US4916246A
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Paramagnetic chelates useful for NMR imaging
Assignee: Bracco International BV
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Filing: 1987-01-12
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Granted: 1990-04-10
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Expires: 2007-01-12
Abstract
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, SO 3 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; R 1 is the same as R 2 or is --CH 2 COOZ, --CH(CH 3 )COOZ, CH 2 CH 2 --N(CH 2 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 SO 3 H; R 2 is --CH 2 COOZ, --CH(CH 3 )COOZ, ##STR2## wherein R 3 is --CH 2 COOZ, --CH(CH 3 )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 --(CH 2 ) m -- may also be --CH 2 --C(CH 3 ) 2 --.
Inventors
- 👤 Ernst Felder
- 👤 Fulvio Uggeri
- 👤 Luciano Fumagalli
- 👤 Giorgio Vittadini
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-02 13:30
CPC Classifications
A; A61; A61K; A61K31/00; A61K31/28
Claims Analysis
Total Claims: 37
Claim 1
Independent Claim
245 words
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 --(CH 2 ) m --; --CH 2 --C(CH 3 ) 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; R 1 is --CH 2 COOZ; --CH(CH 3 )COOZ; --(CH 2 ) n --N(CH 2 COOZ) 2 ; hydroxy-arylalkyl radical, in which the aryl radical is unsubstituted or substituted by hydroxy; R 2 is --CH 2 COOZ: --CH(CH 3 )COOZ; ##STR52## wherein R 3 is --CH 2 COOZ; --CH(CH 3 )COOZ; a monovalent radical having the structure S--CH--COOZ; X is a direct chemical bond; --O--; --S--; --NH--; --N--CH 2 COOZ; --N--CH(CH 3 )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.
Claim 2
Dependent Claim
245 words
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 --(CH 2 ) m --; --CH 2 --C(CH 3 ) 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; R 1 is --CH 2 COOZ; --CH(CH 3 )COOZ; --(CH 2 ) n --N(CH 2 COOZ) 2 ; hydroxy-arylalkyl radical, in which the aryl radical is unsubstituted or substituted by hydroxy; R 2 is --CH 2 COOZ: --CH(CH 3 )COOZ; ##STR52## wherein R 3 is --CH 2 COOZ; --CH(CH 3 )COOZ; a monovalent radical having the structure S--CH--COOZ; X is a direct chemical bond; --O--; --S--; --NH--; --N--CH 2 COOZ; --N--CH(CH 3 )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.
Claim 3
Dependent Claim
10 words
The compound according to claim 1 wherein Me.sup.(a+) is Gd.sup.(3+).
Claim 4
Dependent Claim
28 words
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.
Claim 5
Dependent Claim
39 words
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.
Claim 6
Dependent Claim
27 words
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.
Claim 7
Dependent Claim
70 words
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:
Claim 8
Dependent Claim
70 words
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:
Claim 9
Dependent Claim
111 words
--CH 2 OR 5 ; 2. --C(CH 3 ) 2 --CH 2 OR 5 ; wherein R 5 is (a) phenyl; (b) benzyl; (c) 1-8 carbon alkyl; (d) dihydroxy substituted lower alkyl; (e) --H; (f) (CH 2 CH 2 O) P CH 3 wherein p is an integer number between 1 and 5; and R 4 is --(CH 2 ) n --X--(CH 2 ) n --N(CH 2 COOZ) 2 wherein X is: (a) a direct chemical bond; (b) --O--; (c) --N--CH 2 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.
Claim 10
Dependent Claim
111 words
--CH 2 OR 5 ; 2. --C(CH 3 ) 2 --CH 2 OR 5 ; wherein R 5 is (a) phenyl; (b) benzyl; (c) 1-8 carbon alkyl; (d) dihydroxy substituted lower alkyl; (e) --H; (f) (CH 2 CH 2 O) P CH 3 wherein p is an integer number between 1 and 5; and R 4 is --(CH 2 ) n --X--(CH 2 ) n --N(CH 2 COOZ) 2 wherein X is: (a) a direct chemical bond; (b) --O--; (c) --N--CH 2 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.
Claim 11
Dependent Claim
16 words
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.
Claim 12
Dependent Claim
20 words
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.
Claim 13
Dependent Claim
20 words
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.
Claim 14
Dependent Claim
20 words
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.
Claim 15
Dependent Claim
20 words
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.
Claim 16
Dependent Claim
15 words
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.
Claim 17
Dependent Claim
15 words
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.
Claim 18
Dependent Claim
15 words
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.
Claim 19
Dependent Claim
15 words
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.
Claim 20
Dependent Claim
16 words
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.
Claim 21
Dependent Claim
16 words
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.
Claim 22
Dependent Claim
15 words
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.
Claim 23
Dependent Claim
15 words
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.
Claim 24
Dependent Claim
15 words
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.
Claim 25
Dependent Claim
15 words
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.
Claim 26
Dependent Claim
15 words
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.
Claim 27
Dependent Claim
28 words
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.
Claim 28
Dependent Claim
162 words
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 --CH 2 --OR 5 wherein R 5 is: (a) benzyl; (b) --CH 2 --CH 2 phenyl; (c) lower alkyl of 1-3 carbon atoms; (d) H; and R 4 is ##STR57## wherein Y is: (1) benzyl; (2) --CH 2 --CH 2 phenyl; (3) lower alkyl of 1 to 3 carbon atoms; (4) H X is (a) a direct chemical bond; (b) --O--; (c) --N--CH 2 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.
Claim 29
Dependent Claim
162 words
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 --CH 2 --OR 5 wherein R 5 is: (a) benzyl; (b) --CH 2 --CH 2 phenyl; (c) lower alkyl of 1-3 carbon atoms; (d) H; and R 4 is ##STR57## wherein Y is: (1) benzyl; (2) --CH 2 --CH 2 phenyl; (3) lower alkyl of 1 to 3 carbon atoms; (4) H X is (a) a direct chemical bond; (b) --O--; (c) --N--CH 2 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.
Claim 30
Dependent Claim
28 words
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.
Claim 31
Dependent Claim
179 words
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 --CH 2 --O--R 5 ; --C(CH 3 ) 2 --CH 2 --O--R 5 ; wherein R 5 is (a) H; (b) lower alkyl of 1 to 3 carbon atoms; (c) dihydroxy substituted lower alkyl; (d) (CH 2 CH 2 O) 1-5 CH 3 ; R 4 is ##STR59## wherein Y is (a) H; (b) lower alkyl (1-3 carbon atoms); (c) dihydroxysubstituted lower alkyl; (d) (CH 2 CH 2 O) 1-5 CH 3 ; X is (a) a direct chemical bond; (b) --O--; (c) --N--CH 2 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.
Claim 32
Dependent Claim
179 words
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 --CH 2 --O--R 5 ; --C(CH 3 ) 2 --CH 2 --O--R 5 ; wherein R 5 is (a) H; (b) lower alkyl of 1 to 3 carbon atoms; (c) dihydroxy substituted lower alkyl; (d) (CH 2 CH 2 O) 1-5 CH 3 ; R 4 is ##STR59## wherein Y is (a) H; (b) lower alkyl (1-3 carbon atoms); (c) dihydroxysubstituted lower alkyl; (d) (CH 2 CH 2 O) 1-5 CH 3 ; X is (a) a direct chemical bond; (b) --O--; (c) --N--CH 2 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.
Claim 33
Dependent Claim
10 words
The compound according to claim 26 wherein Me.sup.(a+) is Fe.sup.(3+).
Claim 34
Dependent Claim
28 words
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.
Claim 35
Dependent Claim
122 words
A salt of Fe, Mn or Gd complex of a substituted α-amino propionic acid of formula ##STR60## 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 --CH 2 --O--R 5 ; --C(CH 3 ) 2 --CH 2 --O--R 5 ; wherein R 5 is (a) lower alkyl of 1 to 3 carbon atoms; (b) benzyl; (c) (CH 2 CH 2 O) 1-5 CH 3 ; n is the integer 1 or 2; Z is H or a negative charge.
Claim 36
Dependent Claim
122 words
A salt of Fe, Mn or Gd complex of a substituted α-amino propionic acid of formula ##STR60## 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 --CH 2 --O--R 5 ; --C(CH 3 ) 2 --CH 2 --O--R 5 ; wherein R 5 is (a) lower alkyl of 1 to 3 carbon atoms; (b) benzyl; (c) (CH 2 CH 2 O) 1-5 CH 3 ; n is the integer 1 or 2; Z is H or a negative charge.
Claim 37
Dependent Claim
28 words
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.
References Cited (Backward Citations)
US4647447A
Cited
US4687658A
Cited
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| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
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| 3.5 Years (Year 4) | 1993-04-09 | 1993-10-09 | 1994-04-10 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1997-04-09 | 1997-10-09 | 1998-04-10 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2001-04-09 | 2001-10-09 | 2002-04-10 | $7700.00 | Window Closed / Lapsed |