Claims for Patent: 4,916,246

Summary for Patent: 4,916,246

Title:	Paramagnetic chelates useful for NMR imaging
Abstract:	Compounds suitable for NMR imaging having the formula: ##STR1## wherein a is 2 or 3;b is an integer from 0 to 4;Me.sup.(a+) is Fe.sup.(2+), Fe.sup.(3+), Gd.sup.(3+), or Mn.sup.(2+) ;E.sup.(b+) is an ion of an alkali metal, alkaline earth metal, alkyl ammonium, alkanol ammonium, polyhydroxyalkyl ammonium, or basic protonated amino acid, said ions representing a total charge of b;m is an integer from 1 to 5;R is H, alkyl with from 1 to 8 carbon atoms, alkyl with from 1 to 8 carbon atoms wherein from 1 to 5 carbons are substituted with OH; aralkyl with 1 to 4 aliphatic carbon atoms; phenyl or phenyl substituted by halogen, hydroxyl, carboxyl, carboxamide, ester, SO3 H, sulfonamide, lower alkyl, lower hydroxy alkyl, amino, acylamino; (poly)oxa-alkyl with 1 to 50 oxygen atoms and from 3 to 150 carbon atoms, wherein 1 to 5 hydrogen atoms may be substituted by OH;R1 is the same as R2 oris --CH2 COOZ, --CH(CH3)COOZ, CH2 CH2 --N(CH2 COOZ)2, a hydroxy arylalkyl, hydroxy pyridylalkyl, hydroxy aryl(carboxy)alkyl or hydroxy pyridyl-(carboxy)alkyl radical, where the aryl or pyridyl radical may be substituted by hydroxyl, hydroxy alkyl, alkyl, halogen, carboxyl or SO3 H;R2 is --CH2 COOZ, --CH(CH3)COOZ, ##STR2## wherein R3 is --CH2 COOZ, --CH(CH3)COOZ or a monovalent radical having the structure ##STR3## X is a direct chemical bond, --O--, --S--, --NH--, ##STR4## n is the integer 2 or 3, with the proviso that when X represents a direct bond, n is 1, 2 or 3;Z is hydrogen or a unit of negative charge, and --(CH2)m -- may also be --CH2 --C(CH3)2 --.
Inventor(s):	Ernst Felder, Fulvio Uggeri, Luciano Fumagalli, Giorgio Vittadini
Assignee:	Bracco International BV
Application Number:	US07/002,115
Patent Claims:	1. A compound having the formula ##STR51## wherein: a is 2 or 3;b is an integer from 0 to 4; Me.sup.(a+) is Fe.sup.(2+), Fe.sup.(3+), Gd.sup.(3+), or Mn.sup.(2+) ; E.sup.(b+) is one or more physiologically biocompatible cation of an inorganic or an organic base or amino acid, said cation representing a total positive charge of b units; S is the group --A-O-R wherein; A is --(CH2)m --; --CH2 --C(CH3)2 --; m is an integer from 1 to 5 R is H; linear or branched alkyl of 1 to 8 carbon atoms, said carbon atoms being unsubstituted or substituted by one or more hydroxy group; aralkyl of 1 to 4 aliphatic carbon atoms; phenyl or phenyl substituted by halogen, amino or hydroxy; (poly)-oxa-alkyl of 1 to 10 oxygen atoms and from 3 to 30 carbon atoms; R1 is --CH2 COOZ; --CH(CH3)COOZ; --(CH2)n --N(CH2 COOZ)2 ; hydroxy-arylalkyl radical, in which the aryl radical is unsubstituted or substituted by hydroxy; R2 is --CH2 COOZ: --CH(CH3)COOZ; ##STR52## wherein R3 is --CH2 COOZ; --CH(CH3)COOZ; a monovalent radical having the structure S--CH--COOZ; X is a direct chemical bond; --O--; --S--; --NH--; --N--CH2 COOZ; --N--CH(CH3)COOZ; n is the integer 2 or 3, with the proviso that when X is a direct chemical bond, n is 1, 2 or 3; Z is H or a negative charge. 2. The compound according to claim 1 wherein Me.sup.(a+) is Gd.sup.(3+). 3. In a media for NMR contrast imaging which contains an agent for influencing relaxation time, the improvement which comprises said agent being a compound according to claim 1. 4. The compound of claim 1 wherein ##STR53## is selected from the group consisting of 3-hydroxy-2-N-[2'-N'-[2"-N",N"-bis-(carboxymethyl)-aminoethyl]-N'-(carboxymethyl)-aminoethyl]-N-(carboxymethyl)-amino-propionic acid,3-phenylmethoxy-2-N-[2'N'-[2"-N"N"-bis-(carboxymethyl)-aminoethyl]-N'-(carboxymethyl)-aminoethyl]-N-(carboxymethyl)-aminopropionic acid, 3-methoxy-2-N,N-bis-[2'-N,N'-bis-(carboxymethyl)-aminoethyl]-aminopropionic acid, 3-phenylmethoxy-2-N,N-bis-[2'-N',N'-bis-(carboxymethyl)-aminoethyl]-aminopropionic acid, 4-(3,6,9,12,15-pentaoxahexadecyloxy)-3,3-dimethyl-2-N-[2'-N'-[2"-N",N"-bis-(carboxymethyl)-aminoethyl]-N'-carboxymethyl)-aminoethyl-N-(carboxymethyl)-amino-butyric acid, 4-(3,6,9,12,15-pentaoxahexadecyloxy)-3,3-dimethyl-2-N, N-bis-[2'-N',N'-bis-(carboxymethyl)-aminoethyl]amino-butyric acid, 3-hydroxy-2-N-[2'-N',N'-bis-(carboxymethyl)-aminoethyl]-N-(carboxymethyl)-amino-propionic acid, 3-phenylmethoxy-2-N-[2'-N',N'-bis-(carboxymethyl)aminoethyl]-N-(carboxymethyl-amino-propionic acid, 3-octyloxy-2-N-[2'-N',N'-bis-(carboxymethyl)-aminoethyl]-N-(carboxymethyl)-amino-propionic acid, N,N'-bis-(2-hydroxy-1-carboxy-1-ethyl)-N,N'-bis-(carboxymethyl)-ethylene diamine, 4-methoxy-3,3-dimethyl-2-N-[2'-N',N'-bis-(carboxymethyl)-aminoethyl]-N-(carboxymethyl)-amino-butyric acid, 3-phenylmethoxy-2-N-[2-[2-N',N'-bis-(carboxymethyl)-aminoethoxy]-ethyl]-N-(carboxymethyl)-aminopropionic acid. 5. The compound of claim 1 wherein Me.sup.(a+) is Fe.sup.(3+) and ##STR54## is selected from the group consisting of N,N'-bis-(2-methoxy-1-carboxy-1-ethyl)-N,N'-bis-(2-hydroxy phenylmethyl)-ethylene diamine,N,N'-bis-(3,6,9,12-tetraoxa-1-carboxy-1-tridecyl)-N,N'-bis-(2-hydroxy-phenylmethyl)-ethylene diamine, N,N'-bis-(3-methoxy-2,2-dimethyl-1-carboxy-1-propyl)-N,N'bis-(2-hydroxy-phenylmethyl)-ethylene diamine, N,N'-bis-3-(2,3-dihydroxypropoxy)-2,2-dimethyl-1-carboxy-1-propyl)-N,N'-bis-(2-hydroxy-phenylmethyl)-ethylene diamine. 6. A salt of a Fe, Mn, or Gd complex of a substituted α-amino propionic acid of formula ##STR55## wherein: a is 2 or 3;b is an integer from 0 to 4; Me.sup.(a+) is Fe.sup.(2+), Fe.sup.(3+), Gd.sup.(3+), or Mn.sup.(2+) ; E.sup.(b+) is one or more physiologically biocompatible cation of an inorganic or an organic base or amino acid, said cation representing a total positive charge of b units; S is: 1. --CH2 OR5 ;2. --C(CH3)2 --CH2 OR5 ; wherein R5 is(a) phenyl; (b) benzyl; (c) 1-8 carbon alkyl; (d) dihydroxy substituted lower alkyl; (e) --H; (f) (CH2 CH2 O)P CH3 wherein p is an integer number between 1 and 5; and R4 is --(CH2)n --X--(CH2)n --N(CH2 COOZ)2 wherein X is:(a) a direct chemical bond; (b) --O--; (c) --N--CH2 COOZ: and n is 1, 2 or 3 when X is a direct bond or the integer is 2 or 3 and Z is H or a negative charge. 7. The compound according to claim 6 which is the complex gadolinium compound of 3-phenylmethoxy-2-N-[2'-N'-[2"-N", N"-bis-(carboxymethyl)-aminoethyl]-N'-(carboxymethyl)-aminoethyl]-N-(carboxymethyl-aminopropionic acid. 8. The compound according to claim 6 which is the sodium salt of the complex gadolinium compound of 3-phenylmethoxy-2-N-[2'-N'-[2"-N", N"-bis-(carboxymethyl)-aminoethyl]-N'-(carboxymethyl)-aminoethyl]-N(carboxymethyl)-aminopropionic acid. 9. The compound according to claim 6 which is the tris-(hydroxymethyl)-aminoethane salt of the complex gadolinium compound of 3-phenylmethoxy-2-N-[2'-N'-[2"-N", N"-bis-(carboxymethyl)-aminoethyl]-N-(carboxymethyl)-aminoethyl]-N-(carboxymethyl)-aminopropionic acid. 10. The compound according to claim 6 which is the serinol salt of the complex gadolinium compound of 3-phenylmethoxy-2-N-[2'-N'-[2"-N", N"-bis-(carboxymethyl)-aminoethyl]-N'-(carboxymethyl)-aminoethyl]-N-(carboxymethyl)-aminopropionic acid. 11. The compound according to claim 6 which is the L-ornithine salt of the complex gadolinium compound of 3-phenylmethoxy-2-N-[2'-N'-[2"-N", N"-bis-(carboxymethyl)-aminoethyl]-N'-(carboxymethyl)-aminoethyl]-N-(carboxymethyl)-aminopropionic acid. 12. The compound according to claim 6 which is the complex gadolinium compound of 3-phenylmethoxy-2-N-[2-N'-N'-bis-(carboxymethyl)-aminoethoxy]-ethyl]-N(carboxymethyl)-aminopropionic acid. 13. The compound according to claim 6 which is the complex gadolinium compound of 3-phenylmethoxy-2-N-[2-N',N'-bis-(carboxymethyl)-aminoethyl]-N-(carboxymethyl)-aminopropionic acid. 14. The compound according to claim 6 which is the complex gadolinium compound of 3-hydroxy-2-N[2-N',N'-bis-(carboxymethyl)-aminoethyl]-N-(carboxymethyl)-aminopropionic acid. 15. The compound according to claim 6 which is the complex gadolinium compound of 3-hydroxy-2-N-[2'-N'-[2"-N",N"-bis-(carboxymethyl)-aminoethyl]-N'-(carboxymethyl)-aminoethyl]-N-(carboxymethyl)-aminopropionic acid. 16. The compound according to claim 6 which is the complex gadolinium compound of 3-n-octyloxy-2-N-[2-N', N'-bis(carboxymethyl)-aminoethyl]-N-(carboxymethyl)-aminopropionic acid. 17. The compound according to claim 6 which is the complex gadolinium compound of 3-methoxy-2-N-[2-N',N'-bis (carboxymethyl)-aminoethyl]-N-(carboxymethyl)-aminopropionic acid. 18. The compound according to claim 6 which is the complex gadolinium compound of 3-methoxy-2-N-[2'-N'-[2"-N",N"-bis-(carboxymethyl)-aminoethyl]-N'-(carboxymethyl)-aminoethyl]N-(carboxymethyl)-aminopropionic acid. 19. The compound according to claim 6 which is the complex gadolinium compound of 3-(2,3-dihydroxypropoxy)-2-N-[2'-N'[2"-N",N"-bis-(carboxymethyl)-aminoethyl]-N'-(carboxymethyl)-aminoethyl]-N-(carboxymethyl)-aminopropionic acid. 20. The compound according to claim 6 which is the complex gadolinium compound of 3-phenoxy-2-N-[2'-N'[2"-N",N"-bis-(carboxymethyl)-aminoethyl]-N'-(carboxymethyl)-aminoethyl]-N-(carboxymethyl)-aminopropionic acid. 21. The compound according to claim 6 which is the complex gadolinium compound of 3-(3,6,9-trioxadecyloxy)-2-N-[2'-N-[2"-N",N"-bis-(carboxymethyl)-aminoethyl]-N'-(carboxymethyl)-aminoethyl]-N-(carboxymethyl)-aminopropionic acid. 22. The compound according to claim 6 which is the complex gadolinium compound of 4-methoxy-3,3-dimethyl-2-N-[2-N',N'-bis-(carboxymethyl)-aminoethyl]-N-(carboxymethyl)-aminobutyric acid. 23. In a media for NMR contrast imaging which contains an agent for influencing relaxation time, the improvement which comprises said agent being a compound according to claim 6. 24. A salt of a Fe, Mn or Gd complex of a substituted α-amino propionic acid of formula ##STR56## wherein: a is 2 or 3;b is an integer from 0 to 4; Me.sup.(a+) is Fe.sup.(2+), Fe.sup.(3+), Gd.sup.(3+), or Mn.sup.(2+) ; E.sup.(b+) is one or more physiologically biocompatible cation of an inorganic or an organic base or amino acid, said cation representing a total positive charge of b units; wherein S is --CH2 --OR5 wherein R5 is:(a) benzyl; (b) --CH2 --CH2 phenyl; (c) lower alkyl of 1-3 carbon atoms; (d) H; and R4 is ##STR57## wherein Y is: (1) benzyl;(2) --CH2 --CH2 phenyl; (3) lower alkyl of 1 to 3 carbon atoms; (4) H X is(a) a direct chemical bond; (b) --O--; (c) --N--CH2 COOZ; and n is 1 when X is a direct chemical bond or 2 when X is (b) or (c); Z is H or a negative charge. 25. In a media for NMR contrast imaging which contains an agent for influencing relaxation time, the improvement which comprises said agent being a compound according to claim 24. 26. A salt of a Fe, Mn or Gd complex of a substituted α-amino propionic acid of formula ##STR58## wherein: a is 2 or 3;b is an integer from 0 to 4; Me.sup.(a+) is Fe.sup.(2+), Fe.sup.(3+), Gd.sup.(3+), or Mn.sup.(2+); E.sup.(b+) is one or more physiologically biocompatible cation of an inorganic or an organic base or amino acid, said cation representing a total positive charge of b units; S is --CH2 --O--R5 ; --C(CH3)2 --CH2 --O--R5 ; wherein R5 is(a) H; (b) lower alkyl of 1 to 3 carbon atoms; (c) dihydroxy substituted lower alkyl; (d) (CH2 CH2 O)1-5 CH3 ; R4 is ##STR59## wherein Y is(a) H; (b) lower alkyl (1-3 carbon atoms); (c) dihydroxysubstituted lower alkyl; (d) (CH2 CH2 O)1-5 CH3 ; X is(a) a direct chemical bond; (b) --O--; (c) --N--CH2 COOZ; and n is 1 when X is (a) or 2 when X is (b) or (c); and Z is H or a negative charge. 27. The compound according to claim 26 wherein Me.sup.(a+) is Fe.sup.(3+). 28. In a media for NMR contrast imaging which contains an agent for influencing relaxation time, the improvement which comprises said agent being a compound according to claim 26. 29. A salt of Fe, Mn or Gd complex of a substituted α-amino propionic acid of formula ##STR60## wherein: a is 2 or 3b is an integer from 0 to 4; Me.sup.(a+) is Fe.sup.(2+), Fe.sup.(3+), Gd.sup.(3+), or Mn.sup.(2+) ; E.sup.(b+) is one or more physiologically biocompatible cation of an inorganic or an organic base or amino acid, said cation representing a total positive charge of b units; S is --CH2 --O--R5 ; --C(CH3)2 --CH2 --O--R5 ; whereinR5 is(a) lower alkyl of 1 to 3 carbon atoms; (b) benzyl; (c) (CH2 CH2 O)1-5 CH3 ; n is the integer 1 or 2; Z is H or a negative charge. 30. In a media for NMR contrast imaging which contains an agent for influencing relaxation time, the improvement which comprises said agent being a compound according to claim 29.