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EP-4741400-A1 - MULTIMERIC MANGANESE CONTRAST AGENTS

EP4741400A1EP 4741400 A1EP4741400 A1EP 4741400A1EP-4741400-A1

Abstract

The present disclosure relates to new manganese (Mn 2+ ) chelate compounds, to methods of preparing said compounds, to the use of said compounds as contrast agents in diagnostic imaging such as magnetic resonance imaging (MRI) and to their use in a mammalian body.

Inventors

  • The designation of the inventor has not yet been filed

Assignees

  • Bayer Aktiengesellschaft

Dates

Publication Date
20260513
Application Date
20241112

Claims (13)

  1. A compound of general formula (I), wherein represents a group selected from in which * represents the point of attachment to R 1 and p is an integer selected from 1 and 2, R 1 represents a group selected from in which * represents the point of attachment to A, R 2 and R 2' are each independently selected from a hydrogen atom and a methyl group; R 3 and R 3' are each independently selected from a hydrogen atom, a C 1 -C 3 alkyl group and a -(CH 2 ) m -(C=O)(NH)-(CH 2 )-(CH(OH)) n -CH 2 OH group, wherein m is an integer of from 1 to 3 and n is an integer of from 0 to 5; R 4 , R 4' , R 5 and R 5' are each independently selected from a hydrogen atom and a C 1 -C 3 alkyl group; and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
  2. The compound of formula (I) according to claim 1, wherein R 3 and R 3' are each independently selected from a hydrogen atom and a C 1 -C 3 alkyl group and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
  3. The compound of formula (I) according to any of claims 1 or 2, wherein at least one, preferably wherein at least two of R 3 , R 3' , R 4 , R 4' , R 5 and R 5' are not a hydrogen atom and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
  4. The compound of formula (I) according to any of claims 1 or 2, wherein at least one, preferably wherein at least two of R 3 , R 3' , R 4 , R 4' , R 5 and R 5' are a C 1 -C 3 alkyl group and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
  5. The compound of formula (I) according to any of claims 1 or 2 wherein at least one, preferably wherein at least two of R 3 , R 3' , R 4 , R 4' , R 5 and R 5' are each independently selected from a methyl group and an ethyl group and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
  6. The compound of formula (I) according to any of claims 1 to 5, wherein represents a group selected from and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
  7. The compound of formula (I) according to any of claims 1 to 6 selected from the group consisting of 2,2',2",2"'-{[2,2-bis({[3,9-bis(carboxymethyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13-carbonyl]amino}methyl)propane-1,3-diyl]bis[carbamoyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13,3,9-triyl]}tetraacetic acid, 2,2',2",2‴-({2,2-bis[(2-{[3,9-bis(carboxymethyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13-carbonyl]amino}acetamido)methyl]propane-1,3-diyl}bis[azanediyl(2-oxoethane-2,1-diyl)carbamoyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13,3,9-triyl])tetraacetic acid, (2R,2'S,2"R,2‴S)-2,2',2",2‴-{(2,2-bis[({3-[(1 R )-1-carboxyethyl]-9-[(1S)1-carboxyethyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13-carbonyl}amino)methyl]propane-1,3-diyl)bis[carbamoyl-6-oxa-3,9,15-triazabicyclo [9.3.1]pentadeca-1(15),11,13-triene-13,3,9-triyl]}tetrapropanoic acid, 2,2',2",2‴-{[2,2-bis({[3,9-bis(1-carboxyethyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13-carbonyl]amino}methyl) propane-1,3-diyl]bis[carbamoyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13,3,9-triyl]}tetrapropanoic acid, (2 R ,2' S ,2" R ,2‴ S )-2,2',2",2‴-{(2,2-bis{[2-({3-[(1 R )-1-carboxyethyl]-9-[(1 S )-1-carboxyethyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13-carbonyl}amino)acetamido] methyl}propane-1,3-diyl)bis[azanediyl(2-oxoethane-2,1-diyl)carbamoyl{6-oxa-3,9,15-triazabicyclo[9.3.1] pentadeca-1(15),11,13-triene-13,3,9-triyl}]}tetrapropanoic acid, 2,2',2",2‴-{[2,2-bis({[3,9-bis(carboxymethyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-12-carbonyl]amino}methyl)propane-1,3-diyl]bis[carbamoyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15), 11, 13-triene-12,3,9-triyl]}tetraacetic acid, 2,2',2",2‴-({2,2-bis[(2-{[3,9-bis(carboxymethyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1 (15), 11, 13-triene-12-carbonyl]amino}acetamido) methyl]propane-1,3-diyl}bis[azanediyl(2-oxoethane-2, 1-diyl)carbamoyl-6-oxa-3,9, 15-triazabicyclo[9.3.1]pentadeca-1 (15), 11, 13-triene-12,3,9-triyl])tetraacetic acid, 2,2',2",2‴-{[2,2-bis({2-[3,9-bis(carboxymethyl)-6-oxa-3,9,15-triazabicyclo[9.3.1] pentadeca-1 (15),11,13-trien-13-yl]acetamido}methyl)propane-1,3-diyl]bis[azanediyl(2-oxoethane-2,1-diyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1 (15),11,13-triene-13,3,9-triyl]}tetraacetic acid, (2 R ,2' S ,2" R ,2‴ S )-2,2',2",2"'-({2,2-bis[(2-{3-[(1 R )-1-carboxyethyl]-9-[(1 S )-1-carboxyethyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-trien-13-yl}acetamido)methyl]propane-1,3-diyl}bis[azanediyl(2-oxoethane-2,1-diyl){6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13,3,9-triyl}])tetrapropanoic acid, (2 R *,2' S *,2" RS ,2‴ SR )-2,2',2",2‴-{(2,2-bis{[({3-[(1 RS )-1-carboxyethyl]-9-[(1 SR )-1-carboxy ethyl]-6-oxa-3,9,15-triazabicyclo[9.3.1] pentadeca-1(15),11,13-trien-12-yl} carbonyl)amino] methyl}propane-1,3-diyl)bis[carbamoyl-6-oxa-3,9,15-triazabicyclo[9.3.1] pentadeca-1(15),11, 13-triene-12,3,9-triyl]}tetrapropanoic acid, (2 R *,2' R *,2" RS ,2‴ RS )-2,2',2",2‴-({2,2-bis[({3,9-bis[(1 RS )-1-carboxyethyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-12-carbonyl}amino)methyl]propane-1,3-diyl}bis[carbamoyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-12,3,9-triyl]) tetrapropanoic acid, 2,2',2",2‴-{[2,2-bis({3-[3,9-bis(1-carboxyethyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15), 11,13-trien-13-yl]propanamido}methyl)propane-1,3-diyl]bis[azanediyl(3-oxopropane-3,1-diyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13,3,9-triyl]}tetra propanoic acid, 2,2',2",2‴-([2,2-bis({[3,9-bis(carboxymethyl)-4-methyl-6-oxa-3,9,15-triazabicyclo[9.3.1]penta deca-1(15), 11,13-triene-13-carbonyl]amino}methyl)propane-1,3-diyl]bis{carbamoyl[4-methyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13,3,9-triyl]})tetraacetic acid, 2,2',2",2‴-([2,2-bis({[3,9-bis(carboxymethyl)-4-ethyl-6-oxa-3,9,15-triazabicyclo[9.3.1]penta deca-1(15),11,13-triene-13-carbonyl]amino}methyl) propane-1,3-diyl] bis{carbamoyl[4-ethyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13,3,9-triyl]})tetraacetic acid, 2,2',2",2‴-{[2,2-bis({[3,9-bis(carboxymethyl)-5-methyl-6-oxa-3,9,15-triazabicyclo[9.3.1]penta deca-1(15), 11,13-triene-13-carbonyl]amino}methyl)propane-1,3-diyl]bis[carbamoyl(5-methyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13,3, 9-triyl)]}tetraacetic acid, (2 R ,2' S ,2" R ,2‴ S )-2,2',2",2"'-{(2,2-bis[({3-[(1 R )1-carboxypropyl]-9-[(1 S )-1-carboxypropyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13-carbonyl}amino)methyl] propane-1,3-diyl)bis[carbamoyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13,3,9-triyl]}tetrabutanoic acid, (2 R *,2' S *,2" RS ,2‴ SR )-2,2',2",2‴-{(2,2-bis{[({3-[(1 RS )-1-carboxypropyl]-9-[(1 SR )-1-carboxy propyl]-6-oxa-3,9,15-triazabicyclo[9.3.1] pentadeca-1(15),11, 13-trien-13-yl}carbonyl)amino] methyl}propane-1,3-diyl)bis [carbamoyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11, 13-triene-13,3,9-triyl]}tetrabutanoic acid, 2,2'-({2,2-bis({[3-(1-carboxyethyl)-9-(carboxymethyl)-6-oxa-3,9, 15-triazabicyclo [9.3.1] pentadeca-1(15),11,13-triene-13-carbonyl]amino}methyl)propane-1,3-diyl}bis {carbamoyl[9-(carboxymethyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13,3-diyl]}) dipropanoic acid, 2,2',2",2‴-{[2,2-bis({[3,9-bis(carboxymethyl)-8-methyl-6-oxa-3,9,15-triazabicyclo[9.3.1] pentadeca-1(15), 11,13-triene-12-carbonyl]amino}methyl)propane-1,3-diyl]bis[carbamoyl(8-methyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-12,3,9-triyl)]} tetraacetic acid, (2 S ,2' S ,2" S ,2‴ S )-2,2',2",2‴-{(2,2-bis[({3,9-bis[(1 S )-1-carboxyethyl]-6-oxa-3,9,15-triazabicyclo [9.3.1]pentadeca-1(15),11,13-triene-13-carbonyl}amino)methyl]propane-1,3-diyl)bis [carbamoyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13,3,9-triyl]} tetrapropano and (2 R ,2' R ,2" R ,2‴ S )-2,2',2",2‴-{(2,2-bis[({3,9-bis[(1 R )-1-carboxyethyl]-6-oxa-3,9,15-triaza bicyclo[9.3.1]pentadeca-1(15), 11,13-triene-13-carbonyl}amino)methyl]propane-1,3-diyl)bis [carbamoyl-6-oxa-3,9,15-triazabicyclo[9.3.1] pentadeca-1(15),11,13-triene-13,3,9-triyl]} tetrapropanoic acid and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
  8. The compound of formula (I) according to any of claims 1 to 7 in the form of a complex with Mn 2+ and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
  9. The compound of formula (I) according to claim 8 selected from the group consisting of: tetramanganese(2+) 2,2',2",2‴-{[2,2-bis({[3,9-bis(carboxylatomethyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13-carbonyl]amino}methyl)propane-1,3-diyl]bis[carbamoyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13,3,9-triyl]}tetraacetate, tetramanganese(2+) 2,2',2",2‴-({2,2-bis[(2-{[3,9-bis(carboxylatomethyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13-carbonyl]amino}acetamido)methyl] propane-1,3-diyl}bis[azanediyl(2-oxoethane-2,1-diyl)carbamoyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13,3,9-triyl])tetraacetate, tetramanganese(2+) (2 R ,2' S ,2" R ,2‴ S )-2,2',2",2‴-{(2,2-bis[({3-[(1 R )-1-carboxylatoethyl]-9-[(1 S )1-carboxylatoethyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13-carbonyl}amino)methyl] propane-1,3-diyl)bis[carbamoyl-6-oxa-3,9,15-triazabicyclo [9.3.1]pentadeca-1(15),11,13-triene-13,3,9-triyl]}tetrapropanoate, tetramanganese(2+) 2,2',2",2‴-{[2,2-bis({[3,9-bis(1-carboxylatoethyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13-carbonyl]amino}methyl) propane-1,3-diyl]bis[carbamoyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13,3,9-triyl]}tetrapropanoate, tetramanganese(2+) (2 R ,2' S ,2" R ,2‴ S )-2,2',2",2‴-{(2,2-bis{[2-({3-[(1 R )-1-carboxylato ethyl]-9-[(1 S )-1-carboxylatoethyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15), 11,13-triene-13-carbonyl}amino)acetamido]methyl}propane-1,3-diyl)bis[azanediyl(2-oxoethane-2,1-diyl)carbamoyl{6-oxa-3,9,15-triazabicyclo[9.3.1] pentadeca-1(15),11,13-triene-13,3,9-triyl}]}tetrapropanoate, tetramanganese(2+) 2,2',2",2‴-{[2,2-bis({[3,9-bis(carboxylatomethyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-12-carbonyl]amino}methyl)propane-1,3-diyl]bis[carbamoyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-12,3,9-triyl]}tetraacetate, tetramanganese(2+) 2,2',2",2‴-({2,2-bis[(2-{[3,9-bis(carboxylatomethyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-12-carbonyl]amino}acetamido) methyl]propane-1,3-diyl}bis[azanediyl(2-oxoethane-2,1-diyl)carbamoyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-12,3,9-triyl])tetraacetate, tetramanganese(2+) 2,2',2",2‴-{[2,2-bis({2-[3,9-bis(carboxylatomethyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1 (15),11,13-trien-13-yl]acetamido}methyl)propane-1,3-diyl]bis[azanediyl(2-oxoethane-2,1-diyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13,3,9-triyl]}tetraacetate, tetramanganese(2+) (2 R ,2' S ,2" R ,2‴ S )-2,2',2",2‴-({2,2-bis[(2-{3-[(1 R )-1-carboxylatoethyl]-9-[(1 S )-1-carboxylatoethyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-trien-13-yl}acetamido)methyl]propane-1,3-diyl}bis[azanediyl(2-oxoethane-2,1-diyl){6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13,3,9-triyl}])tetrapropanoate, tetramanganese(2+) (2 R *,2' S *,2" RS ,2‴ SR )-2,2',2",2‴-{(2,2-bis{[({3-[(1 RS )-1-carboxylato ethyl]-9-[(1SR)-1-carboxylatoethyl]-6-oxa-3,9,15-triazabicyclo[9.3.1] pentadeca-1(15),11,13-trien-12-yl}carbonyl)amino]methyl}propane-1,3-diyl)bis[carbamoyl-6-oxa-3,9,15-triazabicyclo [9.3.1]pentadeca-1(15),11,13-triene-12,3,9-triyl]}tetrapropanoate, tetramanganese(2+) (2 R *,2' R *,2" RS ,2‴ RS )-2,2',2",2‴-({2,2-bis[({3,9-bis[(1 RS )-1-carboxylato ethyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-12-carbonyl}amino) methyl]propane-1,3-diyl}bis[carbamoyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11, 13-triene-12,3,9-triyl])tetrapropanoate, tetramanganese(2+) 2,2',2",2‴-{[2,2-bis({3-[3,9-bis(1-carboxylatoethyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-trien-13-yl]propanamido}methyl)propane-1,3-diyl] bis[azanediyl(3-oxopropane-3,1-diyl)-6-oxa-3,9,15-triazabicyclo[9.3.1] pentadeca-1(15),11, 13-triene-13,3,9-triyl]}tetrapropanoate, tetramanganese(2+) 2,2',2",2‴-([2,2-bis({[3,9-bis(carboxylatomethyl)-4-methyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13-carbonyl]amino}methyl)propane-1,3-diyl] bis{carbamoyl[4-methyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13,3,9-triyl]})tetraacetate, tetramanganese(2+) 2,2',2",2‴-([2,2-bis({[3,9-bis(carboxylatomethyl)-4-ethyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13-carbonyl]amino}methyl)propane-1,3-diyl] bis{carbamoyl[4-ethyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13,3,9-triyl]})tetraacetate, tetramanganese(2+) 2,2',2",2‴-{[2,2-bis({[3,9-bis(carboxylatomethyl)-5-methyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13-carbonyl]amino}methyl)propane-1,3-diyl] bis[carbamoyl(5-methyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13,3, 9-triyl)]}tetraacetate, tetramanganese(2+) (2 R ,2' S ,2" R ,2‴ S )-2,2',2",2‴-{(2,2-bis[({3-[(1 R )1-carboxylatopropyl]-9-[(1S)-1-carboxylatopropyl]-6-oxa-3,9,15-triazabicyclo[9.3.1] pentadeca-1(15),11,13-triene-13-carbonyl}amino)methyl] propane-1,3-diyl) bis [carbamoyl-6-oxa-3,9,15-triazabicyclo[9.3.1] pentadeca-1(15),11,13-triene-13,3,9-triyl]}tetrabutanoate, tetramanganese(2+) (2 R *,2' S *,2" RS ,2‴ SR )-2,2',2",2‴-{(2,2-bis{[({3-[(1 RS )-1-carboxylato propyl]-9-[(1SR)-1-carboxylatopropyl]-6-oxa-3,9,15-triazabicyclo[9.3.1] pentadeca-1(15),11, 13-trien-13-yl}carbonyl)amino]methyl}propane-1,3-diyl)bis [carbamoyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13,3,9-triyl]}tetrabutanoate, tetramanganese(2+) 2,2'-({2,2-bis({[3-(1-carboxylatoethyl)-9-(carboxylatomethyl)-6-oxa-3,9, 15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13-carbonyl]amino}methyl)propane-1,3-diyl}bis{carbamoyl[9-(carboxylatomethyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15), 11,13-triene-13,3-diyl]})dipropanoate, tetramanganese(2+) 2,2',2",2‴-{[2,2-bis({[3,9-bis(carboxylatomethyl)-8-methyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-12-carbonyl]amino}methyl)propane-1,3-diyl]bis[carbamoyl(8-methyl-6-oxa-3,9,15-triazabicyclo[9.3.1] pentadeca-1(15),11,13-triene-12,3,9-triyl)]}tetraacetate, tetramanganese(2+) (2 S ,2' S ,2" S ,2‴ S )-2,2',2",2‴-{(2,2-bis[({3,9-bis[(1 S )-1-carboxylatoethyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13-carbonyl}amino)methyl] propane-1,3-diyl)bis[carbamoyl-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13,3,9-triyl]}tetrapropanoate and tetramanganese(2+) (2 R ,2' R ,2" R ,2‴ S )-2,2',2",2‴-{(2,2-bis[({3,9-bis[(1 R )-1-carboxylatoethyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-13-carbonyl} amino)methyl] propane-1,3-diyl)bis[carbamoyl-6-oxa-3,9,15-triazabicyclo[9.3.1] pentadeca-1(15),11,13-triene-13,3,9-triyl]}tetrapropanoate. and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
  10. Use of a compound according to any one of claims 1 to 9 for diagnostic imaging, preferably for magnetic resonance imaging.
  11. The compounds according to any one of claims 1 to 9 for use in diagnostic imaging, preferably for magnetic resonance imaging.
  12. Use of the compounds according to any one of claims 1 to 9 or mixtures thereof for the manufacture of diagnostic agents, preferably for the manufacture of contrast agents for magnetic resonance imaging.
  13. A method of imaging body tissue in a patient, comprising the steps of administering to the patient an effective amount of one or more compounds according to claim 8 or 9 in a pharmaceutically acceptable carrier, and subjecting the patient to magnetic resonance imaging.

Description

FIELD The present disclosure relates to new manganese (Mn2+) chelate compounds, to methods of preparing said compounds, to the use of said compounds as contrast agents in diagnostic imaging such as magnetic resonance imaging (MRI) and to their use in a mammalian body. BACKGROUND The Magnetic Resonance Imaging (MRI) technique is non-invasive and can provide information on the anatomy, function and metabolism of tissues in vivo. Unenhanced MRI scans of tissue anatomy and function make use of the hydrogen atoms in water to generate the image. Apart from differences in the local water content, the basic contrast in the MR image mainly results from regional differences in the intrinsic relaxation times T1 and T2, each of which can be chosen to dominate image contrast. However, the intrinsic contrast provided by the water T1 and T2 and changes in their values brought about by tissue pathology are often too limited to enable a sensitive and specific diagnosis. To overcome these limits the proton relaxation times can be influenced by the presence of paramagnetic ions. Commercial Gadolinium-based Contrast Agents (GBCAs) contain at least one paramagnetic ion of the rare earth metal Gadolinium (Gd3+), which possesses the highest number of unpaired electrons of any stable ion (seven), creating a high magnetic moment that is effective at enhancing proton relaxation. Paramagnetic contrast media shorten the T1 (longitudinal) and T2 (transversal) relaxation times of surrounding water protons to indirectly produce a signal-enhancing effect. The efficacy of an agent to shorten relaxation times is called relaxivity (r1 and r2), which is dependent on the ligand surrounding the paramagnetic ion and influenced by extrinsic factors including temperature, magnetic field strength and the matrix (water, solid tissue, or blood) (Lauffer RB et al., Paramagnetic metal complexes as water proton relaxation agents for NMR imaging: theory and design. Chem Rev. 1987;87(5):901-27; Caravan P et al., Gadolinium(III) chelates as MRI contrast agents: structure, dynamics, and applications. Chem Rev. 1999;99(9):2293-352). Since unchelated Gd3+ ions are toxic, extracellular GBCAs require ligands chelating the Gd3+ ion. Gd-DTPA (gadopentetic acid, marketed as Magnevist, Bayer), Gd-DTPA-BMA (gadodiamide, marketed as Omniscan, Ge Healthcare) and Gd-BOPTA (gadobenate, marketed as MultiHance, Bracco) are classified as linear GBCAs based on the chain-like ligand structure. Gd-DOTA (gadoterate, e.g., marketed as Dotarem, Guerbet), Gd-HP-DO3A (gadoteridol, marketed as ProHance, Bracco) and Gd-DO3A-butrol (gadobutrol, e.g., marketed as Gadovist, Bayer) contain cage-like ligands and are classified as macrocyclic agents. Macrocyclic agents are more stable against dissociation and Gd3+ release compared to linear agents (Frenzel et al. Invest Radiol. 2008 Dec;43(12):817-28.) In 2014, a first study showed an increased signal intensity (SI) in the dentate nucleus (DN) and globus pallidus (GP) brain areas on unenhanced T1-weighted (T1w) MR images in patients with normal renal function who received multiple linear gadolinium-based contrast agent (GBCA) administrations (Kanda et al. Radiology 2014 Mar;270(3):834-41). This led to a thorough evaluation of GBCA safety including regulatory activities and intensive research on Gd retention in organs after use of GBCA. In March 2017, the European Union (EU) suspended the marketing authorization for all multi-purpose linear GBCAs while supporting the continued use of macrocyclic GBCAs. Following this decision, the MRI market moved away from linear Gadolinium-based agents and increased efforts and strategies to reduce or replace Gd. Nonetheless, a new high relaxivity GBCA received market authorization in the US (gadopiclenol, marketed as Elucirem, Guerbet, and VUEWAY, Bracco) in 2022, which allows for a reduced dose while maintaining diagnostic efficacy. Other efforts include artificial intelligence approaches to further reduce gadolinium dose by creating virtual enhanced images comparable to full-dose images. Thus, there is a long-standing desire to abandon GBCAs and to replace them with alternative contrast agents which remains unfulfilled to date. In particular, there is an increased long-standing medical need for new non-Gd contrast agents for magnetic resonance imaging. Endogenous paramagnetic elements have been considered as non-Gd alternatives for MRI. Manganese, one such endogenous paramagnetic element, is an essential trace element for several enzymes in the human body and possesses five unpaired electrons in its bivalent state. To date, no multi-purpose contrast agent based on endogenous manganese is commercially available. Only one liver-specific Mn complex has been approved as a contrast agent for MRI: Mn-DPDP (mangafodipir, marketed as TeslaScan). Mn-DPDP (GE Healthcare) was approved for liver imaging at clinical doses of 0.005 mmol/kg but was withdrawn by the manufacturer from both the US and EU markets in 200