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US 5,334,371 AGranted
Marcocyclic polyaza bicyclo compounds containing 5 or 6 membered rings, and method for MRI
AssigneeSchering Corporation
InventorsHeinz Gries, Bernd Raduchel, Johannes Platzek, Hanns-Joachim Weinmann, Wolf-Rudiger Press, Ulrich Speck
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Abstract
The macrocyclic compounds of the following formula I and IV, defined herein and their salts with inorganic and/or organic bases, amino acids or amino acid amides are valuable diagnostic and therapeutic agents.
Claims49
In a method of NMR diagnostics wherein a patient is subjected to NMR imaging, the improvement comprising administering to said patient an effective amount of a compound of general formula I ##STR28## wherein represents a single bond or double bond;
- q is 1 or 2;
- A and B, being the same or different are each straight-chain or branched C.sub.2-6 alkylene;
- D is N, .dbd.C.dbd.O, --NR.sup.2 --, --CHR.sup.3 --, or .dbd.CR.sup.3 --;
- E is N, S, O, ##STR29## F is (--CHR.sup.8 --).sub.n or (.dbd.CR.sup.8 --).sub.n ;
- Z is an H atom or --CH.sub.2 COOY;
- Y, in each case, is a hydrogen atom or a metal ion equivalent of an element with atomic numbers 21-29, 31, 32, 37-39, 42-44, 49 or 57-83;
- R.sup.1 is an H atom, a halogen atom, or a C.sub.1 -C.sub.6 alkyl group;
- R.sup.2 is H or C.sub.1 -C.sub.6 alkyl;
- R.sup.3 is H, a halogen atom, phenyl, or a C.sub.1 -C.sub.6 alkyl group optionally substituted by one or more phenyl and/or hydroxy group(s), OR.sup.5, ##STR30## R.sup.4 is a hydroxy group, H, C.sub.1-6 -alkyl, or a C.sub.1 -C.sub.6 alkyl group which is optionally hydroxylated or carboxylated;
- R.sup.5 is C.sub.1 -C.sub.6 alkyl optionally substituted by 1 to 3 hydroxy groups;
- R.sup.6 and R.sup.7, independently from one another, are each H, C.sub.1-6 -alkyl optionally substituted by 1 to 3 hydroxy groups, phenyl optionally substituted by 1 to 3 hydroxy groups or benzyl optionally substituted by 1 to 3 hydroxy group, or R.sup.6 and R.sup.7 together with the nitrogen atom form a saturated or unsaturated 5 or 6 membered ring optionally containing an additional N atom, O atom, S atom or a carbonyl group, said 5 or 6 membered ring being optionally substituted by 1 to 3 C.sub.1-6 -alkyl groups optionally substituted by 1 to 3 hydroxy groups, or one of the substituents R.sup.6 or R.sup.7 is ##STR31## R.sup.8 is an H atom, a halogen atom, or a C.sub.1-6 -alkyl group or G;
- m is 0 or 1;
- n is 0 or 1;
- G is a second macrocycle of general formula II bonded by a direct bond, a bis(carbonylamino) group or by a C.sub.1 -C.sub.20 alkylene group optionally having carbonyl groups, carbonylamino groups, or O atoms on the ends thereof and optionally contains one or more oxygen atom(s), Z--, C.sub.1-10 -acyl groups, C.sub.1-10 -hydroxyacyl substituted imino groups, one to two C--C double bonds and/or one to two C--C triple bonds ##STR32## D.sup.1 has the same meaning as D, with the exception that D.sup.1 does not contain the substituent G, or D.sup.1 is ##STR33## and F.sup.1 has the same meaning as F, with the exception that F.sup.1 does not contain the substituent G, or F.sup.1 is ##STR34## as well as the salts thereof formed with inorganic and/or organic bases, amino acids or amino acid amides;
- wherein at least two of the groups Z are each --CH.sub.2 COOY in which the substituents Y are metal ion equivalents of at least one element with atomic numbers 21-29, 42, 44 or 58-70;
- with the proviso that the macrocyclic compound of general formula I contains not more than one radical G.
13 more elements
In a method of NMR diagnostics comprising subjecting a patient to NMR imaging, the improvement wherein said patient is administered an effective amount of a physiologically compatible macrocyclic compound of Formula IV ##STR38## wherein is a single or double bond;
- Q is a N atom or NH;
- X.sup.1 is H, --(CH.sub.2).sub.n --R.sup.1 or ##STR39## n is 1, 2, 3, 4, or 5;
- m is 0, 1 or 2;
- R.sup.1 is H or OH;
- X.sup.2 is H, --(CH.sub.2).sub.n --R.sup.1, ##STR40## --(CH.sub.2).sub.n --(O).sub.l --(CH.sub.2).sub.k --(C.sub.6 H.sub.4).sub.q --R.sup.2 ;
- k is 0, 1, 2, 3 or 4;
- l and q are each independently 0 or 1;
- R.sup.2 is H, C.sub.1 -C.sub.4 -alkoxy, a functional group capable of binding to a bio- or macromolecule, or a bio- or macromolecule bound via a functional group;
- A.sup.1, A.sup.2, B.sup.1, B.sup.2, C.sup.1, C.sup.2, D.sup.1, D.sup.2, E.sup.1, E.sup.2, F.sup.1 and F.sup.2 are each independently H, --(CH.sub.2).sub.n --R.sup.1, ##STR41## --(CH.sub.2).sub.n --(O).sub.l --(CH.sub.2).sub.k --(C.sub.6 H.sub.4).sub.q --R.sup.2 ;
- G is H, C.sub.1 -C.sub.4 -alkoxy, a functional group capable of binding to a bio- or macromolecule, or a bio- or macromolecule bound via a functional group, or a second macrocycle, bound via K, of general formula V ##STR42## K is a direct bond, a bis(carbonylamino) group, or a C.sub.1 -C.sub.14 -alkylene group which optionally carries at the ends thereof carbonyl groups, carbonylamino groups or oxygen atoms, and which optionally contains one or several oxygen atom(s), hydroxymethylene, CH(X.sup.2)COOZ-substituted imino, acyl-substituted imino, and/or hydroxy-acyl-substituted imino groups, and/or one to two C--C-double and/or C--C-triple bonds;
- and
- Z in each case is H or a metal ion equivalent of an element of atomic number 21-29, 31, 32, 37-39, 42-44, 49 or 57-83;
- wherein any or all remaining CO.sub.2 H groups can each optionally be present as an ester or amide;
- wherein at least two of the Z groups are metal ion equivalents of at least one element of atomic numbers 21-29, 42, 44 or 58-70;
- and
- physiologically acceptable salts thereof with inorganic and/or organic bases, amino acids or amino acid amides;
- with the provisos that:
- (a) at least 8 of the 12 ring substituents A.sup.1 through F.sup.2 each stand for a hydrogen atom,
- (b) X.sup.1 and X.sup.2 stand simultaneously for hydrogen only if at least one of the ring substituents A.sup.1 through F.sup.2 is not H, and
- (c) the macrocycle of general Formula IV contains no more than one bio- or macromolecule.
17 more elements
Dependencies are inferred from the claim text.