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Claims for Patent: 4,916,246

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Claims 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, SO.sub.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.sub.1 is the same as R.sub.2 or is --CH.sub.2 COOZ, --CH(CH.sub.3)COOZ, CH.sub.2 CH.sub.2 --N(CH.sub.2 COOZ).sub.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.sub.3 H; R.sub.2 is --CH.sub.2 COOZ, --CH(CH.sub.3)COOZ, ##STR2## wherein R.sub.3 is --CH.sub.2 COOZ, --CH(CH.sub.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.sub.2).sub.m -- may also be --CH.sub.2 --C(CH.sub.3).sub.2 --.
Inventor(s): Felder; Ernst (Riva S. Vitale, CH), Uggeri; Fulvio (Codogno, IT), Fumagalli; Luciano (Milan, IT), Vittadini; Giorgio (Milan, IT)
Assignee: Bracco Chimica S.p.A. (Milan, IT)
Application Number:07/002,115
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 --(CH.sub.2).sub.m --; --CH.sub.2 --C(CH.sub.3).sub.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.sub.1 is --CH.sub.2 COOZ; --CH(CH.sub.3)COOZ; --(CH.sub.2).sub.n --N(CH.sub.2 COOZ).sub.2 ; hydroxy-arylalkyl radical, in which the aryl radical is unsubstituted or substituted by hydroxy;

R.sub.2 is --CH.sub.2 COOZ: --CH(CH.sub.3)COOZ; ##STR52## wherein R.sub.3 is --CH.sub.2 COOZ; --CH(CH.sub.3)COOZ; a monovalent radical having the structure S--CH--COOZ;

X is a direct chemical bond; --O--; --S--; --NH--; --N--CH.sub.2 COOZ; --N--CH(CH.sub.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.

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'-(carboxy methyl)-aminoethyl]-N-(carboxymethyl)-amino-propionic acid,

3-phenylmethoxy-2-N-[2'N'-[2"-N"N"-bis-(carboxymethyl)-aminoethyl]-N'-(carb oxymethyl)-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]-aminopr opionic 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)-a mino-propionic acid,

3-phenylmethoxy-2-N-[2'-N',N'-bis-(carboxymethyl)aminoethyl]-N-(carboxymeth yl-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-(car boxymethyl)-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-pheny lmethyl)-ethylene diamine,

N,N'-bis-(3-methoxy-2,2-dimethyl-1-carboxy-1-propyl)-N,N'bis-(2-hydroxy-phe nylmethyl)-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 .alpha.-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. --CH.sub.2 OR.sub.5 ;

2. --C(CH.sub.3).sub.2 --CH.sub.2 OR.sub.5 ; wherein R.sub.5 is

(a) phenyl;

(b) benzyl;

(c) 1-8 carbon alkyl;

(d) dihydroxy substituted lower alkyl;

(e) --H;

(f) (CH.sub.2 CH.sub.2 O).sub.P CH.sub.3 wherein p is an integer number between 1 and 5;

and R.sub.4 is --(CH.sub.2).sub.n --X--(CH.sub.2).sub.n --N(CH.sub.2 COOZ).sub.2

wherein X is:

(a) a direct chemical bond;

(b) --O--;

(c) --N--CH.sub.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.

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-(carbo xymethyl-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(carbox ymethyl)-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-(carbox ymethyl)-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-(carbo xymethyl)-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-(carbo xymethyl)-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(car boxymethyl)-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-(carboxymet hyl)-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)-am inopropionic 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'-(carboxy methyl)-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'-(carboxy methyl)-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)-aminoethy l]-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'-(carboxym ethyl)-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)-aminoethy l]-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-(car boxymethyl)-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 .alpha.-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.sub.2 --OR.sub.5 wherein R.sub.5 is:

(a) benzyl;

(b) --CH.sub.2 --CH.sub.2 phenyl;

(c) lower alkyl of 1-3 carbon atoms;

(d) H;

and R.sub.4 is ##STR57## wherein Y is: (1) benzyl;

(2) --CH.sub.2 --CH.sub.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.sub.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.

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 .alpha.-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.sub.2 --O--R.sub.5 ; --C(CH.sub.3).sub.2 --CH.sub.2 --O--R.sub.5 ;

wherein R.sub.5 is

(a) H;

(b) lower alkyl of 1 to 3 carbon atoms;

(c) dihydroxy substituted lower alkyl;

(d) (CH.sub.2 CH.sub.2 O).sub.1-5 CH.sub.3 ;

R.sub.4 is ##STR59## wherein Y is

(a) H;

(b) lower alkyl (1-3 carbon atoms);

(c) dihydroxysubstituted lower alkyl;

(d) (CH.sub.2 CH.sub.2 O).sub.1-5 CH.sub.3 ;

X is

(a) a direct chemical bond;

(b) --O--;

(c) --N--CH.sub.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.

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 .alpha.-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.sub.2 --O--R.sub.5 ; --C(CH.sub.3).sub.2 --CH.sub.2 --O--R.sub.5 ;

wherein

R.sub.5 is

(a) lower alkyl of 1 to 3 carbon atoms;

(b) benzyl;

(c) (CH.sub.2 CH.sub.2 O).sub.1-5 CH.sub.3 ;

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.
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