhmann-Giampieri, Jurgen Conrad
Life of this patent
Estimating the term…
Abstract
Compounds of general formula I ##STR1## wherein Z.sup.1, Z.sup.2, X, R.sup.2 and R.sup.3 are as herein defined, are valuable pharmaceutical agents. In particular, the compounds are useful as contrast agents in NMR diagnosis.
Claims23
A compound of general formula I ##STR6## in which Z.sup.1 and Z.sup.2 are each, independently, H or --(CH.sub.2).sub.m --(C.sub.6 H.sub.4).sub.q --(O).sub.k --(CH.sub.2).sub.n --(C.sub.6 H.sub.4).sub.l --(O).sub.r --R;
- m and n are each, independently, 0-20;
- k, l, q and r are each, independently, 0 or 1;
- R is H, C.sub.1 -C.sub.6 -alkyl, OR.sup.1 -substituted C.sub. -C.sub.6 alkyl or CH.sub.2 COOR.sup.1 ;
- R.sup.1 is H, C.sub.1 -C.sub.6 alkyl or benzyl;
- R.sup.2 is a saturated, unsaturated, straight-chain or branched-chain or cyclic non-aromatic hydrocarbyl group with up to 20 C-atoms which is substituted by a carboxyl group, a sulfone group, a carboxyl group esterified with C.sub.1 -C.sub.6 alkyl or benzyl, or a sulfone group esterified witb C.sub.1 -C.sub.6 alkyl or benzyl,
- an aryl group of up to 10 C-atoms which is substituted by a carboxyl group, a sulfone group, a carboxyl group esterified with C.sub.1 -C.sub.6 alkyl or benzyl, or a sulfone group esterified with C.sub.1 -C.sub.6 alkyl or benzyl or
- an aralkyl group of up to 16 C-atoms which is substituted by a carboxyl group, a sulfone group, a carboxyl group esterified with C.sub.1 -C.sub.6 alkyl or benzyl, or a sulfone group esterified with C.sub.1 -C.sub.6 alkyl or benzyl;
- R.sup.3 is H or a saturated, unsaturated, straight-chain or branched-chain or cyclic non-aromatic hydrocarbyl group with up to 20 C-atoms which is optionally substituted by a carboxyl group, a sulfone group, a carboxyl group esterified with C.sub.1 -C.sub.6 alkyl or benzyl, or a sulfone group esterified with a C.sub.1 -C.sub.6 alkyl or benzyl,
- an aryl group of up to 10 C-atoms which is optionally substituted by a carboxyl group, a sulfone group, a carboxyl group esterified with C.sub.1 -C.sub.6 alkyl or benzyl, or a sulfone group esterified with a C.sub.1 -C.sub.6 alkyl or benzyl or
- an aralkyl group of up to 16 C-atoms which is optionally substituted by a carboxyl group, a sulfone group, a carboxyl group esterified with C.sub.1 -C.sub.6 alkyl or benzyl, or a sulfone group esterified with a C.sub.1 -C.sub.6 alkyl or benzyl;
- X in each case is H or a metal ion equivalent of an element of atomic numbers 21-29, 31, 32, 37-40, 42-44, 49 or 57-83;
- wherein acid groups are, in each case, optionally present as an ester with C.sub.1 -C.sub.6 alkyl, benzyl or 4-methoxybenzyl, or as an amide wherein the nitrogen atom of said amide is substituted by at least one saturated or unsaturated straight-chain, branched-chain or cyclic hydrocarbon radical with up to 5 C atoms, wherein said at least one hydrocarbon radical is optionally substituted by 1-3 hydroxy groups and/or 1-3 C.sub.1 -C.sub.4 alkoxy groups, or said amide is in the form of a 5- or 6-membered heterocyclic ring with inclusion of the amide nitrogen atom;
- or
- a salt thereof with an inorganic and/or organic base, an amino acid or an amino acid amide,
- provided that
- at least one of substituents Z.sup.1 and Z.sup.2 is H, and
- if n and l are each 0, then k and r are not both 1.
14 more elements
Process for the production of compounds of general formula I ##STR7## in which Z.sup.1 and Z.sup.2 each stand for a hydrogen atom or the radical
- --(CH.sub.2).sub.m --(C.sub.6 H.sub.4).sub.q --(O).sub.k --(CH.sub.2).sub.l --(CH.sub.6 H.sub.4).sub.l --(O).sub.r --R,
- in which
- m and n independently mean numbers 0-20,
- k, l, q and r independently mean numbers 0 and 1 and
- R means a hydrogen atom, an optionally OR.sup.1 -- substituted C.sub.1 -C.sub.6 alkyl radical or a CH.sub.2 COOR.sup.1 group with R.sup.1 meaning a hydrogen atom, a C.sub.1 -C.sub.6 alkyl radical or a benzyl group,
- R.sup.2 stands for a saturated, unsaturated, straight-chain or branched-chain or cyclic non-aromatic hydrocarbyl group with up to 20 C-atoms, an aryl group of up to 10 C-atoms or aralkyl group of up to 16 C-atoms, all substituted by a carboxyl group or a sulfone group,
- R.sup.3 stands for a hydrogen atom or for a saturated, unsaturated, straight-chain or branched-chain or cyclic non-aromatic hydrocarbyl group with up to 20 C-atoms, an aryl group of up to 10 C-atoms or aralkyl group of up to 16 C-atoms, in each case being optionally substituted by a carboxyl group or a sulfone group,
- X stands for a hydrogen atom and/or a metal ion equivalent of an element of atomic numbers 21-29, 31, 32, 37-40, 42-44, 49 or 57-83, provided that at least one of substituents Z.sup.1 and Z.sup.2 stands for a hydrogen atom, that--if n and l each stand for the number 0--k and r are not the number 1 at the same time and that the radical of the acid groups is optionally present as an ester or amide as well as their salts with inorganic and/or organic bases, amino acids or amino acid amides,
- wherein, compounds of general formulas II and III ##STR8## in which Z.sup.1 and Z.sup.2 have the above-indicated meanings,
- R.sup.4 stands for the radical of an activated carbonyl group or for OR.sup.5 and
- R.sup.5 represents a hydrogen atom or a C.sub.1 -C.sub.6 alkyl radical, with amino acids of general formula IV ##STR9## in which R.sup.2 and R.sup.3 have the above-mentioned meanings, are reacted, the thus obtained complexing agent acids of general formula I with X meaning a hydrogen atom with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 31, 32, 37-40, 42-44, 49 or 57-83 are reacted and then, if desired, still present acidic hydrogen atoms are substituted by cations of inorganic and/or organic bases, amino acids or amino acid amides or the corresponding acid groups are completely or partially converted to esters or amides.
8 more elements
A gadolinium complex of 6,9-bis(carboxymethyl)-4-(4-ethoxybenzyl)-3-(10-carboxydecylcarbamoylmethy l)-3,6,9-triazaundecanedioic acid or a salt thereof with inorganic base, organic base, an amino acid or an, amino acid amide.
Dependencies are inferred from the claim text.