Paramagnetic chelates useful for NMR imaging
First Claim
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 5R 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.
4 Assignments
0 Petitions
Accused Products
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 or
is --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 --.
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Citations
31 Claims
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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. - View Dependent Claims (2, 3, 4, 5)
- a is 2 or 3;
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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; - View Dependent Claims (8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 29, 31)
- -amino propionic acid of formula ##STR55## wherein;
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7. --CH2 OR5 ;
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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.
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25. 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.
- -amino propionic acid of formula ##STR56## wherein;
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27. 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.
- -amino propionic acid of formula ##STR58## wherein;
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30. 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 ;wherein R5 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.
- -amino propionic acid of formula ##STR60## wherein;
Specification
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- Resources
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Current AssigneeBracco International B.V. (Bracco SPA)
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Original AssigneeBracco Chimica SPA
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InventorsUggeri, Fulvio, Felder, Ernst, Vittadini, Giorgio, Fumagalli, Luciano
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Primary Examiner(s)Rosen, Sam
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Application NumberUS07/002,115Time in Patent Office1,184 DaysField of Search534/15, 534/16, 546/5, 546/11, 546/261, 556/1, 556/45, 556/138US Class Current424/9.36CPC Class CodesA61K 31/28 Compounds containing heavy ...
