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Details for Patent: 5,132,409

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Details for Patent: 5,132,409

Title: Macrocyclic chelating agents and chelates thereof
Abstract:Macrocyclic derivatives of 1,4,7,10-tetraazacyclododecane of general formula (I) hereinbelow, wherein A is a group of formula (II) hereinbelow, in which R is H or alkyl or optionally substituted benzyl or a H(OCH.sub.2 CH.sub.2).sub.1-4-, Me(OCH.sub.2 CH.sub.2).sub.1-4-, or Et(OCH.sub.2 CH.sub.2).sub.1-4- group, X or O--R.sub.1, in which R.sub.1 is H or alkyl, hydroxyalkyl, alkoxyalkyl, alkoxyhydroxyalkyl or a polyoxaalkyl group or X is --NR.sub.2 R.sub.3, in which R.sub.2 and R.sub.3 are H or alkyl, hydroxyalkyl, alkoxyalkyl or alkoxyhydroxyalkyl, and B.sub.1, B.sub.2 and B.sub.3 have the same meanings as A or are H or a group of formula (III) hereinbelow, in which R.sub.4 is H or alkyl, Y is a O--R.sub.5 group, wherein R.sub.5 is H or alkyl, hydroxyalkyl, alkoxyalkyl, alkoxyhydroxyalkyl or a polyoxaalkyl group, or Y is a --NR.sub.6 R.sub.7 group, wherein R.sub.6 and R.sub.7 are H or alkyl, hydroxyalkyl, alkoxyalkyl, or alkoxyhydroxyalkyl, said derivatives optionally being salified, and the complex salts thereof, are used as pharmaceuticals and/or diagnostic agents. ##STR1##
Inventor(s): Felder; Ernst (Rive S. Vitale, CH), Musu; Carlo (Milan, IT), Fumagalli; Luciano (Milan, IT), Uggeri; Fulvio (Milan, IT)
Assignee: Bracco Industria Chimica S.p.A. (Milan, IT)
Filing Date:Nov 27, 1989
Application Number:07/449,883
Claims:1. A 1, 4, 7, 10-tetraazacyclododecane compound of formula I ##STR11## wherein A is a group of formula ##STR12## in which R is H or a C.sub.1 -C.sub.5 straight or branched alkyl group, or a benzyl group which is unsubstituted or mono- or poly-substituted on the aromatic ring by halogen, hydroxy, carboxy, carbamoyl, alkoxycarbonyl, sulphamoyl, lower alkyl, lower hydroxyalkyl, amino, acylamino, acyl, hydroxyacyl groups, or a group of formula H(OCH.sub.2 CH.sub.2).sub.1-4 --, Me(OCH.sub.2 CH.sub.2).sub.1-4 --,

X is a O--R.sub.1 group in which R.sub.1 is H or a C.sub.1 -C.sub.5 alkyl, hydroxyalkyl alkoxyalkyl, alkoxyhydroxyalkyl group, or a polyoxaalkyl group having 1 to 15 oxygen atoms and 3 to 45 carbon atoms, or X is a --NR.sub.2 R.sub.3 group in which R.sub.2 and R.sub.3, are the same or different, and are H, C.sub.1 -C.sub.6 alkyl, hydroxyalkyl, alkoxyalkyl or alkoxyhydroxyalkyl groups having up to 5 hydroxy groups and

B.sub.1, B.sub.2 and B.sub.3, are the same or different, and have the same meaning as A or they are H or a group of formula ##STR13## in which R.sub.4 is H or a C.sub.1 -C.sub.5 straight or branched alkyl group,

Y is a O--R.sub.5 group in which R.sub.5 is H or a C.sub.1 -C.sub.5 alkyl, hydroxyalkyl, alkoxyalkyl, alkoxyhydroxyalkyl group, or a polyoxyalkyl group having 1 to 15 oxygen atoms and 3 to 45 carbon atoms, or Y is a --NR.sub.6 R.sub.7 group in which R.sub.6 and R.sub.7, are the same or different, and are H or C.sub.1 -C.sub.6 alkyl, hydroxyalkyl, alkoxyalkyl or alkoxyhydroxyalkyl groups having up to 5 hydroxy groups,

and a salt of said compound of formula I with an organic base which is a member selected from the group consisting of primary, secondary, tertiary amines or with a basic aminoacid or with an inorganic base having a cation which is sodium, potassium or lithium,

and a chelate of said compound of formula I or of a salt thereof with a di- or trivalent ion of a metal element having atomic number ranging from 20 to 31,39,42 to 44,49, 57 to 83, wherein said chelate is neutral or acidic or salified with an organic base which is a member selected from the group consisting of primary, secondary, tertiary amines or with a basic aminoacid or with an inorganic base having a cation which is sodium, potassium or lithium.

2. 1,4,7,10-Tetraazacyclododecane derivatives of general formula II ##STR14## wherein R,R.sub.4,X and Y have the meanings defined in claim 1, and the chelates thereof with appropriate bi- or trivalent ions of metal elements having atomic numbers from 20 to 31, 39, 42, 43, 44, 49 or from 57 to 83.

3. 1,4,7,10-Tetraazacyclododecane derivatives of general formula III ##STR15## wherein R and X have the meanings defined in claim 1, and the chelates thereof with appropriate bi- or trivalent ions of metal elements having atomic numbers from 20 to 31, 39, 42, 43, 44, 49 or from 57 to 83.

4. Serine derivatives of general formula IV ##STR16## wherein R.sub.8 is H or benzyl, X.sub.1 is OH, --NH.sub.2, --NHCH.sub.2 CH.sub.2 OH, --NHCH(CH.sub.2 OH).sub.2, --NHCH.sub.2 CH(OH)CH.sub.2 OH, --N(CH.sub.2 CH.sub.2 OH).sub.2, --NH--CH.sub.2 --CH(OH)--CH.sub.2 OCH.sub.3 or --NH--CH.sub.2 --CH(OH)--CH(OH)--CH.sub.2 OH, and the chelates thereof with appropriate bi- or trivalent ions of metal elements having atomic numbers from 20 to 31, 38, 42, 43, 44, 49, or from 57 to 83.

5. A chelate of a compound as claimed in claim 1, in which the chelate metal ion if Fe.sup.(2+), Fe.sup.(3+), Cu.sup.(2+), Gd.sup.(3+), Eu.sup.(3+), Dy.sup.(3+) or Mn.sup.(2+).

6. Chelates as claimed in claim 2 with the ions of the following radioisotopes: .sup.51 Cr, .sup.68 Ga, .sup.111 In, .sup.99m Tc, .sup.140 La, .sup.168 Yb.

7. A compound as claimed in claim 1, selected from the group consisting of:

2-(1,4,7,10-tetraazacyclododecane-1-yl)-3-benzyloxypropionic acid,

2-(1,4,7,10-tetraazacyclododecane-1-yl)-3-hydroxypropionic acid,

2-[1,4,7,10-tetraaza-4-(1-carboxy-2-benzyloxy-ethyl)-cyclododecane-1-yl]-3- benzyloxypropionic acid,

2-[1,4,7,10-tetraaza-4-(1-carboxy-2-hydroxy-ethyl)-cyclododecane-1-yl]-3-hy droxypropionic acid,

2-[1,4,7,10-tetraaza-7-(1-carboxy-2-benzyloxy-ethyl)-cyclododecane-1-yl]-3- benzyloxypropionic acid,

2-[1,4,7,10-tetraaza-7-(1-carboxy-2-hydroxy-ethyl)-cyclododecane-1-yl]-3-hy droxypropionic acid,

2-[1,4,7,10-tetraaza-4,7-di(1-carboxy-2-benzyloxy-ethyl)-cyclododecane-1-yl ]-3-benzyloxypropionic acid,

2-[1,4,7,10-tetraaza-4,7-di(1-carboxy-2-hydroxy-ethyl)-cyclododecane-1-yl]- 3-hydroxypropionic acid,

2-[1,4,7,10-tetraaza-4-(1-carboxy-2-benzyloxy-ethyl)-7,10-di(carboxymethyl) -cyclododecane-1-yl]-3-benzyloxypropionic acid,

2-[1,4,7,10-tetraaza-4-(1-carboxy-2-hydroxy-ethyl)-7,10-di(carboxymethyl)-c yclododecane-1-yl]-3-hydroxypropionic acid,

2-[1,4,7,10-tetraaza-7-(1-carboxy-2-benzyloxy-ethyl)-4,10-di(carboxymethyl) -cyclododecane-1-yl]-3-benzyloxypropionic acid,

2-[1,4,7,10-tetraaza-7-(1-carboxy-2-hydroxy-ethyl)-4,10-di(carboxymethyl)-c yclododecane-1-yl]-3-hydroxypropionic acid,

2-[1,4,7,10-tetraaza-4,7-di(1-carboxy-2-benzyloxy-ethyl)-10-carboxymethyl-c yclododecane-1-yl]-3-benzyloxypropionic acid,

2-[1,4,7,10-tetraaza-4,7-di(1-carboxy-2-hydroxy-ethyl)-10-carboxymethyl-cyc lododecane-1-yl]-3-hydroxypropionic acid,

2-[1,4,7,10-tetraaza-4,7,10-tri(carboxymethyl)-cyclododecane-1-yl]-3-benzyl oxypropionic acid,

2-[1,4,7,10-tetraaza-4,7,10-tri(carboxymethyl)-cyclododecane-1-yl]-3-hydrox ypropionic acid,

2-(1,4,7,10-tetraazacyclododecane-1-yl)-3-benzyloxy-propionamide,

2-(1,4,7,10-tetraazacyclododecane-1-yl)-3-hydroxy-propionamide,

2-(1,4,7,10-tetraazacyclododecane-1-yl)-3-benzyloxy-N-(2-hydroxyethyl)-prop ionamide,

2-(1,4,7,10-tetraazacyclododecane-1-yl)-3-hydroxy-N-(2-hydroxyethyl)-propio namide,

2-(1,4,7,10-tetraazacyclododecane-1-yl)-3-benzyloxy-N-(1,3-dihydroxyisoprop yl)-propionamide,

2-(1,4,7,10-tetraazacyclododecane-1-yl)-3-hydroxy-N-(1,3-dihydroxyisopropyl )-propionamide,

2-(1,4,7,10-tetraazacyclododecane-1-yl)-3-benzyloxy-N-(2,3-dihydroxypropyl) -propionamide,

2-(1,4,7,10-tetraazacyclododecane-1-yl)-3-hydroxy-N-(2,3-dihydroxypropyl)-p ropionamide,

2-(1,4,7,10-tetraazacyclododecane-1-yl)-3-benzyloxy-N,N-di(2-hydroxyethyl)- propionamide,

2-(1,4,7,10-tetraazacyclododecane-1-yl)-3-hydroxy-N,N-di-(2-hydroxyethyl)-p ropionamide,

2-[1,4,7,10-tetraaza-4,7,10-tri(carboxymethyl)-cyclododecane-1-yl]-3-benzyl oxy-propionamide,

2-[1,4,7,10-tetraaza-4,7,10-tri(carboxymethyl)-cyclododecane-1-yl]-3-hydrox y-propionamide,

2-[1,4,7,10-tetraaza-4,7,10-tri(carboxymethyl)-cyclododecane-1-yl]-3-benzyl oxy-N-(2-hydroxyethyl)-propionamide,

2-[1,4,7,10-tetraaza-4,7,10-tri(carboxymethyl)-cyclododecane-1-yl]-3-hydrox y-N-(2-hydroxyethyl)-propionamide,

2-[1,4,7,10-tetraaza-4,7,10-tri(carboxymethyl)-cyclododecane-1-yl]-3-benzyl oxy-N-(1,3-dihydroxyisopropyl)-propionamide,

2-[1,4,7,10-tetraaza-4,7,10-tri(carboxymethyl)-cyclododecane-1-yl]-3-hydrox y-N-(1,3-dihydroxyisopropyl)-propionamide,

2-[1,4,7,10-tetraaza-4,7,10-tri(carboxymethyl)-cyclododecane-1-yl]-3-benzyl oxy-N-(2,3-dihydroxypropyl)-propionamide,

2-[1,4,7,10-tetraza-4,7,10-tri(carboxymethyl)-cyclododecane-1-yl]-3-hydroxy -N-(2,3-dihydroxypropyl)-propionamide,

2-[1,4,7,10-tetraaza-4,7,10-tri(carboxymethyl)-cyclododecane-1-yl]-3-benzyl oxy-N,N-di(2-hydroxyethyl)-propionamide,

2-[1,4,7,10-tetraaza-4,7,10-tri(carboxymethyl)-cyclododecane-1-yl]-3-hydrox y-N,N-di(2-hydroxyethyl)-propionamide,

the respective chelate complexes with Fe.sup.(3+), Cu.sup.(2+), Mn.sup.(2+), Gd.sup.(3+), Dy.sup.(3+), In.sup.(3+), La.sup.(3+), Yb.sup.(3+) and the corresponding salts with D(-)-N-methylglucamine.

8. A method for the preparation of a metal chelate of a 1,4,7,10-tetraazacyclododecane compound of formula I ##STR17## wherein A is a group of formula ##STR18## in which R is H or a C.sub.1 -C.sub.5 straight or branched alkyl group, or a benzyl group which is unsubstituted or mono- or poly-substituted on the aromatic ring by halogen, hydroxy, carboxy, carbamoyl, alkoxycarbonyl, sulphamoyl, lower alkyl, lower hydroxyalkyl, amino, acylamino, acyl, hydroxyacyl groups, or a group of formula H(OCH.sub.2 CH.sub.2).sub.1-4 --, Me(OCH.sub.2 CH.sub.2).sub.1-4 -- or Et(OCH.sub.2 CH.sub.2).sub.1-4 --,

X is a O--R.sub.1 group in which R.sub.1 is H or a C.sub.1 -C.sub.5 alkyl, hydroxyalkyl, alkoxyalkyl, alkoxyhydroxyalkyl group, or a polyoxaalkyl group having 1 to 15 oxygen atoms and 3 to 45 carbon atoms, or X is a --NR.sub.2 R.sub.3 group in which R.sub.2 and R.sub.3, are the same or different, and are C.sub.1 -C.sub.6 alkyl, hydroxyalkyl, alkoxyalkyl or alkoxyhydroxyalkyl groups having up to 5 hydroxy groups and

B.sub.1, B.sub.2 and B.sub.3, are the same or different, and have the same meaning as A or they are H or a group of formula ##STR19## in which R.sub.4 is H or a C.sub.1 -C.sub.5 straight or branched alkyl group, Y is a O--R.sub.5 group in which R.sub.5 is H or a C.sub.1 -C.sub.5 alkyl, hydroxyalkyl, alkoxyalkyl, alkoxyhydroxyalkyl group, or a polyoxaalkyl group having 1 to 15 oxygen atoms and 3 to 45 carbon atoms, or Y is a --NR.sub.6 R.sub.7 group in which R.sub.6 and R.sub.7 are the same or different, and are H or C.sub.1 -C.sub.6 alkyl, hydroxyalkyl, alkoxyalkyl or alkoxyhydroxyalkyl groups having up to 5 hydroxy groups, which consists in reacting a salt or an oxide of a metal selected from the metals having atomic numbers from 20 to 31, 39,42,43,44,49 or from 57 to 83 with said compound of formula I or a salt thereof in the presence of an acid or a base in an amount necessary for neutralization.

9. A compound according to claim 1 which is the D(-)-N-methylglucamine salt of the chelate complex of Gd(3+) with 2-[1,4,7,10-tetraaza-4,7-di(1-carboxy-2-benzyloxy-ethyl)-10-carboxymethyl- cyclododecane-1-yl]-3-benzyloxypropionic acid.

10. A compound according to claim 1 which is the Gd (3+)complex with 2-[1,4,7,10-tetraaza-4,7,10-tri(carboxymethyl)-cyclododecane-1-yl]-3-benzy loxy-[N-methyl-N(D-1-deoxyglucitol)]-propionamide.

11. A compound according to claim 1 which is the Gd(3+)complex with 2-[1,4,7,10-tetraaza-4,7,10-tri(carboxymethyl)-cyclododecane-1-yl]-3-(L)-b enzyloxy-N-methyl-N(D-1-deoxyglucitol)]-propionamide.

12. A compound according to claim 1 which is Gd(3+)complex with 2-[1,4,7,10-tetraaza-4,7,10-tri(carboxymethyl)-cyclododecane-1-yl]3-hydrox y-[N-methyl-N-(D)-1-deoxy-glucitol)]-propionamide.

13. A compound according to claim 1 which is the Gd(3+)complex with 2-[1,4,7,10-tetraaza-4,7,10-tri(carboxymethyl)-cyclododecane-1-yl]3-(L)-hy droxy-[N-methyl-N-(D-1-deoxyglucitol)]-propionamide.

14. The compound according to claim 1 wherein said organic base is ethanolamine, diethanolamine, morpholine, glucamine, N,N-dimethylglucamine or N-methyl-glucamine.

15. The compound according to claim 1 wherein said basic aminoacid is lysine, arginine or omithine.

16. The compound according to claim 1 wherein said inorganic base is sodium hydroxide, potassium hydroxide or lithium hydroxide.

17. The method according to claim 8 wherein said acid necessary for the neutralization is an inorganic or organic acid, said inorganic acid having an anion which is a member selected from the group consisting of chloride, bromide, iodide or sulfate, said organic acid being acetic, succinic, citric, fumaric or maleic.

18. The method according to claim 8 wherein said base necessary for neutralization is an inorganic or organic base, said inorganic base having a cation which is sodium, potassium or lithium, said organic base being a primary, secondary or tertiary amine or a basic aminoacid.
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